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 production 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.

Cancer as a Metabolic Disorder

I received an inquiry via Twitter “Has anyone thought about using a sugar medium (similar to PET scans) to deliver chemo drugs?”

Although no one would use PET scans nor the PET reagents as therapy, the question is actually profound. There is a growing recognition that cancer is not a genetic disease but instead a metabolic disorder. One could not attend a lecture at the American Association of Cancer Research without there being reference to Otto Warburg’s 1956 paper “On the Origin of Cancer Cells” that described the metabolic basis of human malignancy.

Despite our myopic focus on cancer genomics, there is a growing recognition that cancer represents dysregulated energy metabolism. The high utilization of glucose, a hallmark of malignantly transformed cells, (and the target of PET scan diagnostics), in part reflects the process of aerobic glycolysis, whereby cells provided ample oxygen nonetheless eschew the efficiency of mitochondrial oxidative phosphorylation in favor of seemingly inefficient lactate production.

Into this new realm of biochemically driven developments, a growing number of therapeutic agents that target glucose metabolism are finding their way into the clinic. To the dismay of some, the mutations that our molecular biologists identify are increasingly found to represent intermediates of cellular metabolism, forcing many to go back to relearn biochemistry. Thus, the avidity for glucose represented by uptake of the PET scan reagent F18 fluorodeoxyglucose by tumor cells, is a diagnostic application of what, in the future, may provide meaningful therapeutic opportunities.

Looking Forward to TEDxSoCal

I remember my first recollection of the TED (Technology Entertainment Design) conferences, which have been held annually for almost two decades. Drawing together innovators in a broad spectrum of disciplines, these programs have become an institution unto themselves. With invited speakers ranging from Harvard’s Edward O. Wilson to business leaders, like Microsoft’s Bill Gates, the lectures cover a panoply of interesting topics.

It was with a sense of delight that I received an invitation to speak at the TEDxSoCal conference on July 16 at the Long Beach Terrace Theater. As the date approaches, I am looking forward to the event with great anticipation. Since the event is sold out, I understand I’ll have 800 attendees in the audience.

What an interesting opportunity to engage this group in a discussion of cancer biology with our focus on biochemistry and metabolism. This is timely in the context of Gina Kolata’s recent article in the New York Times on the failures of genomics platforms in the field of functional profiling for cancer treatment.

I will report next week on this experience.