The Case for the Metabolic Basis of Cancer Gains Traction

Researchers from the Huntsman Cancer Institute at the University of Utah reported an interesting finding with far-reaching implications.

In their study of the rare tumor known as alveolar soft part sarcoma (ASPS), they examined the well-established chromosomal translocation that occurs between chromosomes 17 and X. This results in the 250px-Protein_ASPSCR1_PDB_2al3production of a fusion protein dubbed ASPSCR1-TFE3. Like other fusion proteins described in malignancies such as lymphoma, acute pro-myelocytic leukemia and chronic myelogenous leukemia, a novel function occurs when two disparate genomic elements are spliced together.

In this instance, the ASPSCR1-TFE3 gene product functions as a lactate transporter. Strikingly, every mouse in which the gene was up regulated developed a tumor. The locations of tumor, in the skull and near the eye, both represented areas of high lactate concentration. In humans, this tumor occurs in skeletal muscle, also associated with high lactate production.

Since 1930, when Otto Warburg first described increased glycolysis (preferential use of sugars) in tumor cells, investigators have pondered the implication of inefficient glucose metabolism in the face of adequate oxygenation.

Human metabolism relies upon mitochondrial function to efficiently liberate the maximum amount of energy in the form of ATP from each glucose molecule. Glycolysis occurring in the cell cytoplasm is highly inefficient and produces only 1/18 of the amount of ATP that a full molecule of glucose can produce through mitochondrial oxidative phosphorylation. Recent molecular biological studies have established that the preferential use of glycolysis may represent the cells need to direct glucose away from energy production and toward the creation of essential structures like amino acids, lipids, and nucleic acids. With the rapid turnover of glucose, cells produce an overwhelming amount of lactate, which is then transported out of the cell. At least this has been the working hypothesis over many years.

More recently, investigators have begun to examine how lactate metabolism may represent the interplay between stromal fibroblast cells and tumor cells. Indeed, many tumor cells are now known to increase lactate uptake reflecting increased lactate production by fibroblasts that have been commandeered in the tumor microenvironment.

Lactate uptake is under the control of a family of transporters known as monocarboxylate transporters, of which nine have been described. These are expressed differently in various tissues, have different affinities for lactate and transport in one direction or another. These processes appear to be under the control of the major regulator of oxygen metabolism known as HIF-1 alpha. As cancer cells adapt to a high lactate environment, they can survive in low oxygen tension.

The preferential use of lactate as a source of energy is contrary to many dictates of current metabolic research that suggest that tumor cells preferentially use glucose and have limited capacity to utilize non-glucose energy sources like the ketone bodies acetoacetate and beta-hydroxybutyrate. Substantial literature on ketogenic diets suggests that these ketone bodies deprive cancer cells of needed nutrition and energy. The current discovery by the Utah investigators, as well as interesting work conducted by researchers in Italy on the prostate cancer, provide a new angle on some of these principles of cancer metabolism.

As the investigators from Utah note, the alveolar soft part sarcoma is a rare tumor, but the implications of these findings could be profound, as they force us to re-think tumorigenesis and the metabolic basis of cancer.

About Dr. Robert A. Nagourney
Dr. Nagourney received his undergraduate degree in chemistry from Boston University and his doctor of medicine at McGill University in Montreal, where he was a University Scholar. After a residency in internal medicine at the University of California, Irvine, he went on to complete fellowship training in medical oncology at Georgetown University, as well as in hematology at the Scripps Institute in La Jolla. During his fellowship at Georgetown University, Dr. Nagourney confronted aggressive malignancies for which the standard therapies remained mostly ineffective. No matter what he did, all of his patients died. While he found this “standard of care” to be unacceptable, it inspired him to return to the laboratory where he eventually developed “personalized cancer therapy.” In 1986, Dr. Nagourney, along with colleague Larry Weisenthal, MD, PhD, received a Phase I grant from a federally funded program and launched Oncotech, Inc. They began conducting experiments to prove that human tumors resistant to chemotherapeutics could be re-sensitized by pre-incubation with calcium channel blockers, glutathione depletors and protein kinase C inhibitors. The original research was a success. Oncotech grew with financial backing from investors who ultimately changed the direction of the company’s research. The changes proved untenable to Dr. Nagourney and in 1991, he left the company he co-founded. He then returned to the laboratory, and developed the Ex-vivo Analysis - Programmed Cell Death ® (EVA-PCD) test to identify the treatments that would induce programmed cell death, or “apoptosis.” He soon took a position as Director of Experimental Therapeutics at the Cancer Institute of Long Beach Memorial Medical Center. His primary research project during this time was chronic lymphocytic leukemia. He remained in this position until the basic research program funding was cut, at which time he founded Rational Therapeutics in 1995. It is here where the EVA-PCD test is used to identity the drug, combinations of drugs or targeted therapies that will kill a patient's tumor - thus providing patients with truly personalized cancer treatment plans. With the desire to change how cancer care is delivered, he became Medical Director of the Todd Cancer Institute at Long Beach Memorial in 2003. In 2008, he returned to Rational Therapeutics full time to rededicate his time and expertise to expand the research opportunities available through the laboratory. He is a frequently invited lecturer for numerous professional organizations and universities, and has served as a reviewer and on the editorial boards of several journals including Clinical Cancer Research, British Journal of Cancer, Gynecologic Oncology, Cancer Research and the Journal of Medicinal Food.

3 Responses to The Case for the Metabolic Basis of Cancer Gains Traction

  1. faith c. drummond says:

    Dr. Nagourney,

    This all sounds very interesting IF ONLY I could understand it. Is there a way to explain it to non-scientific laypersons like myself? Also, what’s the bottom line – the take home message – for those of us with advanced stage cancer (mine is ovarian) who are fortunate enough to be in remission? Thanks!

    • First and foremost, the achievement of a remission is the best of all possible news. Congratulations. Secondly, the complexity of the recent blog reflects the underlying complexity of human metabolomics(the study of metabolism at the cellular level). To clarify the take home message, these investigators showed that by changing the way an otherwise normal cell uses its foodstuffs (in this case lactate) they could change these normal cells into cancer cells. This stunning observation supports the concept of cancer as a metabolic disorder. Metabolism is the process by which (mostly glucose) is utilized to produce energy. The field of metabolomics flies face in the face of our contemporary scientific focus upon cancer as an exclusively genetic disorder, promoted most recently by a widely viewed piece on 60 minutes. Human biology is demonstrably more complex than its DNA blueprint.

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