It is now widely recognized that the tumor microenvironment promotes
cancer cell growth and
metastasis via changes in
cytokine secretion and extracellular matrix remodeling. However, the role of
tumor stromal cells in providing energy for epithelial
cancer cell growth is a newly emerging paradigm. For example, we and others have recently proposed that
tumor growth and
metastasis is related to an energy imbalance. Host cells produce energy-rich nutrients via catabolism (through autophagy, mitophagy, and aerobic glycolysis), which are then transferred to
cancer cells to fuel anabolic
tumor growth. Stromal cell-derived L-
lactate is taken up by
cancer cells and is used for mitochondrial oxidative phosphorylation (OXPHOS) to produce
ATP efficiently. However, "parasitic" energy transfer may be a more generalized mechanism in
cancer biology than previously appreciated. Two recent papers in Science and Nature Medicine now show that lipolysis in host tissues also fuels
tumor growth. These studies demonstrate that
free fatty acids produced by host cell lipolysis are re-used via beta-oxidation (beta-OX) in
cancer cell mitochondria. Thus, stromal catabolites (such as
lactate,
ketones,
glutamine and
free fatty acids) promote
tumor growth by acting as high-energy onco-metabolites. As such, host catabolism, via autophagy, mitophagy and lipolysis, may explain the pathogenesis of
cancer-associated
cachexia and provides exciting new druggable targets for novel therapeutic interventions. Taken together, these findings also suggest that
tumor cells promote their own growth and survival by behaving as a "parasitic organism." Hence, we propose the term "Parasitic
Cancer Metabolism" to describe this type of metabolic coupling in
tumors. Targeting
tumor cell mitochondria (OXPHOS and beta-OX) would effectively uncouple
tumor cells from their hosts, leading to their acute
starvation. In this context, we discuss new evidence that high-energy onco-metabolites (produced by the stroma) can confer drug resistance. Importantly, this metabolic chemo-resistance is reversed by blocking OXPHOS in
cancer cell mitochondria with drugs like
Metformin, a mitochondrial "
poison." In summary, parasitic
cancer metabolism is achieved architecturally by dividing
tumor tissue into at least two well-defined opposing "metabolic compartments:" catabolic and anabolic.