"Two years ago we were so excited about getting any type of clinical trial going. Unfortunately, the only clinical trial that could get any traction was one that the patients had no chance of living with standard care treatments. In other words, they had no chance of living. Today, there is at least one open clinical trial to evaluate the ketogenic diet in cancers that aren't advance, aka - not hopeless. Another trial is being designed to study metastatic cancer and will be looking at combining the ketogenic diet and hyperbaric oxygen therapy (HBOT) - this is based on a recent publication by Dr. Dominic D'agostino at USF. Simply put, there is no longer a question if the ketogenic diet works, there is only a question of how to make metabolic therapies more effective. I've written several times in our group about the need to do two things when you use a metabolic therapy. First, starve the cancer with the ketogenic diet and second, use therapeutics to "kill" the cancer cells and make them go into apoptosis once they are starving. We, as part of the Pet Cancer Trial, are using therapeutics like DCA, chloroquine and mebendazole to push starving cells toward death. So that's where we are today, looking at the first clinical trial and marveling how far we've come and how fast we're going. We simply have to find a way to convince people to stop using protocols that treat the symptoms of cancer and start using protocols that treat the cause of cancer. This Facebook group is the perfect place to grow disciples and groom ketogenic diet champions.
Nontoxic Cancer Therapy Proves Effective Against Metastatic Cancer
June 5, 2013 — A combination
of nontoxic dietary and hyperbaric oxygen therapies effectively
increased survival time in a mouse model of aggressive metastatic
cancer, a research team from the Hyperbaric Biomedical Research
Laboratory at the University of South Florida has found.
Assistant Professor
ddagosti@health.usf.edu
http://scienceblog.cancerresearchuk.org/2012/03/01/new-clue-to-how-cancer-cells-beat-oxygen-starvation/
Doesn't cancer need oxygen to grow?
http://www.drweil.com/drw/u/id/QAA322213
Can Oxygen Cure Cancer?
I have heard that disease cannot live in the presence of oxygen. Is this true? If so, can oxygen therapy be used to treat cancer? 
|
|
| A |
Answer (Published 1/5/2004)
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Oxygen therapy is being promoted on the Internet as a treatment
for cancer, but there is no evidence that it works. The notion that
oxygen might destroy cancer cells goes back to the 1930s when Otto
Warburg, MD, a Nobel Prize winner, discovered that compared to normal
cells, cancer cells have a low respiration rate. He proposed that if
cancer cells survive and grow in a low oxygen environment, they would
die off if exposed to higher levels of oxygen. Since then, we've learned
that Dr. Warburg was wrong. Oxygen doesn't slow cancer growth - tumors
grow rapidly in tissues well supplied with oxygenated blood and the
opposite is true, too: depriving tumors of oxygen doesn't stimulate
their growth. Moreover, a study published in the Spring/Summer 1998
issue of Scientific Review of Alternative Medicine noted that
since human tissues require 200 to 250 ml of oxygen per minute, an
additional 20 ml that could be dissolved in all of the plasma of a
normal weight adult would hardly be enough to make a difference in the
amount of oxygen cancer cells would receive.Hyperbaric oxygen therapy and cancer--a review.SourceDepartment of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway. ingrid.moen@biomed.uib.noAbstract
Hypoxia
is a critical hallmark of solid tumors and involves enhanced cell
survival, angiogenesis, glycolytic metabolism, and metastasis.
Hyperbaric oxygen (HBO) treatment has for centuries been used to improve
or cure disorders involving hypoxia and ischemia, by enhancing the
amount of dissolved oxygen in the plasma and thereby increasing O(2)
delivery to the tissue. Studies on HBO and cancer have up to recently
focused on whether enhanced oxygen acts as a cancer promoter or not. As
oxygen is believed to be required for all the major processes of wound
healing, one feared that the effects of HBO would be applicable to
cancer tissue as well and promote cancer growth. Furthermore, one also
feared that exposing patients who had been treated for cancer, to HBO,
would lead to recurrence. Nevertheless, two systematic reviews on HBO
and cancer have concluded that the use of HBO in patients with
malignancies is considered safe. To supplement the previous reviews, we
have summarized the work performed on HBO and cancer in the period
2004-2012. Based on the present as well as previous reviews, there is no
evidence indicating that HBO neither acts as a stimulator of tumor
growth nor as an enhancer of recurrence. On the other hand, there is
evidence that implies that HBO might have tumor-inhibitory effects in
certain cancer subtypes, and we thus strongly believe that we need to
expand our knowledge on the effect and the mechanisms behind tumor
oxygenation.
| |
Does hyperbaric oxygen have a cancer-causing or -promoting effect? A review of the pertinent literature.
Source
Department of Radiation Oncology, Wayne State University, Detroit, Michigan.Abstract
We
reviewed all known published reports or studies related to a possible
cancer-causing or growth-enhancing effect by hyperbaric oxygen.
Published articles were retrieved using Medline searches for the period
1960-1993. Additional references were obtained from bibliographies
included in those articles discovered in the computer search. Also,
hyperbaric medicine text books and the published proceedings of
international hyperbaric conferences were visually searched. Studies and
reports discovered in this fashion and related to the topic were
included in the review. Twenty-four references were found: 12 were
clinical reports, 11 were animal studies, and 1 reported both an animal
study and a clinical report. Three clinical reports suggested a positive
cancer growth enhancement, whereas 10 clinical reports showed no cancer
growth enhancement. Two animal studies suggested a positive
cancer-enhancing effect, and 10 animal studies showed no such effect.
(The report that included both animals and humans is counted in both
groups). The vast majority of published reports show no cancer growth
enhancement by HBO exposure. Those studies that do show growth
enhancement are refuted by larger subsequent studies, are mixed studies,
or are highly anecdotal. A review of published information fails to
support a cancer-causing or growth-enhancing effect by HBO.
Comment in
Comments on "Does hyperbaric oxygen have a cancer-causing or -promoting effect?". [Undersea Hyperb Med. 1996]Lack of Oxygen in Cancer Cells Leads to Growth and Metastasis
Sep. 13, 2012 — It seems as
if a tumor deprived of oxygen would shrink. However, numerous studies
have shown that tumor hypoxia, in which portions of the tumor have
significantly low oxygen concentrations, is in fact linked with more
aggressive tumor behavior and poorer prognosis. It's as if rather than
succumbing to gently hypoxic conditions, the lack of oxygen commonly
created as a tumor outgrows its blood supply signals a tumor to grow and
metastasize in search of new oxygen sources -- for example, hypoxic
bladder cancers are likely to metastasize to the lungs, which is
frequently deadly.
A University of Colorado Cancer Center study recently published in the journal Cancer Research details
a mechanism by which these hypoxic conditions create aggressive cancer,
with possible treatment implications for cancers including breast,
ovarian, colorectal, pancreatic, prostate, bladder and other cancers.
"We've known that the protein HIF-1a is overexpressed in hypoxic tumors. And we've known that the cancer stem cell marker CD24 is overexpressed in many tumors. This study shows a link between the two -- the HIF-1a of hypoxia creates the overexpression of CD24. And it's this CD24 that creates a tumor's aggressive characteristics of growth and metastasis," says Dan Theodorescu, MD, PhD, director of the University of Colorado Cancer Center and the paper's senior author.
Outgrowing the blood supply leads to tumor hypoxia, which leads to overexpression of HIF-1a, which signals the production of CD24, which makes tumors grow and metastasize. In addition to aggression, CD24 has also been shown to confer resistance to chemotherapy, allowing this small population of cells to regrow the tumor once chemotherapy ends, leading to relapse and disease progression.
"Now imagine we target CD24," Theodorescu says. "Either by removing a cell's ability to make CD24 or by killing cells marked by this protein, it's likely we could disarm this most dangerous population of cells."
Theodorescu and colleagues showed this by adjusting levels of HIF-1a and CD24 in cancer cell samples and animal models. With HIF-1a low and yet CD24 artificially high, cells retained the ability to grow and metastasize. With CD24 low and yet HIF-1a artificially high, cell survival and proliferation decreased.
"It seems CD24 overexpression in hypoxic cells drives growth and metastasis in these hypoxic tumors," Theodorescu says. "Now we have a rational target: CD24 for these hypoxic tumors."
"We've known that the protein HIF-1a is overexpressed in hypoxic tumors. And we've known that the cancer stem cell marker CD24 is overexpressed in many tumors. This study shows a link between the two -- the HIF-1a of hypoxia creates the overexpression of CD24. And it's this CD24 that creates a tumor's aggressive characteristics of growth and metastasis," says Dan Theodorescu, MD, PhD, director of the University of Colorado Cancer Center and the paper's senior author.
Outgrowing the blood supply leads to tumor hypoxia, which leads to overexpression of HIF-1a, which signals the production of CD24, which makes tumors grow and metastasize. In addition to aggression, CD24 has also been shown to confer resistance to chemotherapy, allowing this small population of cells to regrow the tumor once chemotherapy ends, leading to relapse and disease progression.
"Now imagine we target CD24," Theodorescu says. "Either by removing a cell's ability to make CD24 or by killing cells marked by this protein, it's likely we could disarm this most dangerous population of cells."
Theodorescu and colleagues showed this by adjusting levels of HIF-1a and CD24 in cancer cell samples and animal models. With HIF-1a low and yet CD24 artificially high, cells retained the ability to grow and metastasize. With CD24 low and yet HIF-1a artificially high, cell survival and proliferation decreased.
"It seems CD24 overexpression in hypoxic cells drives growth and metastasis in these hypoxic tumors," Theodorescu says. "Now we have a rational target: CD24 for these hypoxic tumors."
New clue to how cancer cells beat oxygen starvation
CHCHD4 switches on a survival mechanism in low oxygen
Scientists in labs around the world are working to uncover the molecular machinery that allows cells to do this. And they hope to outsmart tumours by developing treatments that break these mechanisms.
This month our scientists discovered an important part of the oxygen-sensing machinery of tumour cells, which may be an early step towards a new way to treat cancer.
