Emerging Interest in Metabolic Pathways to Tumorigenesis

A Conversation With Ralph DeBerardinis, MD, PhD, and Thomas N. Seyfried, PhD

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Ralph DeBerardinis, MD, PhD

Ralph DeBerardinis, MD, PhD

Thomas N. Seyfried, PhD

Thomas N. Seyfried, PhD

Although genetic aberrations are considered a major reason for cancer development, the importance of metabolic alterations in cancer development has emerged as a crucial aspect of contemporary cancer research. Better understanding of the metabolic traits in cancer cells could aid researchers in identifying novel molecular targets, leading to more effective strategies in the management of cancer. To shed light on this emerging line of inquiry, The ASCO Post spoke with two researchers in the field of cancer metabolism: Ralph DeBerardinis, MD, PhD, Chief, Division of Pediatric Genetics and Metabolism, UT Southwestern Medical Center; and Thomas N. Seyfried, PhD, Professor of Biology, Boston College.

Glucose Deprivation and Cancer

Please describe how cancer cells adjust to glucose deprivation.

Dr. DeBerardinis: Cancer cells, like many nonmalignant cells, can use a number of different fuels to generate energy and biosynthetic precursors for growth. Glucose is abundant and feeds many essential pathways in cancer cells and seems to be the preferred fuel in some contexts. However, many cancer cells adapt to low-glucose conditions by consuming alternative fuels such as fatty acids, amino acids, and lactate. Metabolic flexibility may help explain why we haven’t had much success yet in targeting glucose metabolism in cancer. We clearly need to understand more about how cells adapt to glucose deprivation and which cancer cells prefer other fuels even when glucose is present.

Oxidative Stress

What role does oxidative stress play in tumorigenesis?

Dr. DeBerardinis: Oxidative stress plays a number of roles in tumorigenesis. There is good evidence that high levels of oxidative stress are mutagenic and may promote tumor initiation. In established tumors, though, oxidative stress seems to impose a barrier on tumor progression.

In mouse models of melanoma, for example, oxidative stress limits the ability of individual cancer cells to form distant metastases; in these models, treating mice with antioxidants enhances metastasis. This area of cancer metabolism needs more study because we don’t fully understand the underlying mechanisms.

Targeting Metabolic Activities

Are we looking at ways to target tumor cell mitochondria that would effectively uncouple tumor cells from their hosts, leading to their acute starvation?

Dr. DeBerardinis: We would love to do this, but so far, many of the metabolic activities the field has been trying to target are also active in normal tissues. We are constantly looking for metabolic activities with an elevated importance in malignant cells, either because their activities are activated by oncogenic signaling or because pathways that consume alternative fuels have been suppressed. We are using intraoperative infusions with isotope-labeled nutrients such as [13C]glucose to compare metabolic pathways between intact human tumors and adjacent benign tissue. We believe this approach gives us the best opportunity to develop an accurate view of cancer metabolism in its native context.

Fermentation Pathways

The shift from respiration to fermentation is a common metabolic hallmark of cancer. Could you briefly explain how this shift drives the dysregulated growth of tumors?

Dr. Seyfried: Differentiated cells do not proliferate because they are under active control, coming largely from mitochondria-linked metabolic homeostasis. During cancer formation, a variety of insults negatively impact the structure and function of the mitochondria, causing a gradual shift to fermentation metabolism. This shift can happen by actions of many provocative agents such as chemical carcinogens, inherited mutations, and inflammation. Chronic exposure to any of these agents can alter mitochondrial function. Based on the biologic principle that mitochondrial structure determines mitochondrial function, these abnormalities compromise effective energy production through OxPhos. Fermentation metabolism becomes necessary to compensate for the OxPhos deficiency.

If the mitochondrial damage is acute, the cell dies from catrostrophic energy failure. However, during a gradual insult, the impaired mitochondria signal the nucleus to upregulate oncogenes, which are transcription factors for glucose and glutamine fermentation pathways. New information shows that besides glucose, glutamine can serve as a fuel for mitochondrial substrate level phosphorylation (mSLP)—another fermentation mechanism called the Warburg Q-Effect. Using glutamine as a major substrate, mSLP is now recognized as the missing link in Warburg’s central theory that aerobic fermentation compensates for dysfunctional respiration in cancer. The dysregulated growth of cancer cells is nothing more than the cell falling back on its default state of unbridled proliferation fueled by fermentation metabolism.

Somatic Mutation Theory

The theory that mitochondrial damage is a significant factor in tumorigenesis remains controversial. Are there emerging data to support this theory?

Dr. Seyfried: Most current research centers on the prevailing somatic mutation theory: Cancer is a genetic disease involving nuclear mutations in oncogenes and tumor-suppressor genes. Tumors contain two to eight driver gene mutations that control the tumorigenic phenotype.

However, there are inconsistencies with the somatic nuclear gene theory of cancer demonstrated by numerous nuclear cytoplasmic transfer experiments between tumorigenic and nontumorigenic cells. Many renowned investigators have shown that tumorigenicity is suppressed when cytoplasm from nontumorigenic cells, containing normal mitochondria, is combined with nuclei from tumor cells.

Despite the fact that the investigators used different tumor models and experimental designs, they came to a similar conclusion: Normal cytoplasm containing normal mitochondria suppresses tumorigenesis, and mitochondria that are defective enhance tumorigenesis. The results were exactly the opposite of what was expected: The cell with a normal cytoplasm and a cancerous nucleus was normal; the cell with a normal nucleus and a cancerous cytoplasm was cancerous.

Moreover, damage to the nuclear DNA, typically thought to be a root cause of cancer, is actually an effect of the damaged mitochondria and irregular metabolism. The metabolic waste products of fermentation can destabilize the morphogenetic field of the tumor microenvironment and contribute to inflammation, angiogenesis, and disease progression. Given that mitochondria play a central role in tumorigenesis, targeting mitochondrial fermentation together with cytoplasmic fermentation provides therapeutic opportunities. 

DISCLOSURE: Dr. DeBerardinis is an advisor for Agios Pharmaceuticals. Dr. Seyfried reported no conflicts of interest.