Tumor tissues often experience hypoxia owing
Tumor tissues often experience hypoxia owing to accelerated growth rates of malignant cells, accumulation of metabolic products, disorganization of tumor blood vessels, and high interstitial fluid pressures (Makino et al., 2001). In response to AAD treatment, tumor vascular density often decreases to an extremely low level, creating an elevated hypoxic environment (Rapisarda and Melillo, 2012). It is known that tumor hypoxia can exacerbate expression levels of growth factors and cytokines, which circumvent the drug targets and create possible resistance (Casanovas et al., 2005). Hypoxia may also change the composition of various cell types within the tumor microenvironment (TME), leading to alteration of cancer invasiveness and drug responses (Cao et al., 2009).
Unlike most healthy cells, cancer cells exhibit distinctive features of uncontrolled cell proliferation (Hanahan and Weinberg, 2011). To cope with the unlimited growth, expansion, and dissemination, cancer cells must efficiently produce energy, even in poorly oxygenated and nutrient-scarce microenvironments (Beloribi-Djefaflia et al., 2016). Cancer cells show exacerbated glucose uptake and glycolysis-dependent metabolism (i.e., the Warburg effect; Warburg, 1956). In addition, malignant cells also rely on glutamine consumption to obtain carbon, amino-nitrogen for producing nucleotides, amino acids, and lipid biosynthesis. