Cancer Cells: Oxygen Debt, Glucose Consumption, Mutations

Is it possible to starve cancer to death?

Theodor Boveri is a German biologist who is known in the science world for discovering the origins of cancer. He discovered that if one was to fertilize sea-urchin eggs with two sperm rather than one, it would result in some of the cells ending up with the wrong number of chromosomes and their failure to develop properly because of it. Boveri was able to make the connection between cancer cells and their abnormal chromosomes. He concluded that whatever caused the cancer had to do with these chromosomes.

Otto Warburg was also a German scientist who was studying sea-urchin eggs during the same period as Boveri. Both these scientists' research and work were recognized by the world for their breakthrough in our understanding of cancer. The difference between Warburg and Boveri is that Warburg was not interested in the chromosomes but instead his focus was on energy and how the eggs fueled their growth.

When he started to look at the sea-urchin's cells and compared them to the cells of a tumor in a rat, he discovered that the sea-urchin eggs increased their oxygen consumption as they grew. He expected a similar outcome for the extra oxygen in the rat tumor. The cancer cells fueled their growth by engulfing large amounts of glucose (blood sugar), then breaking the sugar down without the use of oxygen. The results did not make any sense because oxygen fueled reactions are much more efficient pathway to turn food into energy, especially since there was more than enough oxygen available for the cancer cells to use. However, when Warburg tested other tumors as well as human tumors he observed the same outcome every time. The cancer cells were craving glucose- not oxygen.

In 1956  people began criticizing Warbug's hypothesis that cancer is the problem of energy. His response was an example of two engines where one is being driven by complete combustion and the other by incomplete combustion of coal. A man, he continued, who is not knowledgeable about engines, their structure, and their purpose may find a difference between the two where he may even be able to smell it. Warbug saw complete combustion as respiration and incomplete combustion as turning nutrients into energy without oxygen (aka: fermentation).

Fermentation provides a useful backup when oxygen can’t reach cells quickly enough to keep up with demand. (Our muscle cells turn to fermentation during intense exercise.) Warbug thought that defects prevent cancer cells from being able to use respiration, but scientists now widely agree that this is wrong. A growing tumor can be thought of as a construction site, and as today’s researchers explain it, the Warbug effect opens the gates for more and more trucks to deliver building materials (in the form of glucose molecules) to make “daughter” cells.

Today the 'Warbug Effect' is found in 80 percent of cancers through the use of PET scans. Positron emission tomography (PET) scan helps physicians to stage and diagnose cancer in their patients. PET scans work by showing regions in the body where the cells are consuming excess glucose. The more glucose a tumor consumes, the worse is the prognosis. Warbug came to the conclusion that the reason cells consume this extra glucose from their surroundings is because they cannot use oxygen correctly. Because of this, there is damage indicated in respiration of these cells and the beginning of the cancer's journey.

 

Warburg stated that when a tumor becomes dependent on a steady flow of nutrients, it becomes vulnerable as it has shown its fatal weakness. After the 'Warbug Effect', he continued to research the enzymes involved in fermentation and to explore the possibility of blocking the process in cancer cells. The challenge Warbug faced then against cancer being an incredibly persistent foe is the same one that metabolism researchers face today. Blocking one metabolic pathway has been shown to slow down and even stop tumor growth in some cases, but tumors tend to find another way.

Near the end of his life, Warbug strongly believed that most cancers were preventable. He thought that the chemicals that are added to food and used in agriculture could cause tumors by interfering with respiration. Revisiting the 'Warburg Effect' has given researchers new goals and hypothesis to develop of how diet is linked to the nation's obesity and diabetes epidemics. Sugar heavy diets can result in permanently elevated levels of the hormone insulin which maybe be driving cells to the Warburg effect and cancer.