Oxygen sensor
As tumours rapidly grow and expand, the network of blood vessels bringing oxygen to their cells can’t keep up, leaving some cells starved of oxygen, or ‘hypoxic’. This would kill normal cells, but cancer cells have evolved to beat these conditions by switching on a protein called hypoxia-inducible factor (HIF), which in turn switches on other molecules inside the cell.This cascade, called the HIF response, encourages new blood vessels to grow around and into the tumour. It also helps the tumour to adapt to hypoxic conditions by using alternative methods to produce energy.
A cell generates energy to grow and survive inside tiny ‘power stations’ called mitochondria, by using oxygen to fuel chemical reactions. And it’s been known for some time that mitochondria have an important role in flicking the ‘HIF’ switch.
But researchers were in the dark as to exactly how mitochondria are involved. So a team at University College London, led by Dr Margaret Ashcroft, set out to investigate.
Flicking the switch
The research, published in this month’s Journal of Clinical Investigation, delved into mitochondria’s inner workings and found that oxygen levels are monitored by a protein called CHCHD4. When oxygen levels fall below a critical level, this protein activates the HIF response.In lab experiments, the researchers also varied the levels of CHCHD4 in cells starved of oxygen. When CHCHD4 was blocked entirely, it stopped the action of HIF in cells, stopping cancer cells from growing and – importantly – preventing the growth of new blood vessels.
But when too much CHCHD4 was switched on in oxygen-starved cancer cells, large amounts of HIF were activated. This kick started a sequence of events that allowed cells to survive in low oxygen.
And it seems CHCHD4 has this HIF-activating role in a number of different types of cancer. The team looked at samples from 236 breast cancer patients, and found that levels of CHCHD4 were greatest in samples that were most aggressive, and came from patients with poorer survival. They also found raised levels of CHCHD4 in samples from patients with pancreatic cancers and gliomas (a form of brain tumour).
Again, in these cancers, they found that increased levels of CHCHD4 were associated with more aggressive tumours and poorer survival.
New treatment opportunity?
As we said above, tumour cells that are able to thrive despite low oxygen levels are more likely to be resistant to treatment. Previous research has shown that targeting the HIF response can block tumour growth and spread, and improves the effect of drugs that halt the growth of new blood vessels (so-called ‘anti-angiogenics’), so these results could hold promise for more effective cancer treatments in the future.Dr Ashcroft thinks the work opens a new area in our understanding of how tumour cells adapt and survive in an environment with little oxygen.
“We can now look at new ways of targeting this process by modulating the action of CHCHD4, hopefully leading to new drugs that could be used against those cancers that are difficult to treat,” she told us.
Her team now plans to continue this work in further studies, and we’ll be keeping an eager eye on her progress in this exciting field.
Reference
Yang, J. et al. (2012). Human CHCHD4 mitochondrial proteins regulate cellular oxygen consumption rate and metabolism and provide a critical role in hypoxia signaling and tumor progression Journal of Clinical Investigation, 122 (2), 600-611 DOI: 10.1172/JCI58780
New
findings on the protein CDCP1 provide a link between the low oxygen
environments of some tumors, and their ability to spread between sites
in the body. Despite the fact that many cancer cells thrive without
oxygen, understanding the molecular pathways involved gives researchers a
chance to suffocate these tumors for good.
Most cells in the human body can’t survive for long without oxygen—the element we gulp in with every breath is vital to building molecules, carrying out chemical reactions, and storing energy. But cancerous cells aren’t like other cells in the body. Many tumors, in fact, thrive under conditions of low oxygen, called hypoxia. And tumors depleted of oxygen have been found, time and time again, to be more dangerous, faster growing, faster spreading, and more resistant to treatments than other tumors. Why? Cells have built in programs that put them into crisis mode when oxygen levels in their neighborhood drop; altering their metabolism to make it more efficient, turning off cell death pathways in a desperate attempt to survive, and spurring the growth of new blood vessels toward the area. This hypoxia-induced ultra-survival program is just what tumor cells need to help them evade death and grow uncontrollably.
The new PNAS Early Edition paper by Emerling et. al. serves as a reminder that many unexpected cancer-linked genes may tie back to this hypoxia program in tumor cells. It also brings the results back to real patients, suggesting a potential new drug target for those with oxygen-depleted cancers.
Emerling et. al. were studying the response of tumor cells to hypoxia when they noticed that whenever the amount of oxygen dropped, levels of the protein CDCP1 increased. CDCP1 had never before been linked to oxygen, but in a 2011 PNAS paper by Liu et. al., CDCP1 had been connected to the ability of melanomas to spread throughout the body. More CDCP1 meant a higher chance of the melanoma spreading to the lung, for example. Until now, however, scientists didn’t have a good idea of why this was true, or why different cancers had different levels of CDCP1.
The team of researchers involved in the new paper—mostly based at Harvard Medical School and its associated hospitals—began testing the link between CDCP1 and oxygen to see if it could explain the protein’s role in helping cancers spread. Usually, cancer cells cut off from oxygen are more likely to migrate away from the tumor, the first step in spreading to distant organs. But when Emerling et. al. shut off CDCP1 in a group of cancer cells, low oxygen levels no longer increased the cells’ ability to migrate away—the protein acted as an off-switch against the cancer spreading. CDCP1, the results suggest, could be a missing link between hypoxia and tumor metastasis.
- See more at: http://firstlook.pnas.org/suffocating-cancers-that-thrive-without-oxygen/#sthash.FPA0b1gi.dpuf
Most cells in the human body can’t survive for long without oxygen—the element we gulp in with every breath is vital to building molecules, carrying out chemical reactions, and storing energy. But cancerous cells aren’t like other cells in the body. Many tumors, in fact, thrive under conditions of low oxygen, called hypoxia. And tumors depleted of oxygen have been found, time and time again, to be more dangerous, faster growing, faster spreading, and more resistant to treatments than other tumors. Why? Cells have built in programs that put them into crisis mode when oxygen levels in their neighborhood drop; altering their metabolism to make it more efficient, turning off cell death pathways in a desperate attempt to survive, and spurring the growth of new blood vessels toward the area. This hypoxia-induced ultra-survival program is just what tumor cells need to help them evade death and grow uncontrollably.
The new PNAS Early Edition paper by Emerling et. al. serves as a reminder that many unexpected cancer-linked genes may tie back to this hypoxia program in tumor cells. It also brings the results back to real patients, suggesting a potential new drug target for those with oxygen-depleted cancers.
Emerling et. al. were studying the response of tumor cells to hypoxia when they noticed that whenever the amount of oxygen dropped, levels of the protein CDCP1 increased. CDCP1 had never before been linked to oxygen, but in a 2011 PNAS paper by Liu et. al., CDCP1 had been connected to the ability of melanomas to spread throughout the body. More CDCP1 meant a higher chance of the melanoma spreading to the lung, for example. Until now, however, scientists didn’t have a good idea of why this was true, or why different cancers had different levels of CDCP1.
The team of researchers involved in the new paper—mostly based at Harvard Medical School and its associated hospitals—began testing the link between CDCP1 and oxygen to see if it could explain the protein’s role in helping cancers spread. Usually, cancer cells cut off from oxygen are more likely to migrate away from the tumor, the first step in spreading to distant organs. But when Emerling et. al. shut off CDCP1 in a group of cancer cells, low oxygen levels no longer increased the cells’ ability to migrate away—the protein acted as an off-switch against the cancer spreading. CDCP1, the results suggest, could be a missing link between hypoxia and tumor metastasis.
- See more at: http://firstlook.pnas.org/suffocating-cancers-that-thrive-without-oxygen/#sthash.FPA0b1gi.dpuf
New
findings on the protein CDCP1 provide a link between the low oxygen
environments of some tumors, and their ability to spread between sites
in the body. Despite the fact that many cancer cells thrive without
oxygen, understanding the molecular pathways involved gives researchers a
chance to suffocate these tumors for good.
Most cells in the human body can’t survive for long without oxygen—the element we gulp in with every breath is vital to building molecules, carrying out chemical reactions, and storing energy. But cancerous cells aren’t like other cells in the body. Many tumors, in fact, thrive under conditions of low oxygen, called hypoxia. And tumors depleted of oxygen have been found, time and time again, to be more dangerous, faster growing, faster spreading, and more resistant to treatments than other tumors. Why? Cells have built in programs that put them into crisis mode when oxygen levels in their neighborhood drop; altering their metabolism to make it more efficient, turning off cell death pathways in a desperate attempt to survive, and spurring the growth of new blood vessels toward the area. This hypoxia-induced ultra-survival program is just what tumor cells need to help them evade death and grow uncontrollably.
The new PNAS Early Edition paper by Emerling et. al. serves as a reminder that many unexpected cancer-linked genes may tie back to this hypoxia program in tumor cells. It also brings the results back to real patients, suggesting a potential new drug target for those with oxygen-depleted cancers.
Emerling et. al. were studying the response of tumor cells to hypoxia when they noticed that whenever the amount of oxygen dropped, levels of the protein CDCP1 increased. CDCP1 had never before been linked to oxygen, but in a 2011 PNAS paper by Liu et. al., CDCP1 had been connected to the ability of melanomas to spread throughout the body. More CDCP1 meant a higher chance of the melanoma spreading to the lung, for example. Until now, however, scientists didn’t have a good idea of why this was true, or why different cancers had different levels of CDCP1.
The team of researchers involved in the new paper—mostly based at Harvard Medical School and its associated hospitals—began testing the link between CDCP1 and oxygen to see if it could explain the protein’s role in helping cancers spread. Usually, cancer cells cut off from oxygen are more likely to migrate away from the tumor, the first step in spreading to distant organs. But when Emerling et. al. shut off CDCP1 in a group of cancer cells, low oxygen levels no longer increased the cells’ ability to migrate away—the protein acted as an off-switch against the cancer spreading. CDCP1, the results suggest, could be a missing link between hypoxia and tumor metastasis.
