Explaining “How & Why” Cancer Cells Eat Us Alive

Newswise — Four key studies now propose a new theory about how cancer cells grow and survive, allowing researchers to design better diagnostics and therapies to target high-risk cancer patients. These studies were conducted by a large team of researchers at Thomas Jefferson University’s Kimmel Cancer Center.

This new idea also explains why so many cancer patients say that “their cancer is eating them alive” – an accurate observation that has never been understood, the researchers say.

These four new studies, co-published in the September issue of the journal Cell Cycle, provide evidence that tumor growth and metastasis is directly “fueled” by normal supporting cells.

These supporting cells are called fibroblasts, and they produce the stroma (connective tissue) that surrounds tumor cells. As the cancer progresses, increasing numbers of these stromal cells eat themselves to provide recycled nutrients to tumor cells – leading to dramatic weight loss in patients.

They also found that without recycled nutrients provided by fibroblasts, tumor cells are more fragile and die. Based on this breakthrough, the researchers propose that available drugs (now on the market), which sever the “parasitic” connection between tumor cells and fibroblasts, may be effective therapeutics.

“We think we have finally figured out how cancer really works – and this reverses 85 years of dogma, upon which current cancer research and therapy is based,” says the study’s senior investigator, Michael P. Lisanti, M.D., Ph.D., Chairman of Jefferson’s Department of Stem Cell Biology & Regenerative Medicine.

The prevailing theory, known as the Warburg Effect, developed by German researcher Otto Warburg in 1924 (for which he won a Nobel prize), says that tumor cells change their metabolism in order to fuel their own growth. As evidence, Warburg pointed to a lack of mitochondria, which are tiny “power plants,” in laboratory cancer cells, saying these cells have found another way to produce the energy they need.

Richard Pestell, MB, BS, MD, Ph.D, FRACP, director of the Kimmel Cancer Center and co-author on these studies notes, “These studies suggest that the absence of mitochondria in laboratory cancer cells may reflect in part that cultured cells have had to adjust to life outside of their original environment, without their stromal partner.” Drs. Lisanti, Pestell and colleagues found this out by performing a simple experiment in which they mixed cancer cells and fibroblasts together, and then searched for mitochondria. The found the fibroblasts didn’t have any mitochondria, and that the cancer cells had all the mitochondria.

“The Warburg Effect is happening, but it is happening to fibroblasts, not to cancer cells. Fibroblasts have no mitochondria because they are eating them to provide energy to cancer cells, and cancer cells have a ton of mitochondria because they need these power plants to process all the recycled nutrients given to them by fibroblasts, which then helps them grow and spread,” Dr. Lisanti says.
They have dubbed this finding “The Reverse Warburg Effect.”

“It’s amazing,” Dr. Lisanti says. “Much of what we know about cancer is backwards because cancer researchers used isolated tumor cells for most cancer studies. Now, when we put cancer cells back in their stromal environment, we see how cancer cells critically depend on fibroblasts for their survival.”

Tumor cells do this by employing oxidative stress as a weapon. Then, oxidative stress in fibroblasts “tricks” these stromal cells into eating themselves to feed cancer cells, the researchers say. This process of “self-eating” or “self-cannibalism” is called autophagy.

During periods of starvation, normal cells undergo autophagy. This metabolic re-programming allows cells to recycle nutrients by continually eating themselves, including their mitochondria. This permits starving cells to recycle nutrients and to survive under hostile conditions.

Now, Dr. Lisanti and colleagues have figured out how cancer cells take advantage of this recycling process. To satisfy their large appetite, hungry cancer cells induce oxidative stress in the fibroblasts and this stress forces the stromal cells to eat themselves, which provides recycled nutrients or “food” to fuel survival of nearby cancer cells.

“It’s that simple. Cancer cells are eating us alive by stealing nutrients from normal cells using oxidative stress, and by employing those recycled nutrients to support their own growth. Stem cells are then recruited from the bone marrow to produce fresh fibroblasts, to continually fuel cancer cell growth,” Dr. Lisanti says. “For years, cancer patients have said they felt as though the cancer in their body was eating them alive. These patients were right. Essentially, the cancer knows how to induce oxidative stress and turns a local wasting process into a whole-body phenomenon.”

