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.
Highlights
Judah Folkman’s vision of targeting the tumor neovasculature as a new modality of cancer therapeutics has inspired a series of drugs that either exclusively or primarily inhibit VEGF signaling (McIntyre and Harris, 2015; Vasudev and Reynolds, 2014; and references therein) with associated beneficial responses, representing proof of principle and new additions to the armamentarium of anti-cancer drugs
Therapeutic 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
The glucose and lactate transporters GLUT1 and MCT4 are induced in distal hypoxic cells in a HIF1a-dependent fashion, indicative of glycolysis
Summary
Judah Folkman’s vision of targeting the tumor neovasculature as a new modality of cancer therapeutics has inspired a series of drugs that either exclusively (e.g., bevacizumab) or primarily (e.g., sunitinib, axitinib, and sorafenib) inhibit VEGF signaling (McIntyre and Harris, 2015; Vasudev and Reynolds, 2014; and references therein) with associated beneficial responses, representing proof of principle and new additions to the armamentarium of anti-cancer drugs. As with many targeted therapies, clinical responses to angiogenesis inhibitors (AI) are typically limited, manifested as increased, but limited progression-free survival and variable (or no) overall survival (Vasudev and Reynolds, 2014; and references therein) Concurrent with such clinical investigations, a number of preclinical studies of AI in various mouse models of human cancer have revealed multiple forms of adaptive resistance that enable tumors to evade the effects of AI therapy (Bergers and Hanahan, 2008; Clarke and Hurwitz, 2013; Welti et al, 2013; McIntyre and Harris, 2015; Rigamonti et al, 2014; Rivera et al, 2015). The basis for treatment failure lies in part in the development of multiple forms of adaptive resistance to AIs, including revascularization mediated by alternative pro-angiogenic signaling circuits (Casanovas et al, 2005), recruitment of vascular-protective myeloid cells (Shojaei and Ferrara, 2008), and cooption of normal tissue vessels via increased invasion and metastasis (Sennino et al, 2012; Ebos and Kerbel, 2011; Ebos et al, 2009; Paez-Ribes et al, 2009)
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