New studies explain how cancer cells ‘eat us alive’
September 1, 2010
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.”
To read the full article, click on this link:
Ketones and lactate “fuel” tumor growth and metastasis: Evidence that epithelial cancer cells use oxidative mitochondrial metabolism
“Previously, we proposed a new model for understanding the ‘Warburg effect’ in tumor metabolism. In this scheme, cancer-associated fibroblasts undergo aerobic glycolysis and the resulting energy-rich metabolites are then transferred to epithelial cancer cells, where they enter the TCA cycle, resulting in high ATP production via oxidative phosphorylation. We have termed this new paradigm ‘The Reverse Warburg Effect.’ Here, we directly evaluate whether the end-products of aerobic glycolysis (3-hydroxy-butyrate and L-lactate) can stimulate tumor growth and metastasis, using MDA-MB-231 breast cancer xenografts as a model system. More specifically, we show that administration of 3-hydroxy-butyrate (a ketone body) increases tumor growth by ~2.5-fold, without any measurable increases in tumor vascularization/angiogenesis. Both 3-hydroxy-butyrate and L-lactate functioned as chemo-attractants, stimulating the migration of epithelial cancer cells. Although L-lactate did not increase primary tumor growth, it stimulated the formation of lung metastases by ~10-fold. Thus, we conclude that ketones and lactate fuel tumor growth and metastasis, providing functional evidence to support the ‘Reverse Warburg Effect.’”
Autophagy in cancer associated fibroblasts promotes tumor cell survival: Role of hypoxia, HIF1 induction and NFκB activation in the tumor stromal microenvironment
HIF1-alpha functions as a tumor promoter in cancer associated fibroblasts, and as a tumor suppressor in breast cancer cells: Autophagy drives compartment-specific oncogenesis
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