Co-author Ubaldo Martinez-Outschoorn, M.D., a medical oncologist at Jefferson says “Patients have been telling us that cancer is eating them alive for years: Now we know they were right!” One of his cancer patients recently said, “Doc, I can’t eat enough food to maintain my weight. No matter how much I eat, I feel tired, and I am always losing weight.”

“Now that we understand the mechanism, this reverses our thinking about cancer metabolism and about how to stop this stress and starve the cancer cells,” he says.

In one of the published studies, Dr. Lisanti shows that using anti-oxidants can prevent oxidative stress in the fibroblasts, thus cutting off the fuel supply to cancer cells, starving them. “We are now performing drug screening assays to discover new anti-oxidants and other molecules like this,” he says.

The researchers have additionally identified two key metabolites – ketones and lactate – produced by the co-opted fibroblasts that provide high-energy food to the cancer cells. This finding also explains a mystery and provides a warning.

The mystery concerns why people with diabetes are much more likely to develop cancer than non-diabetics. The reason, Dr. Lisanti says, is that diabetic patients produce elevated levels of ketones, and he now shows that ketones fuel cancer cell growth.

The warning comes from the common use of lactate, a type of sugar, in cancer patients. Surgeons often give their cancer patients an intravenous solution of lactate before, during, and after surgery, Dr. Lisanti says. “But we see that cancer cells are using energy-rich fuels, such as lactate, to increase their numbers of mitochondria to power cancer cell growth, survival, and metastasis, so surgeons may want to re-consider or stop this practice.”

The findings have led the researchers to question the value of research using isolated laboratory cancer cells – the basis of most cancer research – and the anticancer drugs that result from it.

For example, genetic mutations have long been thought to be the root cause of cancer, but Dr. Lisanti’s group observed that these alterations might be the consequence of the tumor cell’s interactions with the normal stroma. Oxidative stress induced by cancer cells in fibroblasts feeds back upon cancer cells, amplifying the production of reactive oxygen species (ROS). They believe that ROS is then used by cancer cells to mutate their own genes to promote survival.

“These ROS molecules cause DNA damage in the cancer cells, resulting in genomic instability - random mutations and DNA breakage, as well as abnormal chromosome numbers. This instability helps cancer cells evolve into a more aggressive form,” Dr. Lisanti says.

“So, we see three consequences resulting from activating oxidative stress in normal stromal cells,” he says. “First, it forces stromal cells to make food for cancer cells. Second, this abundance of food protects the cancer cells against death. Finally, oxidative stress modifies cancer cell DNA, causing mutations and allowing them to evolve into a more aggressive form.”

Additionally, the researchers say their new theory of stromal metabolic re-programming suggests that cancer cells do not need blood vessels to feed them, which explains why some angiogensis inhibitors (drugs that shut down blood vessel growth) have not worked – and, in fact, may be dangerous.

“If an aggressive cancer cell can use oxidative stress to extract nutrients from normal stromal cells, it can go anywhere without the need for a blood supply. This may be how cancer cells spread all over the body,” Dr. Lisanti says. “Furthermore, angiogenesis inhibitors induce hypoxia, which is low oxygen, in the stroma. This is exactly the condition that drives nutrient recycling via autophagy. So angiogenesis inhibitors may help provide food or recycled nutrients to feed cancer cells. This explains why angiogenesis inhibitors have been very disappointing in clinical trials, as they may be having just the opposite effect, promoting cancer cell growth and metastasis.”

These new findings also have clear implications for cancer diagnosis, the researchers say. Many of the molecules that Dr. Lisanti’s group identified could be used as diagnostics to identify high-risk cancer patients or to monitor the success of their anti-cancer therapy.

Among them is caveolin-1 (Cav-1), which is produced by fibroblasts. Dr. Lisanti had shown earlier that loss of Cav-1 predicts poor prognosis in breast cancer patients, and is linked to early tumor recurrence, metastasis, and drug resistance. He now understands why, as breast cancer patients with absent stromal Cav-1 are feeding their cancer cells via recycled nutrients. That explains why a loss of stromal Cav-1 is such a good biomarker for identifying high-risk patients.

“The idea that a cancer cell’s local environment is important for tumor growth is now well-accepted by the cancer research community,” Dr. Lisanti says. “Now we show why this notion is correct.”

These studies were funded in part by grants from the NIH/National Cancer Institute, Susan G. Komen for the Cure, The American Cancer Society, The Breast Cancer Alliance, The Falk Medical Research Trust, The Landenberger Research Foundation and The Pennsylvania Department of Health.

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Medicaid Spending Projected to Rise Much Faster Than the Economy

Cumulative Spending on Medicaid Benefits Projected to Reach $4.9
Trillion Over 10 Years

Under current law, spending on Medicaid is expected to substantially
outpace the rate of growth in the U.S. economy over the next decade,
according to a new annual report released today by the Centers for
Medicare & Medicaid Services (CMS).

The report projects that Medicaid benefits spending will increase 7.3
percent from 2007 to 2008, reaching $339 billion and will grow at an
annual average rate of 7.9 percent over the next 10 years, reaching $674
billion by 2017. That compares to a projected rate of growth of 4.8
percent in the general economy.

HHS Secretary Mike Leavitt presented the report today at the fall
meeting of the National Association of State Budget Officers (NASBO).

"This report should serve as an urgent reminder that the current path of
Medicaid spending is unsustainable for both federal and state
governments. We must act quickly to keep state Medicaid programs
fiscally sound," Secretary Leavitt said. "If nothing is done to rein in
these costs, access to health care for the nation's most vulnerable
citizens could be threatened."

Although the CMS Office of the Actuary regularly produces 75-year
projections of Medicare expenditures for the annual report of the
Medicare Board of Trustees, the report released today is the first
annual fiscal report on Medicaid.

The Medicare Trustees Report provides detailed information on the past
and estimated future financial operations of the Hospital Insurance and
Supplementary Medical Insurance Trust Funds. This new annual report on
Medicaid contains analysis of past program trends and projections of
Medicaid expenditures and enrollment for the next 10 years only. Future
reports will expand on content to include longer-range projections and
more extensive analysis.

Medicaid is a federal/state partnership program that provides health
care to certain low-income people and is one of the largest payers for
health care in the United States. For both federal and state
governments, Medicaid is the largest source of general revenue spending
on health services. Notably, Medicaid is the largest source of general
revenue spending for health care for both the Federal government and the
states.

This growth rate compares to spending projections for Medicare of 7.4
percent per year through 2017. Medicaid benefits spending over the next
10 years is projected to be $4.9 trillion. These amounts are in
addition to that spent by federal and state governments on the State
Children's Health Insurance Program (SCHIP).


At this rate, Medicaid growth is projected to slightly exceed growth in
overall health care expenditures, which is projected by CMS actuaries
and economists to increase by 6.7 percent per year over the next 10
years, or over twice the rate of general inflation. Additionally,
Medicaid's share of the Gross Domestic Product (GDP) is projected to
reach about three percent in 2017. The combined share of GDP spending
for Medicare and Medicaid is projected to be 6.9 percent by 2017.

As a partnership program, both states and the federal government pay for
services to Medicaid beneficiaries. The federal government matches
state expenditures based on a formula that yields subsidies ranging from
50 percent to as high as 83 percent. The average federal medical
assistance percentage is 57 percent.

However, even with federal support, states report they are struggling to
meet their share of expanding Medicaid costs. State spending on
Medicaid has remained relatively stable as a share of states' budgets,
averaging about 20 percent from 1995-2007. However, some states such
as Maine are already spending as much as 31 percent of their budgets on
Medicaid, according to NASBO.

NASBO is projecting that state spending on Medicaid will increase by 4.4
percent from 2008 to 2009. NASBO says such an increase would be more
than four times the rate of growth in the average state general fund.

"High and increasing Medicaid spending clearly leaves states less able
to fund other state priorities," said Acting CMS Administrator Kerry
Weems. "This new financial report confirms that America's health care
system faces significant fiscal challenges.

