The role of autophagy in
tumorigenesis is controversial. Both autophagy inhibitors (
chloroquine) and autophagy promoters (
rapamycin) block
tumorigenesis by unknown mechanism(s). This is called the "Autophagy Paradox". We have recently reported a simple
solution to this paradox. We demonstrated that epithelial
cancer cells use oxidative stress to induce autophagy in the tumor microenvironment. As a consequence, the autophagic
tumor stroma generates recycled nutrients that can then be used as chemical building blocks by anabolic epithelial
cancer cells. This model results in a net energy transfer from the
tumor stroma to epithelial
cancer cells (an energy imbalance), thereby promoting
tumor growth. This net energy transfer is both unilateral and vectorial, from the
tumor stroma to the epithelial
cancer cells, representing a true host-parasite relationship. We have termed this new paradigm "The Autophagic
Tumor Stroma Model of
Cancer Cell Metabolism" or "Battery-Operated
Tumor Growth". In this sense, autophagy in the
tumor stroma serves as a "battery" to fuel
tumor growth, progression and
metastasis, independently of angiogenesis. Using this model, the systemic induction of autophagy will prevent epithelial
cancer cells from using recycled nutrients, while the systemic inhibiton of autophagy will prevent stromal cells from producing recycled nutrients-both effectively "starving"
cancer cells. We discuss the idea that
tumor cells could become resistant to the systemic induction of autophagy, by the upregulation of natural endogenous autophagy inhibitors in
cancer cells. Alternatively,
tumor cells could also become resistant to the systemic induction of autophagy, by the genetic silencing/deletion of pro-autophagic molecules, such as
Beclin1. If autophagy resistance develops in
cancer cells, then the systemic inhibition of autophagy would provide a therapeutic
solution to this type of drug resistance, as it would still target autophagy in the
tumor stroma. As such, an anti-
cancer therapy that combines the alternating use of both autophagy promoters and autophagy inhibitors would be expected to prevent the onset of drug resistance. We also discuss why anti-angiogenic
therapy has been found to promote
tumor recurrence, progression and
metastasis. More specifically, anti-angiogenic
therapy would induce autophagy in the
tumor stroma via the induction of stromal
hypoxia, thereby converting a non-aggressive
tumor type to a "lethal" aggressive
tumor phenotype. Thus, uncoupling the metabolic parasitic relationship between
cancer cells and an autophagic
tumor stroma may hold great promise for anti-
cancer therapy. Finally, we believe that autophagy in the
tumor stroma is the local microscopic counterpart of systemic wasting (
cancer-associated
cachexia), which is associated with advanced and metastatic
cancers.
Cachexia in
cancer patients is not due to decreased energy intake, but instead involves an increased basal metabolic rate and increased energy expenditures, resulting in a negative energy balance. Importantly, when
tumors were surgically excised, this increased metabolic rate returned to normal levels. This view of
cachexia, resulting in energy transfer to the
tumor, is consistent with our hypothesis. So,
cancer-associated
cachexia may start locally as stromal autophagy, and then spread systemically. As such, stromal autophagy may be the requisite precursor of systemic
cancer-associated
cachexia.