 

When Watson and Crick discovered the structure of DNA molecule in 1953, scientists began to view cancer as a disease governed by mutated genes. Mutation of genes drive cells into drastically enhanced division and proliferation.  Because of the discovery of the DNA molecule's structure Warburg's Effect and the metabolic catalysts involved became known as 'housekeeping enzymes' which were seen necessary to keep a cell alive but irrelevant to cancer. (A)

In the recent years, 'housekeeping enzymes' have become one of the most promising areas of research in cancer. Scientists wonder if metabolism could prove to be the long-sought “Achilles’ heel” of cancer, a common weak point in a disease that manifests itself in so many different forms. There are typically many mutations involved in a single cancer and a limited number of ways in which the body can produce energy to support rapid growth.

Cancer cells rely on these fuels in a way that healthy cells don’t. The new goal for scientists interested in researching cancer is to use Warbug's discovery to slow or possibly terminate tumors through the disruption of one or more of the various chemical reactions a cell uses to proliferate and starve cancer cells in the process (since their primary necessity to grow is from the nutrients they consume).

James Watson himself is convinced that targeting metabolism is a more promising avenue in current cancer research than gene-centered approaches. Locating the genes that cause cancer has not been helpful and the belief that sequencing an individual's DNA is going to extend a person's lifespan is untrue.  If Watson was to be involved in research today, his focus would by to study biochemistry instead of molecular biology.

If this theory can explain the “why” of the Warburg effect, it still leaves the more pressing question of what, exactly, sets a cell on the path to the Warburg effect and cancer. Scientists at several of the nation’s top cancer hospitals have spearheaded the Warburg revival, in hopes of finding the answer. These researchers, typically molecular biologists by training, have turned to metabolism and the Warburg effect because their own research led each of them to the same conclusion: A number of the cancer-causing genes that have long been known for their role in cell division also regulate cells’ consumption of nutrients. (A)

Craig Thompson is the president and chief executive of the Memorial Sloan Kettering Cancer Center. His research has shown that cells need to receive instructions from other cells to eat, just as they require instructions from other cells to divide. Thompson hypothesized that if he could identify the mutations that lead a cell to eat more glucose than it should, it would go a long way toward explaining how the Warburg effect and cancer begin. He is the most outspoken proponents of this renewed focus on metabolism. Thompson believes that the Warburg effect can be thought of as a social failure: a breakdown of the nutrient-sharing agreement that single-celled organisms signed when they joined forces to become multicellular organisms.

Thompson’s search for mutations didn’t lead him to a gene already well known to molecular biologists as AKT which promotes cell division. He now believes that AKT plays an even more fundamental role in metabolism. The protein created by AKT is part of a chain of signaling proteins that is mutated in up to 80 percent of all cancers. Once these proteins go into overdrive, a cell no longer worries about signals from other cells to eat. Instead the cell begins to eat as much glucose as possible.(A)

Thompson discovered he could induce the 'full Warburg effect' by placing an activated AKT protein into a normal cell. When this happens, the cells begin to do what every single-celled organism will do in the presence of food. They eat as much as it can and make as many copies of itself as possible.Thompson compares the mold spreading across a piece of bread to cancer to show how Warburg’s observation of cancer cells carry out fermentation at almost the same rate of wildly growing yeasts. (A)

Chi Van Dang, director of the Abramson Cancer Center at the University of Pennsylvania, has helped lead the cancer world to an appreciation of how one widely studied gene can profoundly influence a tumor’s metabolism. In 1997, Dang became one of the first scientists to connect molecular biology to the science of cellular metabolism when he demonstrated that MYC — a so-called regulator gene well known for its role in cell proliferation — directly targets an enzyme that can turn on the Warburg effect. Dang recalls that other researchers were skeptical of his interest in a housekeeping enzyme, but he stuck with it because he came to appreciate something critical: Cancer cells can’t stop eating.

Growing cancer cells are missing the internal feedback loops that are designed to conserve resources when food isn't available. They are addicted to nutrients, and when they can not consume enough they begin to die. This addiction explains why changes to metabolic pathways are so common and tend to arise first as a cell progresses toward cancer. Although it is possible that other types of alterations can begin first, however, when they do the incipient tumors lack the access to the nutrients they need to grow. 

Metabolism-centered therapies have produced some tantalizing successes. Agios Pharmaceuticals, a company co-founded by Thompson, is now testing a drug that treats cases of acute myelogenous leukemia that have been resistant to other therapies by inhibiting the mutated versions of the metabolic enzyme IDH 2. In clinical trials of the Agios drug, nearly 40 percent of patients who carry these mutations are experiencing at least partial remissions. (A)

Researchers working in a lab run by Peter Pedersen, a professor of biochemistry at Johns Hopkins, discovered that a compound known as 3-bromopyruvate can block energy production in cancer cells found in rats and rabbits were able to clear advanced liver cancer. (Trials of the drug have yet to begin.) At Penn, Dang and his colleagues are now trying to block multiple metabolic pathways at the same time. In mice, this two-pronged approach has been able to shrink some tumors without debilitating side effects. The goal is not to find a cure but to keep cancer at its quiet state similar to the way patients with hypertension are treated with. When glucose is blocked, the cancer cells begin to use glutamine which is another primary fuel. When both glucose and glutamine are blocked, it is possible that the cancer cells might begin to feed on fatty acids. (still to be determined)

Metformin, a widely prescribed to decrease the glucose in the blood of diabetics, is most well known to treat cancer metabolism of glucose. In the years to come, it might become a new way to treat or prevent some cancers. Since, metformin can influence a number of metabolic pathways, the precise mechanism by which it achieves its anticancer effects remains a source of debate. The results of numerous epidemiological studies have been striking. Diabetics taking metformin seem to be significantly less likely to develop cancer than diabetics who don’t — and significantly less likely to die from the disease when they do. (A)

Lewis Cantley came up with the 'insulin hypothesis' where his research lead to the discovery of how insulin influences what happens inside a cell. Insulin is released by the pancreas and signals cells when to take up glucose. The champion activators of metabolic proteins that Cantley states are linked to cancer are insulin and insulinlike growth factor 1 (aka: IGF-1). He has been seeing in some cases that insulin really is what allows for tumors to begin. Warburg effect can be viewed suggests Cantley as insulin or IGF-1 signaling pathway has gone wrong. When the cells behave as though insulin was ordering it to uptake glucose constantly and grow. His studies are now focused on the effects of diet on mice that have the mutations that are commonly found in colorectal and other cancers.(A)

Elevated insulin is also strongly associated with obesity, which is expected soon to overtake smoking as the leading cause of preventable cancer. Cancers linked to obesity and diabetes have more receptors for insulin and IGF-1, and people with defective IGF-1 receptors appear to be nearly immune to cancer. Retrospective studies, which look back at patient histories, suggest that many people who develop colorectal, pancreatic or breast cancer have elevated insulin levels before diagnosis. It’s perhaps not entirely surprising, then, that when researchers want to grow breast-cancer cells in the lab, they add insulin to the tissue culture. When they remove the insulin, the cancer cells die. (A)

There is no doubt that insulin is pro-cancer with respect to the link between obesity, diabetes, and cancer.  Watson takes metformin for cancer prevention; among its many effects, metformin works to lower insulin levels. Not every cancer researcher, however, is convinced of the role of insulin and IGF-1 in cancer. Robert Weinberg, a researcher at M.I.T.’s Whitehead Institute who pioneered the discovery of cancer-causing genes in the ’80s, has remained somewhat cool to certain aspects of the cancer-metabolism revival. Weinberg says that there isn’t yet enough evidence to know whether the levels of insulin and IGF-1 present in obese people are sufficient to trigger the Warburg effect. (A)

Links:
(A)http://www.nytimes.com/2016/05/15/magazine/warburg-effect-an-old-idea-revived-starve-cancer-to-death.html?smid=tw-nytimes&smtyp=cur&_r=0

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