Metabolic Symbiosis Enables Adaptive Resistance to Anti-angiogenic Therapy that Is Dependent on mTOR Signaling

Abstract

SummaryTherapeutic targeting of tumor angiogenesis with VEGF inhibitors results in demonstrable, but transitory efficacy in certain human tumors and mouse models of cancer, limited by unconventional forms of adaptive/evasive resistance. In one such mouse model, potent angiogenesis inhibitors elicit compartmental reorganization of cancer cells around remaining blood vessels. The glucose and lactate transporters GLUT1 and MCT4 are induced in distal hypoxic cells in a HIF1α-dependent fashion, indicative of glycolysis. Tumor cells proximal to blood vessels instead express the lactate transporter MCT1, and p-S6, the latter reflecting mTOR signaling. Normoxic cancer cells import and metabolize lactate, resulting in upregulation of mTOR signaling via glutamine metabolism enhanced by lactate catabolism. Thus, metabolic symbiosis is established in the face of angiogenesis inhibition, whereby hypoxic cancer cells import glucose and export lactate, while normoxic cells import and catabolize lactate. mTOR signaling inhibition disrupts this metabolic symbiosis, associated with upregulation of the glucose transporter GLUT2.

Metabolic Interactions in the Tumor Microenvironment

“…Similarly, acute hypoxia induced by pharmacological inhibition of angiogenesis drove pancreatic neuroendocrine cancer cells to reorganize into symbiotic networks that share glucose-derived carbon. In other words, glycolytic hypoxic cancer cells produced lactate, and this lactate was used by cancer cells in proximity to blood vessels, and thus oxygen [45]. Similar results were also observed following anti-angiogenic therapy in a breast cancer model [46].…”

“…2A). Perhaps most importantly, co-targeting this pathway with anti-angiogenesis agents and mTOR inhibitors revealed new, unique vulnerabilities in cancer metabolism, which occurred in part by activating glucose uptake in normoxic cancer cells [45]. …”

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

“…Cancers that depend on GLS2 61, 64 , which is not sensitive to BPTES or CB-839, would be unlikely to respond to therapy 174 . The expression of pyruvate carboxylase, which can provide carbon to the TCA cycle through its conversion of pyruvate to oxaloacetate, represents a potential mechanism for glutaminase independence 120,175 .…”

18F-fluoromisonidazole PET and Activity of Neoadjuvant Nintedanib in Early HER2-Negative Breast Cancer: A Window-of-Opportunity Randomized Trial

“…Recently, three simultaneous articles with breast, kidney, and neuroenocrine tumor models treated with different antiangiogenics show mixed responses as well (within the same tumor, some areas become normoxic and others hypoxic; refs. [13][14][15]. In the clinical setting, there are studies suggesting both improved (16) and worsened (17) perfusion after antiangiogenic treatment.…”