The scientists went on to test levels of CDCP1 in cell lines from
real human tumors. Whenever a cancer had high levels of HIF-2α
(hypoxia-inducible factor-2α), a protein that cells produce in response
to low oxygen, it also had high levels of CDCP1, helping solidify the
connection between hypoxia and CDCP1.
Bladder, breast, colorectal, kidney, ovarian, and pancreatic tumors
showed particularly high levels of CDCP1, they found. Moreover, when the
team analyzed the patient data corresponding to the tumor samples, they
discovered that those with higher levels of CDCP1 had decreased
survival times and an increased chance of the cancer spreading.
The results hint that CDCP1 could be an attractive drug target to block the spread of tumors stemming from hypoxic environments. This could be particularly applicable to cases of clear cell renal cell carcinoma (ccRCC)—in many of these kidney cancers, a master oxygen-sensing protein is mutated, and hypoxia programs are constantly activated, whatever levels of oxygen the tumor is exposed to. Thirty percent of patients with ccRCC are diagnosed with metastatic tumors, and the cancer is notoriously hard to treat with chemotherapy. Shutting down CDCP1 might be one way to make these cancers less likely to spread, and more susceptible to treatments—it will take more work, though, to know for sure whether this approach has merit.
- See more at: http://firstlook.pnas.org/suffocating-cancers-that-thrive-without-oxygen/#sthash.FPA0b1gi.dpuf
Most cells in the human body can’t survive for long without oxygen—the element we gulp in with every breath is vital to building molecules, carrying out chemical reactions, and storing energy. But cancerous cells aren’t like other cells in the body. Many tumors, in fact, thrive under conditions of low oxygen, called hypoxia. And tumors depleted of oxygen have been found, time and time again, to be more dangerous, faster growing, faster spreading, and more resistant to treatments than other tumors. Why? Cells have built in programs that put them into crisis mode when oxygen levels in their neighborhood drop; altering their metabolism to make it more efficient, turning off cell death pathways in a desperate attempt to survive, and spurring the growth of new blood vessels toward the area. This hypoxia-induced ultra-survival program is just what tumor cells need to help them evade death and grow uncontrollably.
The new PNAS Early Edition paper by Emerling et. al. serves as a reminder that many unexpected cancer-linked genes may tie back to this hypoxia program in tumor cells. It also brings the results back to real patients, suggesting a potential new drug target for those with oxygen-depleted cancers.
Emerling et. al. were studying the response of tumor cells to hypoxia when they noticed that whenever the amount of oxygen dropped, levels of the protein CDCP1 increased. CDCP1 had never before been linked to oxygen, but in a 2011 PNAS paper by Liu et. al., CDCP1 had been connected to the ability of melanomas to spread throughout the body. More CDCP1 meant a higher chance of the melanoma spreading to the lung, for example. Until now, however, scientists didn’t have a good idea of why this was true, or why different cancers had different levels of CDCP1.
The team of researchers involved in the new paper—mostly based at Harvard Medical School and its associated hospitals—began testing the link between CDCP1 and oxygen to see if it could explain the protein’s role in helping cancers spread. Usually, cancer cells cut off from oxygen are more likely to migrate away from the tumor, the first step in spreading to distant organs. But when Emerling et. al. shut off CDCP1 in a group of cancer cells, low oxygen levels no longer increased the cells’ ability to migrate away—the protein acted as an off-switch against the cancer spreading. CDCP1, the results suggest, could be a missing link between hypoxia and tumor metastasis.
Renal
cell carcinoma patients with high levels of CDCP1 in their tumors
survived, on average, shorter after their date of diagnosis than those
with low levels of CDCP1 in their tumors.
The results hint that CDCP1 could be an attractive drug target to block the spread of tumors stemming from hypoxic environments. This could be particularly applicable to cases of clear cell renal cell carcinoma (ccRCC)—in many of these kidney cancers, a master oxygen-sensing protein is mutated, and hypoxia programs are constantly activated, whatever levels of oxygen the tumor is exposed to. Thirty percent of patients with ccRCC are diagnosed with metastatic tumors, and the cancer is notoriously hard to treat with chemotherapy. Shutting down CDCP1 might be one way to make these cancers less likely to spread, and more susceptible to treatments—it will take more work, though, to know for sure whether this approach has merit.
- See more at: http://firstlook.pnas.org/suffocating-cancers-that-thrive-without-oxygen/#sthash.FPA0b1gi.dpuf
New
findings on the protein CDCP1 provide a link between the low oxygen
environments of some tumors, and their ability to spread between sites
in the body. Despite the fact that many cancer cells thrive without
oxygen, understanding the molecular pathways involved gives researchers a
chance to suffocate these tumors for good.
Most cells in the human body can’t survive for long without oxygen—the element we gulp in with every breath is vital to building molecules, carrying out chemical reactions, and storing energy. But cancerous cells aren’t like other cells in the body. Many tumors, in fact, thrive under conditions of low oxygen, called hypoxia. And tumors depleted of oxygen have been found, time and time again, to be more dangerous, faster growing, faster spreading, and more resistant to treatments than other tumors. Why? Cells have built in programs that put them into crisis mode when oxygen levels in their neighborhood drop; altering their metabolism to make it more efficient, turning off cell death pathways in a desperate attempt to survive, and spurring the growth of new blood vessels toward the area. This hypoxia-induced ultra-survival program is just what tumor cells need to help them evade death and grow uncontrollably.
The new PNAS Early Edition paper by Emerling et. al. serves as a reminder that many unexpected cancer-linked genes may tie back to this hypoxia program in tumor cells. It also brings the results back to real patients, suggesting a potential new drug target for those with oxygen-depleted cancers.
Emerling et. al. were studying the response of tumor cells to hypoxia when they noticed that whenever the amount of oxygen dropped, levels of the protein CDCP1 increased. CDCP1 had never before been linked to oxygen, but in a 2011 PNAS paper by Liu et. al., CDCP1 had been connected to the ability of melanomas to spread throughout the body. More CDCP1 meant a higher chance of the melanoma spreading to the lung, for example. Until now, however, scientists didn’t have a good idea of why this was true, or why different cancers had different levels of CDCP1.
The team of researchers involved in the new paper—mostly based at Harvard Medical School and its associated hospitals—began testing the link between CDCP1 and oxygen to see if it could explain the protein’s role in helping cancers spread. Usually, cancer cells cut off from oxygen are more likely to migrate away from the tumor, the first step in spreading to distant organs. But when Emerling et. al. shut off CDCP1 in a group of cancer cells, low oxygen levels no longer increased the cells’ ability to migrate away—the protein acted as an off-switch against the cancer spreading. CDCP1, the results suggest, could be a missing link between hypoxia and tumor metastasis.
- See more at: http://firstlook.pnas.org/suffocating-cancers-that-thrive-without-oxygen/#sthash.FPA0b1gi.dpuf
Most cells in the human body can’t survive for long without oxygen—the element we gulp in with every breath is vital to building molecules, carrying out chemical reactions, and storing energy. But cancerous cells aren’t like other cells in the body. Many tumors, in fact, thrive under conditions of low oxygen, called hypoxia. And tumors depleted of oxygen have been found, time and time again, to be more dangerous, faster growing, faster spreading, and more resistant to treatments than other tumors. Why? Cells have built in programs that put them into crisis mode when oxygen levels in their neighborhood drop; altering their metabolism to make it more efficient, turning off cell death pathways in a desperate attempt to survive, and spurring the growth of new blood vessels toward the area. This hypoxia-induced ultra-survival program is just what tumor cells need to help them evade death and grow uncontrollably.
The new PNAS Early Edition paper by Emerling et. al. serves as a reminder that many unexpected cancer-linked genes may tie back to this hypoxia program in tumor cells. It also brings the results back to real patients, suggesting a potential new drug target for those with oxygen-depleted cancers.
Emerling et. al. were studying the response of tumor cells to hypoxia when they noticed that whenever the amount of oxygen dropped, levels of the protein CDCP1 increased. CDCP1 had never before been linked to oxygen, but in a 2011 PNAS paper by Liu et. al., CDCP1 had been connected to the ability of melanomas to spread throughout the body. More CDCP1 meant a higher chance of the melanoma spreading to the lung, for example. Until now, however, scientists didn’t have a good idea of why this was true, or why different cancers had different levels of CDCP1.
The team of researchers involved in the new paper—mostly based at Harvard Medical School and its associated hospitals—began testing the link between CDCP1 and oxygen to see if it could explain the protein’s role in helping cancers spread. Usually, cancer cells cut off from oxygen are more likely to migrate away from the tumor, the first step in spreading to distant organs. But when Emerling et. al. shut off CDCP1 in a group of cancer cells, low oxygen levels no longer increased the cells’ ability to migrate away—the protein acted as an off-switch against the cancer spreading. CDCP1, the results suggest, could be a missing link between hypoxia and tumor metastasis.
- See more at: http://firstlook.pnas.org/suffocating-cancers-that-thrive-without-oxygen/#sthash.FPA0b1gi.dpuf
-------
New
findings on the protein CDCP1 provide a link between the low oxygen
environments of some tumors, and their ability to spread between sites
in the body. Despite the fact that many cancer cells thrive without
oxygen, understanding the molecular pathways involved gives researchers a
chance to suffocate these tumors for good.
Most cells in the human body can’t survive for long without oxygen—the element we gulp in with every breath is vital to building molecules, carrying out chemical reactions, and storing energy. But cancerous cells aren’t like other cells in the body. Many tumors, in fact, thrive under conditions of low oxygen, called hypoxia. And tumors depleted of oxygen have been found, time and time again, to be more dangerous, faster growing, faster spreading, and more resistant to treatments than other tumors. Why? Cells have built in programs that put them into crisis mode when oxygen levels in their neighborhood drop; altering their metabolism to make it more efficient, turning off cell death pathways in a desperate attempt to survive, and spurring the growth of new blood vessels toward the area. This hypoxia-induced ultra-survival program is just what tumor cells need to help them evade death and grow uncontrollably.
The new PNAS Early Edition paper by Emerling et. al. serves as a reminder that many unexpected cancer-linked genes may tie back to this hypoxia program in tumor cells. It also brings the results back to real patients, suggesting a potential new drug target for those with oxygen-depleted cancers.
Emerling et. al. were studying the response of tumor cells to hypoxia when they noticed that whenever the amount of oxygen dropped, levels of the protein CDCP1 increased. CDCP1 had never before been linked to oxygen, but in a 2011 PNAS paper by Liu et. al., CDCP1 had been connected to the ability of melanomas to spread throughout the body. More CDCP1 meant a higher chance of the melanoma spreading to the lung, for example. Until now, however, scientists didn’t have a good idea of why this was true, or why different cancers had different levels of CDCP1.
The team of researchers involved in the new paper—mostly based at Harvard Medical School and its associated hospitals—began testing the link between CDCP1 and oxygen to see if it could explain the protein’s role in helping cancers spread. Usually, cancer cells cut off from oxygen are more likely to migrate away from the tumor, the first step in spreading to distant organs. But when Emerling et. al. shut off CDCP1 in a group of cancer cells, low oxygen levels no longer increased the cells’ ability to migrate away—the protein acted as an off-switch against the cancer spreading. CDCP1, the results suggest, could be a missing link between hypoxia and tumor metastasis.
- See more at: http://firstlook.pnas.org/suffocating-cancers-that-thrive-without-oxygen/#sthash.FPA0b1gi.dpuf
Most cells in the human body can’t survive for long without oxygen—the element we gulp in with every breath is vital to building molecules, carrying out chemical reactions, and storing energy. But cancerous cells aren’t like other cells in the body. Many tumors, in fact, thrive under conditions of low oxygen, called hypoxia. And tumors depleted of oxygen have been found, time and time again, to be more dangerous, faster growing, faster spreading, and more resistant to treatments than other tumors. Why? Cells have built in programs that put them into crisis mode when oxygen levels in their neighborhood drop; altering their metabolism to make it more efficient, turning off cell death pathways in a desperate attempt to survive, and spurring the growth of new blood vessels toward the area. This hypoxia-induced ultra-survival program is just what tumor cells need to help them evade death and grow uncontrollably.
The new PNAS Early Edition paper by Emerling et. al. serves as a reminder that many unexpected cancer-linked genes may tie back to this hypoxia program in tumor cells. It also brings the results back to real patients, suggesting a potential new drug target for those with oxygen-depleted cancers.
Emerling et. al. were studying the response of tumor cells to hypoxia when they noticed that whenever the amount of oxygen dropped, levels of the protein CDCP1 increased. CDCP1 had never before been linked to oxygen, but in a 2011 PNAS paper by Liu et. al., CDCP1 had been connected to the ability of melanomas to spread throughout the body. More CDCP1 meant a higher chance of the melanoma spreading to the lung, for example. Until now, however, scientists didn’t have a good idea of why this was true, or why different cancers had different levels of CDCP1.
The team of researchers involved in the new paper—mostly based at Harvard Medical School and its associated hospitals—began testing the link between CDCP1 and oxygen to see if it could explain the protein’s role in helping cancers spread. Usually, cancer cells cut off from oxygen are more likely to migrate away from the tumor, the first step in spreading to distant organs. But when Emerling et. al. shut off CDCP1 in a group of cancer cells, low oxygen levels no longer increased the cells’ ability to migrate away—the protein acted as an off-switch against the cancer spreading. CDCP1, the results suggest, could be a missing link between hypoxia and tumor metastasis.
- See more at: http://firstlook.pnas.org/suffocating-cancers-that-thrive-without-oxygen/#sthash.FPA0b1gi.dpuf
Suffocating cancers that thrive without oxygen
New findings on the protein CDCP1 provide a link between
the low oxygen environments of some tumors, and their ability to spread
between sites in the body. Despite the fact that many cancer cells
thrive without oxygen, understanding the molecular pathways involved
gives researchers a chance to suffocate these tumors for good.
Most cells in the human body can’t survive for long without oxygen—the element we gulp in with every breath is vital to building molecules, carrying out chemical reactions, and storing energy. But cancerous cells aren’t like other cells in the body. Many tumors, in fact, thrive under conditions of low oxygen, called hypoxia. And tumors depleted of oxygen have been found, time and time again, to be more dangerous, faster growing, faster spreading, and more resistant to treatments than other tumors. Why? Cells have built in programs that put them into crisis mode when oxygen levels in their neighborhood drop; altering their metabolism to make it more efficient, turning off cell death pathways in a desperate attempt to survive, and spurring the growth of new blood vessels toward the area. This hypoxia-induced ultra-survival program is just what tumor cells need to help them evade death and grow uncontrollably.
The new PNAS Early Edition paper by Emerling et. al. serves as a reminder that many unexpected cancer-linked genes may tie back to this hypoxia program in tumor cells. It also brings the results back to real patients, suggesting a potential new drug target for those with oxygen-depleted cancers.
Emerling et. al. were studying the response of tumor cells to hypoxia when they noticed that whenever the amount of oxygen dropped, levels of the protein CDCP1 increased. CDCP1 had never before been linked to oxygen, but in a 2011 PNAS paper by Liu et. al., CDCP1 had been connected to the ability of melanomas to spread throughout the body. More CDCP1 meant a higher chance of the melanoma spreading to the lung, for example. Until now, however, scientists didn’t have a good idea of why this was true, or why different cancers had different levels of CDCP1.
The team of researchers involved in the new paper—mostly based at Harvard Medical School and its associated hospitals—began testing the link between CDCP1 and oxygen to see if it could explain the protein’s role in helping cancers spread. Usually, cancer cells cut off from oxygen are more likely to migrate away from the tumor, the first step in spreading to distant organs. But when Emerling et. al. shut off CDCP1 in a group of cancer cells, low oxygen levels no longer increased the cells’ ability to migrate away—the protein acted as an off-switch against the cancer spreading. CDCP1, the results suggest, could be a missing link between hypoxia and tumor metastasis.
The scientists went on to test levels of CDCP1 in cell lines from
real human tumors. Whenever a cancer had high levels of HIF-2α
(hypoxia-inducible factor-2α), a protein that cells produce in response
to low oxygen, it also had high levels of CDCP1, helping solidify the
connection between hypoxia and CDCP1.
Bladder, breast, colorectal, kidney, ovarian, and pancreatic tumors
showed particularly high levels of CDCP1, they found. Moreover, when the
team analyzed the patient data corresponding to the tumor samples, they
discovered that those with higher levels of CDCP1 had decreased
survival times and an increased chance of the cancer spreading.
The results hint that CDCP1 could be an attractive drug target to block the spread of tumors stemming from hypoxic environments. This could be particularly applicable to cases of clear cell renal cell carcinoma (ccRCC)—in many of these kidney cancers, a master oxygen-sensing protein is mutated, and hypoxia programs are constantly activated, whatever levels of oxygen the tumor is exposed to. Thirty percent of patients with ccRCC are diagnosed with metastatic tumors, and the cancer is notoriously hard to treat with chemotherapy. Shutting down CDCP1 might be one way to make these cancers less likely to spread, and more susceptible to treatments—it will take more work, though, to know for sure whether this approach has merit.
Most cells in the human body can’t survive for long without oxygen—the element we gulp in with every breath is vital to building molecules, carrying out chemical reactions, and storing energy. But cancerous cells aren’t like other cells in the body. Many tumors, in fact, thrive under conditions of low oxygen, called hypoxia. And tumors depleted of oxygen have been found, time and time again, to be more dangerous, faster growing, faster spreading, and more resistant to treatments than other tumors. Why? Cells have built in programs that put them into crisis mode when oxygen levels in their neighborhood drop; altering their metabolism to make it more efficient, turning off cell death pathways in a desperate attempt to survive, and spurring the growth of new blood vessels toward the area. This hypoxia-induced ultra-survival program is just what tumor cells need to help them evade death and grow uncontrollably.
The new PNAS Early Edition paper by Emerling et. al. serves as a reminder that many unexpected cancer-linked genes may tie back to this hypoxia program in tumor cells. It also brings the results back to real patients, suggesting a potential new drug target for those with oxygen-depleted cancers.
Emerling et. al. were studying the response of tumor cells to hypoxia when they noticed that whenever the amount of oxygen dropped, levels of the protein CDCP1 increased. CDCP1 had never before been linked to oxygen, but in a 2011 PNAS paper by Liu et. al., CDCP1 had been connected to the ability of melanomas to spread throughout the body. More CDCP1 meant a higher chance of the melanoma spreading to the lung, for example. Until now, however, scientists didn’t have a good idea of why this was true, or why different cancers had different levels of CDCP1.
The team of researchers involved in the new paper—mostly based at Harvard Medical School and its associated hospitals—began testing the link between CDCP1 and oxygen to see if it could explain the protein’s role in helping cancers spread. Usually, cancer cells cut off from oxygen are more likely to migrate away from the tumor, the first step in spreading to distant organs. But when Emerling et. al. shut off CDCP1 in a group of cancer cells, low oxygen levels no longer increased the cells’ ability to migrate away—the protein acted as an off-switch against the cancer spreading. CDCP1, the results suggest, could be a missing link between hypoxia and tumor metastasis.
Renal
cell carcinoma patients with high levels of CDCP1 in their tumors
survived, on average, shorter after their date of diagnosis than those
with low levels of CDCP1 in their tumors.
The results hint that CDCP1 could be an attractive drug target to block the spread of tumors stemming from hypoxic environments. This could be particularly applicable to cases of clear cell renal cell carcinoma (ccRCC)—in many of these kidney cancers, a master oxygen-sensing protein is mutated, and hypoxia programs are constantly activated, whatever levels of oxygen the tumor is exposed to. Thirty percent of patients with ccRCC are diagnosed with metastatic tumors, and the cancer is notoriously hard to treat with chemotherapy. Shutting down CDCP1 might be one way to make these cancers less likely to spread, and more susceptible to treatments—it will take more work, though, to know for sure whether this approach has merit.
