The autophagic tumor stroma model of cancer or “battery-operated tumor growth”

Abstract

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...

Cancer cells metabolically "fertilize" the tumor microenvironment with hydrogen peroxide, driving the Warburg effect

“…[22][23][24][25][26][27] Thus, this type of metabolism (aerobic glycolysis and autophagy in the tumor stroma) is characteristic of a lethal tumor micro-environment, as it fuels anabolic growth in cancer cells, via the production of high-energy nutrients (such as lactate, ketones and glutamine) and other chemical building blocks (fatty acids, nucleotides, amino acids). 4,11,40 Interestingly, we show here that the upstream tumor-initiating event appears to be the secretion of hydrogen peroxide by MCF7 cancer cells under co-culture conditions. This effectively shifts oxidative stress from cancer cells to adjacent stromal fibroblasts, essentially driving autophagy/mitophagy and aerobic glycolysis in tumor stroma.…”

Mitochondrial dysfunction in breast cancer cells prevents tumor growth

“…18,19 Relative to the tumor stroma and normal adjacent ReseaRCh papeR RepORT Cancer-associated fibroblasts, which suffer from oxidative stress, then undergo a variety of catabolic processes to produce mitochondrial fuels in order to feed cancer cells. 15,16,[23][24][25][26] These catabolic cellular programs include autophagy, mitophagy and aerobic glycolysis. Cellular catabolism in the tumor microenvironment induces stromal mitochondrial dysfunction, driving the production of high-energy mitochondrial fuels, such as L-lactate, ketone bodies, glutamine and free fatty acids.…”

“…Cellular catabolism in the tumor microenvironment induces stromal mitochondrial dysfunction, driving the production of high-energy mitochondrial fuels, such as L-lactate, ketone bodies, glutamine and free fatty acids. 15,16,[23][24][25][26] Thus, cancer cells functionally behave as metabolic "parasites," by removing energy from their local environment, via a simple energy-transfer mechanism. 15 Here, to further address the relevance of mitochondrial dysfunction in tumorigenesis, we used a molecular genetic approach.…”

MicroRNA

“…These miRNAs are associated with oxidative stress response and activation of autophagy through HIF1α, promoting cancer cell survival. 37,38 miR-34 has also been implicated in the response to DNA damage through both p53-dependent and -independent mechanisms. 39 Much like the role of autophagy in cancer development, the role that miRNAs play in cancer development and suppresses autophagy induced by etoposide or rapamycin in breast cancer cells.…”