"As a nation we must tackle the difficult job of bringing health care
costs under control and assuring that our health care dollars are buying
the highest quality, most efficient health care services."

Other findings from the report include:

* Average Medicaid enrollment is projected to increase 1.8 percent
to 50 million people in 2008.
* During the next 10 years, average enrollment is projected to
increase at an average annual rate of 1.2 percent and to reach 55.1
million by 2017.
* The estimated average cost of a person covered by Medicaid in
2007 is $6,120; however, per-enrollee spending for non-disabled children
($2,435) and adults ($3,586) was much lower than that for aged ($14,058)
and disabled beneficiaries ($14,858), reflecting the differing health
status of these groups.
* Medicaid represented 14.8 percent of all health care spending in
the United States in 2006.
* Medicaid is projected to grow as a share of the federal budget
from 7.0 percent in 2007 to 8.4 percent by 2013.

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Solid Tumor Cells Not Killed by Radiation and Chemotherapy Become Stronger

Because of the way solid tumors adapt the body's machinery to bring themselves more oxygen, chemotherapy and radiation may actually make these tumors stronger.

"In a sense, these therapies can make the tumor healthier," said Mark W. Dewhirst, D.V.M., Ph.D., professor of radiation oncology at Duke University Medical Center. "Unless the treatment is very effective in killing many if not most tumor cells, you are shooting yourself in the foot."

Dewhirst and colleagues Yiting Cao, M.D., Ph.D., of Duke Pathology, and Benjamin Moeller, M.D., Ph.D. have introduced this counter-intuitive idea at recent conferences and in a review article featured in the June issue of Nature Reviews Cancer.

Radiation and chemotherapy do kill most solid tumor cells, but in the cells that survive, the therapies drive an increase in a regulatory factor called HIF1 (hypoxia-inducible factor 1), which cells use to get the oxygen they need by increasing blood vessel growth into the tumor. Solid tumors generally have low supplies of oxygen, Dewhirst explained and HIF1 helps them get the oxygen they need.

The review article concludes that blocking (HIF1) would provide a clear mechanism for killing solid-tumor cells, particularly cells that are proving resistant to radiation or chemotherapy treatments.

As a part of this work, Dewhirst's team has been studying the phenomenon of rising and falling oxygen levels in tumors, called cycling hypoxia. Oxygen levels have been found to naturally cycle up and down in individual blood vessels as well as large tumor regions. This instability in the tumor's oxygen levels can increase HIF-1 production and cause radiation therapy to fail, Dewhirst said.

"It is my opinion that the whole tumor grows more aggressively because of this pulsation of oxygen at low levels," Dewhirst said. "Most people thought cycling hypoxia was caused by temporary stoppage of blood flow in single blood vessel in tumors. In fact, however, oxygen levels cycle up and down virtually everywhere in the tumor, which is caused by fluctuations in blood flow rate. It has been a challenge to convince people of this."

Dewhirst and colleagues have made movies of oxygen transport in a tumor of a living animal that show the oxygen levels cycle up and down significantly, pulsing in waves seen as color changes in the movies.

The Duke team argues that blocking HIF1 is the consistent answer to tumor growth problems. Blocking HIF1 activity interferes with the tumor's ability to undergo glycolysis (energy production) in low-oxygen conditions, which blocks tumor growth, the authors wrote. Exactly how to accomplish chemotherapy or radiation treatment in the safest, most effective ways, in combination with HIF1 blockade, is still open for exploration, Dewhirst said.

For example, targeting HIF1 in the early stages of tumor growth, especially in very early cancer spread, may help, Dewhirst said. "For a woman who has had a primary breast tumor removed, and who is at high risk for cancer spread, this might be a situation in which you'd target HIF1," he explained. "Blocking HIF1 makes sense during the early stages of angiogenesis, which is the accelerated phase of blood vessel formation. In this way, you could keep the early metastasis sites inactive and prevent them from growing."

The Duke team has completed a phase I trial with a HIF1 inhibitor. "We are actively pursuing this clinically and will be moving this study into Phase 2," Dewhirst said. "We are interested in other applications of HIF-1 inhibition in combination with radiation and chemotherapy for different diseases."