Categories: Medical Sciences
- See more at: http://firstlook.pnas.org/suffocating-cancers-that-thrive-without-oxygen/#sthash.FPA0b1gi.dpufSuffocating cancers that thrive without oxygen
New findings on the protein CDCP1 provide a link between
the low oxygen environments of some tumors, and their ability to spread
between sites in the body. Despite the fact that many cancer cells
thrive without oxygen, understanding the molecular pathways involved
gives researchers a chance to suffocate these tumors for good.
Most cells in the human body can’t survive for long without oxygen—the element we gulp in with every breath is vital to building molecules, carrying out chemical reactions, and storing energy. But cancerous cells aren’t like other cells in the body. Many tumors, in fact, thrive under conditions of low oxygen, called hypoxia. And tumors depleted of oxygen have been found, time and time again, to be more dangerous, faster growing, faster spreading, and more resistant to treatments than other tumors. Why? Cells have built in programs that put them into crisis mode when oxygen levels in their neighborhood drop; altering their metabolism to make it more efficient, turning off cell death pathways in a desperate attempt to survive, and spurring the growth of new blood vessels toward the area. This hypoxia-induced ultra-survival program is just what tumor cells need to help them evade death and grow uncontrollably.
The new PNAS Early Edition paper by Emerling et. al. serves as a reminder that many unexpected cancer-linked genes may tie back to this hypoxia program in tumor cells. It also brings the results back to real patients, suggesting a potential new drug target for those with oxygen-depleted cancers.
Emerling et. al. were studying the response of tumor cells to hypoxia when they noticed that whenever the amount of oxygen dropped, levels of the protein CDCP1 increased. CDCP1 had never before been linked to oxygen, but in a 2011 PNAS paper by Liu et. al., CDCP1 had been connected to the ability of melanomas to spread throughout the body. More CDCP1 meant a higher chance of the melanoma spreading to the lung, for example. Until now, however, scientists didn’t have a good idea of why this was true, or why different cancers had different levels of CDCP1.
The team of researchers involved in the new paper—mostly based at Harvard Medical School and its associated hospitals—began testing the link between CDCP1 and oxygen to see if it could explain the protein’s role in helping cancers spread. Usually, cancer cells cut off from oxygen are more likely to migrate away from the tumor, the first step in spreading to distant organs. But when Emerling et. al. shut off CDCP1 in a group of cancer cells, low oxygen levels no longer increased the cells’ ability to migrate away—the protein acted as an off-switch against the cancer spreading. CDCP1, the results suggest, could be a missing link between hypoxia and tumor metastasis.
The scientists went on to test levels of CDCP1 in cell lines from
real human tumors. Whenever a cancer had high levels of HIF-2α
(hypoxia-inducible factor-2α), a protein that cells produce in response
to low oxygen, it also had high levels of CDCP1, helping solidify the
connection between hypoxia and CDCP1.
Bladder, breast, colorectal, kidney, ovarian, and pancreatic tumors
showed particularly high levels of CDCP1, they found. Moreover, when the
team analyzed the patient data corresponding to the tumor samples, they
discovered that those with higher levels of CDCP1 had decreased
survival times and an increased chance of the cancer spreading.
The results hint that CDCP1 could be an attractive drug target to block the spread of tumors stemming from hypoxic environments. This could be particularly applicable to cases of clear cell renal cell carcinoma (ccRCC)—in many of these kidney cancers, a master oxygen-sensing protein is mutated, and hypoxia programs are constantly activated, whatever levels of oxygen the tumor is exposed to. Thirty percent of patients with ccRCC are diagnosed with metastatic tumors, and the cancer is notoriously hard to treat with chemotherapy. Shutting down CDCP1 might be one way to make these cancers less likely to spread, and more susceptible to treatments—it will take more work, though, to know for sure whether this approach has merit.
Most cells in the human body can’t survive for long without oxygen—the element we gulp in with every breath is vital to building molecules, carrying out chemical reactions, and storing energy. But cancerous cells aren’t like other cells in the body. Many tumors, in fact, thrive under conditions of low oxygen, called hypoxia. And tumors depleted of oxygen have been found, time and time again, to be more dangerous, faster growing, faster spreading, and more resistant to treatments than other tumors. Why? Cells have built in programs that put them into crisis mode when oxygen levels in their neighborhood drop; altering their metabolism to make it more efficient, turning off cell death pathways in a desperate attempt to survive, and spurring the growth of new blood vessels toward the area. This hypoxia-induced ultra-survival program is just what tumor cells need to help them evade death and grow uncontrollably.
The new PNAS Early Edition paper by Emerling et. al. serves as a reminder that many unexpected cancer-linked genes may tie back to this hypoxia program in tumor cells. It also brings the results back to real patients, suggesting a potential new drug target for those with oxygen-depleted cancers.
Emerling et. al. were studying the response of tumor cells to hypoxia when they noticed that whenever the amount of oxygen dropped, levels of the protein CDCP1 increased. CDCP1 had never before been linked to oxygen, but in a 2011 PNAS paper by Liu et. al., CDCP1 had been connected to the ability of melanomas to spread throughout the body. More CDCP1 meant a higher chance of the melanoma spreading to the lung, for example. Until now, however, scientists didn’t have a good idea of why this was true, or why different cancers had different levels of CDCP1.
The team of researchers involved in the new paper—mostly based at Harvard Medical School and its associated hospitals—began testing the link between CDCP1 and oxygen to see if it could explain the protein’s role in helping cancers spread. Usually, cancer cells cut off from oxygen are more likely to migrate away from the tumor, the first step in spreading to distant organs. But when Emerling et. al. shut off CDCP1 in a group of cancer cells, low oxygen levels no longer increased the cells’ ability to migrate away—the protein acted as an off-switch against the cancer spreading. CDCP1, the results suggest, could be a missing link between hypoxia and tumor metastasis.
Renal
cell carcinoma patients with high levels of CDCP1 in their tumors
survived, on average, shorter after their date of diagnosis than those
with low levels of CDCP1 in their tumors.
The results hint that CDCP1 could be an attractive drug target to block the spread of tumors stemming from hypoxic environments. This could be particularly applicable to cases of clear cell renal cell carcinoma (ccRCC)—in many of these kidney cancers, a master oxygen-sensing protein is mutated, and hypoxia programs are constantly activated, whatever levels of oxygen the tumor is exposed to. Thirty percent of patients with ccRCC are diagnosed with metastatic tumors, and the cancer is notoriously hard to treat with chemotherapy. Shutting down CDCP1 might be one way to make these cancers less likely to spread, and more susceptible to treatments—it will take more work, though, to know for sure whether this approach has merit.
Categories: Medical Sciences
- See more at: http://firstlook.pnas.org/suffocating-cancers-that-thrive-without-oxygen/#sthash.FPA0b1gi.dpufHypoxia-inducible factors (HIFs) are transcription factors that respond to changes in available oxygen in the cellular environment, specifically, to decreases in oxygen, or hypoxia.[1]
- ^ Lee, K.; Zhang, H.; Qian, D. Z.; Rey, S.; Liu, J. O.; Semenza, G. L. (2009). "Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization". Proceedings of the National Academy of Sciences 106 (42): 17910. doi:10.1073/pnas.0909353106.
Hypoxia inducible factor-1α as a cancer drug target
+ Author Affiliations
- Requests for Reprints: Garth Powis, Arizona Cancer Center, University of Arizona, Room 3977, 1515 North Campbell Avenue, Tucson, AZ 85724-5024. Phone: (520) 626-6408; Fax: (520) 626-4848. E-mail: gpowis@azcc.arizona.edu
Abstract
The hypoxia inducible factor 1 (HIF-1) is a
heterodimeric transcription factor that is an important regulator of
the growing
tumor's response to hypoxia. HIF-1 activity in
tumors depends on the availability of the HIF-1α subunit, the levels of
which
increase under hypoxic conditions and through the
activation of oncogenes and/or inactivation of tumor suppressor genes.
HIF-1
activates genes that allow the cancer cell to
survive and grow in the hostile hypoxic tumor environment. Increased
tumor HIF-1α
has been correlated with increased angiogenesis,
aggressive tumor growth, and poor patient prognosis, leading to the
current
interest in HIF-1α as a cancer drug target. A
number of anticancer agents have been reported to decrease HIF-1α or
HIF-1 transactivating
activity in cells in culture. However, more
relevant to the agents' antitumor activity is whether HIF-1 is inhibited
in tumors
in vivo. This has been demonstrated for
only a few of the reported HIF-1 inhibitors. Some of the agents are
moving toward clinical
trial where it will be important to demonstrate
that the agents inhibit HIF-1α in patient tumors or, failing this, the
downstream
consequences of HIF-1 inhibition such as decreased
vascular endothelial growth factor formation, and relate this inhibition
to antitumor activity. Only in this way will it be
possible to determine if HIF-1α is a valid cancer drug target in humans.
Human CHCHD4 mitochondrial proteins regulate cellular oxygen consumption rate and metabolism and provide a critical role in hypoxia signaling and tumor progression
1Centre
for Cell Signalling and Molecular Genetics, University College London,
Division of Medicine, Rayne Institute, London, United Kingdom.
2Tumour Biology Section, UCL Cancer Institute, Paul O’Gorman Building, University College London, London, United Kingdom.
3Cancer Research UK Department of Medical Oncology, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
4Faculty of Medical Sciences, University College London, Division of Medicine, Rayne Institute, London, United Kingdom.
2Tumour Biology Section, UCL Cancer Institute, Paul O’Gorman Building, University College London, London, United Kingdom.
3Cancer Research UK Department of Medical Oncology, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
4Faculty of Medical Sciences, University College London, Division of Medicine, Rayne Institute, London, United Kingdom.
