Figure 9.

The autophagic tumor stroma model of cancer: Resolving the autophagy paradox in cancer therapy. Here, we propose that autophagy/mitophagy (AM) in the tumor stroma may be sustaining tumor growth. The large black arrow signifies energy transfer (E.T.) from the stromal cancer associated fibroblasts (CAFs) to the epithelial cancer cells, via stromal autophagy/mitophagy. Thus, inhibition of autophagy in the tumor stroma would be expected to halt or reverse tumor growth. This could explain the effectiveness of known autophagy inhibitors as anti-tumor agents,⁵² such as chloroquine and 3-methyladenine (Upper part). Conversely, induction of autophagy in epithelial cancer cells would also be expected to block or inhibit tumor growth (Lower part). This idea would also explain the anti-tumor activity of agents that activate autophagy, such as mTOR inhibitors.⁶⁵ Thus, using this model, compounds that either systemically block or activate autophagy would both have the same net effect, which is to disrupt the metabolic coupling between the epithelial cancer cells and the tumor stromal fibroblasts. This model directly resolves the long-lived “autophagy paradox”, that both systemic inhibition of autophagy and systemic stimulation of autophagy have the same net effect, which is to inhibit tumor growth. E.T., energy transfer; AM⁺, increased autophagy/mitophagy; AM⁻, decreased autophagy/mitophagy; Rx, therapy with autophagy promoters or inhibitors.