Address
correspondence to: Margaret Ashcroft, Centre for Cell Signalling and
Molecular Genetics, University College London, London, United Kingdom.
Phone: 44.0.20.7679.6205; Fax: 44.0.20.7679.6211; E-mail:
m.ashcroft@ucl.ac.uk.
Authorship note: Jun Yang and Oliver Staples contributed equally to this work.
First published January 3, 2012
Received for publication May 2, 2011, and accepted in revised form November 16, 2011.
Received for publication May 2, 2011, and accepted in revised form November 16, 2011.
Increased
expression of the regulatory subunit of HIFs (HIF-1α or HIF-2α) is
associated with metabolic adaptation, angiogenesis, and tumor
progression. Understanding how HIFs are regulated is of intense
interest. Intriguingly, the molecular mechanisms that link mitochondrial
function with the HIF-regulated response to hypoxia remain to be
unraveled. Here we describe what we believe to be novel functions of the
human gene CHCHD4 in this context. We found that CHCHD4
encodes 2 alternatively spliced, differentially expressed isoforms
(CHCHD4.1 and CHCHD4.2). CHCHD4.1 is identical to MIA40, the homolog of
yeast Mia40, a key component of the mitochondrial disulfide relay system
that regulates electron transfer to cytochrome c. Further
analysis revealed that CHCHD4 proteins contain an evolutionarily
conserved coiled-coil-helix-coiled-coil-helix (CHCH) domain important
for mitochondrial localization. Modulation of CHCHD4 protein expression
in tumor cells regulated cellular oxygen consumption rate and
metabolism. Targeting CHCHD4 expression blocked HIF-1α induction
and function in hypoxia and resulted in inhibition of tumor growth and
angiogenesis in vivo. Overexpression of CHCHD4 proteins in tumor cells
enhanced HIF-1α protein stabilization in hypoxic conditions, an effect
insensitive to antioxidant treatment. In human cancers, increased CHCHD4
expression was found to correlate with the hypoxia gene expression
signature, increasing tumor grade, and reduced patient survival. Thus,
our study identifies a mitochondrial mechanism that is critical for
regulating the hypoxic response in tumors.
NATURAL HIF INHIBITORS
EGCG, a major green tea catechin suppresses breast tumor angiogenesis and growth via inhibiting the activation of HIF-1α and NFκB, and VEGF expression
Cancer Institute,
University of Mississippi Medical Center, Jackson, Mississippi 39216,
USA
Vascular Cell 2013, 5:9 doi:10.1186/2045-824X-5-9
The electronic version of this article is the complete one and can be found online at: http://www.vascularcell.com/content/5/1/9
The electronic version of this article is the complete one and can be found online at: http://www.vascularcell.com/content/5/1/9
| Received: | 29 January 2013 |
| Accepted: | 16 April 2013 |
| Published: | 2 May 2013 |
© 2013 Gu et al.; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
The role of EGCG, a major green tea catechin in breast cancer therapy is poorly understood.
The present study tests the hypothesis that EGCG can inhibit the activation of HIF-1α
and NFκB, and VEGF expression, thereby suppressing tumor angiogenesis and breast cancer
progression. Sixteen eight-wk-old female mice (C57BL/6 J) were inoculated with 10^6
E0771 (mouse breast cancer) cells in the left fourth mammary gland fat pad. Eight
mice received EGCG at 50–100 mg/kg/d in drinking water for 4 weeks. 8 control mice
received drinking water only. Tumor size was monitored using dial calipers. At the
end of the experiment, blood samples, tumors, heart and limb muscles were collected
for measuring VEGF expression using ELISA and capillary density (CD) using CD31 immunohistochemistry.
EGCG treatment significantly reduced tumor weight over the control (0.37 ± 0.15 vs.
1.16 ± 0.30 g; P < 0.01), tumor CD (109 ± 20 vs. 156 ± 12 capillary #/mm^2; P < 0.01),
tumor VEGF expression (45.72 ± 1.4 vs. 59.03 ± 3.8 pg/mg; P < 0.01), respectively.
But, it has no effects on the body weight, heart weight, angiogenesis and VEGF expression
in the heart and skeletal muscle of mice. EGCG at 50 μg/ml significantly inhibited
the activation of HIF-1α and NFκB as well as VEGF expression in cultured E0771 cells,
compared to the control, respectively. These findings support the hypothesis that
EGCG, a major green tea catechin, directly targets both tumor cells and tumor vasculature,
thereby inhibiting tumor growth, proliferation, migration, and angiogenesis of breast
cancer, which is mediated by the inhibition of HIF-1α and NFκB activation as well
as VEGF expression.
Introduction
The term ‘green tea’ refers to the product manufactured from fresh tea leaves by steaming
or drying at elevated temperatures with the precaution to avoid oxidation of the polyphenolic
components known as catechins [1]. The natural product (−)-epigallocatechin-3-gallate (EGCG) accounts for 50-80% of
catechins in green tea, representing 200–300 mg in a brewed cup of green tea [2]. Several other catechins such as (−)-epicatechin-3-gallate (ECG), (−)-epigallocatechin
(EGC), and (−)-epicatechin (EC) are found in lower abundance in green tea [3]. EGCG is defined as a major green tea catechin that contributes to beneficial therapeutic
effects, including anti-oxidant, anti-inflammatory, anti-cancer, and immunomodulatory
effects [4-6]. Studies conducted on cell-culture systems and animal models as well as human epidemiological
studies show that EGCG in green tea could afford protection against a variety of cancer
types [7]. Many studies have shown that EGCG produces anti-cancer effect by modulating the
activity of mitogen-activated protein kinases (MAPKs), IGF/IGF-1 receptor, Akt, NFκB
and HIF-1α [8-12]. A case–control study including 501 breast cancer cases and 594 controls shows that
green tea consumption has a significant trend of decreasing risk in a dose-dependent
manner, after adjusting for potential confounding factors [13]. However, the investigations of green tea or EGCG in breast cancer using animal model
are very limited, and the role of EGCG in breast cancer therapy is poorly understood.
The growth and expansion of a tumor is mainly dependent on angiogenesis, the formation
of new capillaries from pre-existing blood vessels. Avascular tumors are those that
do not grow beyond a maximum size of 1 to 2 mm3 in the absence of neovascularization, and it may be eliminated by a normal immune
system [14]. Angiogenesis requires stimulation of vascular endothelial cells through the release
of angiogenic factors. Of these, the vascular endothelial growth factor (VEGF) is
the most critical regulator in the development of the vascular system and is commonly
overexpressed in a variety of human solid tumors including breast cancer [15]. Cancer cells are under greater hypoxia and oxidative stress than normal cells. Oxygen
radicals and hypoxia co-operatively promote tumor angiogenesis [16]. Hypoxia causes the activation of HIF-1, in which it stimulates VEGF expression.
HIF-1 levels are also increased by oxygen radicals. In addition, oxygen radicals activate
NFκB that also increases VEGF expression. VEGF is a key angiogenic factor that stimulates
the growth of tumors including breast cancer, in which VEGF exerts paracrine (especially
angiogenesis) and autocrine (proliferation and migration) effects to promote progression
of breast cancer [17]. As mentioned above, we believe that EGCG can block highly activated NFκB and HIF-1α
pathways in breast tumor. Therefore, we hypothesizes that EGCG directly targets both
of tumor cells and tumor vasculature, thereby inhibiting tumor growth, proliferation,
migration, and angiogenesis of breast cancer, which is mediated by the inhibition
of HIF-1α and NFκB activation as well as VEGF expression. Also, EGCG treatment has
no significant effects on the body weight, heart weight, angiogenesis and VEGF expression
in normal tissues such as the heart and skeletal muscle.
To test this hypothesis, the present study aimed to determine the following: (a) whether
a relative high oral dose of EGCG inhibits tumor growth, tumor angiogenesis, and VEGF
expression in an immunocompetent mouse model (C57BL/6) of breast cancer; (b) whether
oral EGCG treatment affects angiogenesis and VEGF expression in normal tissues such
as the heart and skeletal muscle in the same mice; and (c) whether EGCG inhibits proliferation,
migration, VEGF expression, the activation of HIF-1α and NFκB in cultured mouse and
human breast cancer cells (E0771, MCF-7 and MDA-MB-231).
Materials and methods
Chemicals and cell lines
EGCG was purchased from Sigma Chemical Co. (St. Louis, MO). The mouse breast cancer
cells (E0771) which were originally isolated from an immunocompetent C57BL/6 mouse,
were provided by Dr. Sirotnak FM at Memorial Sloan Kettering Cancer Center, New York,
NY [18]. Human estrogen-receptor positive breast cancer (MCF-7) cells and human triple negative
breast cancer (MDA-MB-231) cells were purchased from the American Type Culture Collection
(Rockville, MD). All breast cancer cells were maintained as monolayer cultures in
RPMI Medium 1640 (GIBCO) supplemented with 10% FBS (HyClone), 100 U/ml penicillin,
100 μg/ml streptomycin, and 0.25 μg/ml amphotericin B, and incubated at 37°C in a
humidified 5%CO2/air injected atmosphere.
Animal protocols
The protocols were carried out according to the guidelines for the care and use of
laboratory animals implemented by the National Institutes of Health and the Guidelines
of the Animal Welfare Act and were approved by the University of Mississippi Medical
Center’s Institutional Animal Care and Use Committee. 16 female C57BL/6 mice at 7 weeks
of age were purchased from Jackson Laboratory (Bar Harbor, Maine). The mice were allowed
to acclimate for 1 week with standard chaw diet (Teklad, Harlan Sprague Dawley; Indianapolis,
IN) and tap water before beginning the experiments. The eight week old female mice
(n = 16) were inoculated with 10^6 E0771 cells suspended in 100 μl of phosphate-buffered
saline into the left fourth mammary gland fat pad. Then, 8 mice received EGCG (25 mg/50 ml)
in drinking water for 4 weeks and 8 control mice received drinking water only. Each
mouse (20 g) usually drank 2 to 4 ml of water per day. Therefore, EGCG was given around
50 to 100 mg/kg/day to the mice. The body weight of the mice was monitored weekly.
Tumor size was monitored every other day in two perpendicular dimensions parallel
with the surface of the mice using dial calipers. At the end of the experiment, blood
samples, tumors, heart and limb muscles were collected for measuring VEGF expression
using ELISA and average microvascular density (AMVD) or capillary density (CD) using
CD31 immunohistochemistry.
Morphometric analysis of angiogenesis in tumor, the heart and limb muscles
The quantification of blood vessels in mouse breast tumor, the heart and limb muscle
was determined with the modification of a previously reported method [17,19]. Briefly, the tissues were fixed in 4% neutrally buffered paraformaldehyde. For the
heart left ventricular and limb muscle samples, consecutive thin transverse cryosections
(5 μm) were cut along the base-apex axis. Consecutive thin cryosections (5 μm) of
OCT compound (Sakura Finetek, Torrance, CA) embedded tissue samples were fixed in
acetone at 4°C for 10 min. After washing in phosphate-buffered saline (PBS), the sections
were treated with 3% H2O2 for 10 minutes to block endogenous peroxidase activity and were blocked with normal
rabbit serum. Then, the sections were washed in PBS and incubated with rat anti-mouse
CD31 (PECAM-1) monoclonal antibody (BD Pharmingen, San Diego, CA) at a 1:200 dilution
overnight at 4°C. Negative controls were incubated with the rat serum IgG at the same
dilution. All sections were washed in PBS containing 0.05% Tween-20, and were then
incubated with a 2nd antibody, mouse anti-rat IgG (Vector laboratories, Burlingame, CA) at a 1:200 dilution
for 1 hour at room temperature again followed by washing with PBS containing 0.05%
Tween-20. The sections were incubated in a 1:400 dilution of Extravadin Peroxidase
(Sigma, St. Louis, MO) for 30 min. After washing in PBS containing 0.05% Tween-20,
the sections were incubated in peroxidase substrate (Vector laboratories, Burlingame,
CA) for 5 min. The sections were washed in PBS containing 0.05% Tween-20 and were
counterstained with hematoxylin. A positive reaction was indicated by a brown staining.
The microvascular vessels were quantified by manual counting under light microscopy.
A microscopic field (0.7884 mm2) was defined by a grid laced in the eye-piece. At least 20 microscopic fields were
randomly acquired from each tumor for analysis. Any endothelial cell or cell cluster
showing antibody staining and clearly separated from an adjacent cluster was considered
to be a single, countable microvessel. The value of average microvascular density
(AMVD) or capillary density (CD) was determined by calculating the mean of the vascular
counts per mm2 obtained in the microscopic fields for each tissue sample.
Measurements of protein levels of VEGF by ELISA
Protein levels of VEGF in plasma, breast tumor, the heart, the limb muscle, and the
medium cultured with E0771 cells were determined using mouse VEGF ELISA kits (R&D
Systems, Minneapolis, MN), according to the manufacturer’s instructions. The total
proteins of breast tumor, the heart, the limb muscle, and cultured E0771 cells were
extracted using NE-PER Cytoplasmic Extraction Reagents (Pierce, Rockford, IL), according
to the manufacturer’s protocol. The total protein concentration of these tissue extractions
was determined using a Bio-Rad Protein Assay (Bio-Rad Laboratories, Hercules, CA).
The protein concentrations of VEGF were normalized and expressed as pictograms per
milligram of total tissue or cell extraction protein.
Proliferation assay of cultured breast cancer cells
The E0771, MCF-7, and MDA-MB-231cells were seeded into 6-well tissue culture plates
using RPMI Medium 1640 (GIBCO) supplemented with 10% FBS (HyClone), 100 U/ml penicillin,
100 μg/ml streptomycin, and 0.25 μg/ml amphotericin B, and incubated at 37°C in a
humidified 5%CO2/air injected atmosphere. When the monolayer reached about 80% confluence, the cells
were washed with PBS and incubated with fresh RPMI Medium 1640 with 10% FBS in the
absence and presence of EGCG (0, 10, 50 μg/ml) for 18 hours. 3H-thymidine incorporation
assay was used to determine the cell proliferation during the last 6 hours of incubation
as previously described [20].
Migration assay
Migration was determined using BD BioCoat Matrigel Invasion Chamber (BD Bioscience
Discovery Labware, Sedford, MA) according to a previous study, in which only invasive
cells digested the matrix and moved through the insert membrane [21]. 1 × 105 E0771 cells per well in 0.5 ml medium (RPMI Medium 1640) were seeded in the matrigel-coated
upper compartment (insert) of a Transwell (24-well format, 8-μm pore) in the absence
of and presence of EGCG (0, 10, 20, 50 μg/ml) and the medium with 10% FBS was added
to the lower part of the well. After overnight incubation at 37°C and 5% CO2, cells on the upper surface of the insert were removed using a cotton wool swab.
Migrated cells on the lower surface of the insert were stained using DiffQuit (Dada
Behring, Düdinen, Switzerland). The images of migrated cells were taken and the number
of migrated cells was counted using a microscope (Leica, Germany) in a 20× objective.
HIF-1α and NFκB activation (motif binding) assays
We determined HIF-1α and NFκB activation in cultured E0771 cells in the absence and
presence of EGCG (0 and 50 mg/ml) to investigate whether the down-regulation of VEGF
by EGCG is associated with the inhibition of HIF-1α and NFκB activation (n = 6). The
nuclear proteins were extracted by using Active Motif (Carlsbad, CA) nuclear extract
kit. 20 μg nuclear proteins from each sample was used in the TransAM HIF-1α or NFκB
p65 kit (Active Motif), which can measure the binding of activated HIF-1α or NFκB
to its consensus sequence attached to a microwell plate, according the manufacturer’s
instructions.
Statistical analysis
All determinations were performed in duplicated sets. Where indicated, data is presented
as mean ± SE. Statistically significant differences in mean values between the two
groups were tested by an unpaired Student’s t-test. Linear regression was performed
by the correlation analysis between two continuous variables. A value of P < 0.05
was considered statistically significant. All statistical calculations were performed
using SPSS software (SPSS Inc., Chicago, IL).
Results
A relative high oral dose of EGCG significantly inhibits the progression of breast cancer growth
We used a mouse breast cancer model that mimics the human disease, in which the mouse
breast adenocinoma (E0771) cells were injected into the pad of the fourth mammary
gland of female immunocompetent mice (C57BL/6). Immediately after the inoculation
of E0771 cells, the eight week old female mice (n = 8) were given EGCG at 50 to 100 mg/kg/day
in drinking water for four weeks and the control group (n = 8) was given regular drinking
water only. Tumor size was then monitored every other day in two perpendicular dimensions
parallel with the surface of the mice using dial calipers. As indicated in Figure 1A, the tumor cross section area was significantly reduced in the EGCG-treated group
compared to the control group two weeks after the breast cancer inoculation. At the
end of experiment, the tumor cross section area was reduced by 65% (P < 0.01) in EGCG-treated
group compared to the control group (Figure 1A), which was consistent with the reduction in tumor weight (Figure 1B) in EGCG-treated group compared to the control group (0.37 ± 0.15 vs. 1.16 ± 0.30 g;
P <0.01). Clearly, EGCG treatment at 50 to 100 mg/kg/d in drinking water significantly
inhibited the progression of breast cancer growth in the female mice by decreasing
the tumor size and reducing the growth curve of breast cancer. However, there was
no significant difference in the body weight, heart weight, kidney weight, or urinary
protein between the EGCG-treated mice and the control mice.
Figure 1. The inhibition of the progression of breast cancer growth by oral EGCG in the immunocompetant
female mice (C57BL/6) allografted with mouse breast cancer (E0771) cells. EGCG at 50 to 100 mg/kg/day in drinking water for four weeks significantly reduced
a growth curve of breast cancer monitored by the tumor cross section area by 65% (Figure 1A, P < 0.01; n = 8) and tumor weight (Figure 1B, 0.37 ± 0.15 vs. 1.16 ± 0.30 g; P < 0.01; n = 8), compared to the control group.
EGCG suppresses breast tumor angiogenesis and VEGF expression in mice
Growth and expansion of tumor mass are strictly dependent on angiogenesis because
neovascularization permits rapid tumor growth by providing an exchange of nutrients,
oxygen, and paracrine stimuli to the tumor [22]. Therefore, in this study, we used a morphometric analysis of immunohistochemical
staining for CD31 to determine the effect of EGCG on breast tumor angiogenesis in
mice. Representative images of CD31 staining of the breast cancer tumors showed that
the EGCG-treated tumor had lesser microvessels than the control tumor (Figure 2A). Morphometric analysis (Figure 2A) indicated that PDTC treatment caused a significant decrease in average microvessel
density (AMVD, the number of microvessels per mm2 area) of breast tumors compared
to the control breast tumors (109 ± 20 vs. 156 ± 12 microvessels number per mm^2;
n = 8; P < 0.01). These results also suggest that a pronounced decrease in tumor angiogenesis
is associated with a decrease in tumor size of breast cancer tumor in the female mice
treated with EGCG compared to those in the control mice. Figure 2B also demonstrated that EGCG treatment reduced plasma VEGF levels over the control
mice (26.48 ± 3.76 vs. 40.79 ± 3.5 pg/ml; n = 8; P < 0.01) and tumor VEGF expression
over the control mice (45.72 ± 1.4 vs. 59.03 ± 3.8 pg/mg; n = 8; P < 0.01). These
findings suggest that the inhibition of tumor angiogenesis in mice by EGCG is due
to the down-regulation of VEGF because VEGF is a key angiogenic factor.
Figure 2. Oral EGCG at 50–100 mg/kg/d in drinking water significantly reduced intratumoral microvessel
density (Panel A: 109 ± 20 vs. 156 ± 12 microvessel #/mm^2; P < 0.01), plasma VEGF
levels (Panel B; 26.48 ± 3.76 vs. 40.79 ± 3.5 pg/ml; P < 0.01), and tumor VEGF expression
(Panel B; 45.72 ± 1.4 vs. 59.03 ± 3.8 pg/mg; P < 0.01) over the control, respectively
in mice (n = 8). The digital images show CD31 immunohistochemistry staining in OCT-embedded cryosections
of mouse breast cancer tumors obtained from a control (Figure 2A) or EGCG-treated (Figure 2A) mouse.
EGCG directly inhibits proliferation and migration of breast cancer cells
We used a 3H-thymidine incorporation assay to determine the effects of EGCG on the
proliferation of cultured mouse breast cancer cells (E0771), human estrogen receptor
positive breast cancer cells (MCF-7), and triple negative breast cancer cells (MDA-MB-231).
Figure 3A showed that E0771 cells treated with EGCG caused a dose-related decrease in 3H-thymidine
incorporation, decreasing by 22% at 10 μg/ml and by 77% at 50 μg/ml, compared to the
control group (n = 6; P < 0.01). We examined the inhibitory effect of EGCG on E0771
cell migration using BD BioCoat Matrigel Invasion Chamber. Figure 3B demonstrates that EGCG at 10, 20, and 50 μg/ml caused a dose-dependent reduction
of migrated breast cancer (E0771) cells, decreasing by 25%, 48%, and 71%, respectively,
compared to the control group (n = 6; P < 0.01). In the another experiment, as shown
in Figure 3C, we demonstrated that EGCG at 50 μg/ml significantly inhibited the proliferation
of human estrogen receptor positive breast cancer cells (MCF-7) and triple negative
breast cancer cells (MDA-MB-231) by 91% and 52%, respectively, compared to the control
group (n = 6; P < 0.01), but not at 10 μg/ml. These in vitro findings illustrate that EGCG can directly target breast cancer cells by inhibiting
the proliferation and migration.
Figure 3. EGCG caused a dose-related inhibition in 3H-thymidine incorporation, decreasing by
22% at10 μg/ml and by 77% at 50 μg/ml (Panel A, n = 6, P < 0.01), and in migration
(Panel B, n = 6, P < 0.01) in cultured E0771 cells, compared to the control group. In Panel C, EGCG at 50 μg/ml significantly inhibited the proliferation in cultured MCF-7 and
MDA-MB-231 cells, compared to the control group (n = 6; P < 0.01), respectively.
The down-regulation of VEGF expression by EGCG is associated with the inhibition of HIF-1α and NFκB activation
HIF-1 and NFκB pathways are highly activated in breast tumor, in which they can co-operatively
promote tumor angiogenesis by increasing VEGF expression [16]. We used VEGF ELISA kit and HIF-1α and NFκB activation (Motif Binding) assays to
determine whether EGCG could suppress HIF-1α and NFκB activation and VEGF expression
in cultured mouse breast cancer (E0771) cells. Figure 4A showed that EGCG at 50 μg/ml significantly inhibited VEGF expression (1752 ± 49
vs. 2254 ± 91 pg/mg; n = 6; P < 0.01) in cultured E0771 cells, compared to the control.
In the same experiment, EGCG at 50 μg/ml also significantly suppressed the activation
of HIF-1α (0.11 ± 0.02 vs. 0.24 ± 0.02; P < 0.01; Figure 4B) and NFκB (1.15 ± 0.21 vs. 1.61 ± 0.32; n = 6; P < 0.01; Figure 4C), compared to the control, respectively. These results suggest that the inhibition
of HIF-1α and NFκB activation contributes to the down-regulation of VEGF expression.
Figure 4. EGCG at 50 μg/ml significantly inhibited VEGF expression (Panel A, 1752 ± 49 vs. 2254 ± 91 pg/mg,
n = 6, P < 0.01), the activation of HIF-1α (Panel B, 0.11 ± 0.02 vs. 0.24 ± 0.02,
n = 6, P < 0.01) and NFκB (Panel C, 1.15 ± 0.21 vs. 1.61 ± 0.32; n = 6, P < 0.01)
in cultured E0771 cells, compared to the control, respectively.Oral EGCG treatment has no effects on angiogenesis and VEGF expression in normal tissues such as the heart and skeletal muscle in mice
The data showed that there was no significant difference in the body weight (22.38.25 ± 0.51
vs. 22.94 ± 0.57; n = 8; P = 0.9437), heart weight (84.7 ± 11.2 vs. 85.1 vs. 10.6 mg;
n = 8; P = 0.3546), or kidney weight (237.5 ± 9.2 vs. 240.1 ± 8.9 mg; n = 8; P = 0.3735)
between the EGCG-treated mice and the control mice. Figure 5A showed that EGCG treatment did not affect the capillary density (number of capillary/mm^2
area) (3270 ± 162 vs. 3103 ± 226 #/mm^2; n = 8; P = 0.5215) analyzed by CD31 immunochemistry
and morphometric analysis, and VEGF expression (261 ± 22 vs. 245 ± 19 pg/mg; n = 8;
P = 0.4517) determined by ELISA in the mouse heart, compared to the control group,
respectively. Figure 5B showed that there was no significant difference in the capillary density (370 ± 55
vs. 381 ± 44 #/mm^2; n = 8; P = 0.5401), and VEGF expression (225 ± 16 vs. 214 ± 20 pg/mg;
n = 8; P = 0.7825) in the limb skeletal muscles between the EGCG-treated mice and
the control mice, respectively. These findings illustrate that EGCG does not significantly
affect angiogenesis and VEGF expression in the normal tissues such as the heart and
skeletal muscles.
Figure 5. EGCG treatment did not affect the capillary density (3270 ± 162 vs. 3103 ± 226 #/mm^2;
n = 8; P = 0.5215), and VEGF expression (261 ± 22 vs. 245 ± 19 pg/mg; n = 8; P = 0.4517)
in the mouse heart, compared to the control group (Panel A), respectively. There was no significant difference in the capillary density (370 ± 55 vs. 381 ± 44
#/mm^2; n = 8; P = 0.5401), and VEGF expression (225 ± 16 vs. 214 ± 20 pg/mg; n = 8;
P = 0.7825) in the limb skeletal muscles between the EGCG-treated mice and the control
mice (Panel B), respectively. The digital images show CD31 immunohistochemistry staining in OCT-embedded
cryosections of the heart (Panel A) and the limb muscle (Panel B) of control mouse and EGCG-treated mouse, respectively.
Discussion
The major new findings from this study include: 1) a relative high oral dose of EGCG
significantly inhibits the progression of mouse breast cancer growth in female immunocompetent
mice; 2) EGCG significantly suppresses breast tumor angiogenesis and VEGF expression
in these mice; 3) EGCG treatment does not significantly affect angiogenesis and VEGF
expression in the normal tissues such as the heart and skeletal muscles in the same
experiment; 4) EGCG directly inhibits proliferation and migration of cultured mouse
and human breast cancer cells; and 5) the down-regulation of VEGF expression by EGCG
is associated with the inhibition of HIF-1α and NFκB activation. These findings support
the hypothesis that EGCG, a major green tea catechin directly targets both of tumor
cells and tumor vasculature, thereby inhibiting tumor growth, proliferation, migration,
and angiogenesis of breast cancer, which is mediated by the inhibition of HIF-1α and
NFκB activation as well as VEGF expression. Also, EGCG treatment has no significant
effects on angiogenesis and VEGF expression in normal tissues such as the heart and
skeletal muscle.
An important finding of this study is that a relative high oral dose of EGCG treatment
at 50 to 100 mg/kg/day in drinking water significantly slows a growth curve of breast
cancer in C57BL/6 female mice compared to the control group, which is characterized
by 65% and 68% reduction in the tumor cross section area and tumor weight, respectively.
Clearly, oral EGCG treatment is very effective in suppressing progression of breast
cancer in a wild type immunocompetent mouse model. Ullmann et al. reported that peak
plasma concentrations were greater than 3 μg/ml after oral dose of 1600 mg in healthy
human subjects [23]. We believe that oral dose of 50 to 100 mg/kg/day in human can reach the effective
plasma concentrations of EGCG against breast cancer. Recent methods developed for
the stereoselective total synthesis of EGCG, and structurally related catechins, could
provide new sources of these compounds for biomedical use [24]. Our next step is clinical trial for EGCG in breast cancer therapy.
That's 6 pills (400mg) for a 110lbs person.
Alternative to oxygen therapies on HBOT? How to increase oxygen uptake?
Effects of qigong on cardiorespiratory changes: a preliminary study.
Source
Life College, Sports Health Science, Marietta, GA 30060.Abstract
Qigong,
a special form of breathing exercise, was investigated to examine its
effect on cardiorespiratory changes. Ten volunteers (five males and five
females) participated in a 20-minute group instructional session for 10
consecutive days before testing of its treatment effects. The testing
protocol followed a C1-T-C2 design, where C1, T, and C2 represented the
first, treatment, and second control period, respectively. Each period
consisted of a 5-minute interval, and thus each testing session
consisted of 15 minutes. The results indicated there were no
statistically significant differences (p > 0.05) in heart rate or
tidal volume for the three 5-minute periods. There was a significant
decrease (p < 0.05) in respiratory exchange ratio between T and C2. A
significant increase in ventilatory efficiency for carbon dioxide
production was found between C1 and T. Statistically significant
differences (p < 0.05) were found in the volume of oxygen consumed
and carbon dioxide produced, frequency of breath, expired ventilation,
and ventilatory efficiency for oxygen produced between the T and the two
control periods. This preliminary study of Qigong demonstrates that the
subjects were able to learn the technique in a short period of time.
The data also suggest that, with an improvement of nearly 20% in
ventilatory efficiency for oxygen uptake and carbon dioxide production,
this technique may have useful therapeutic value.
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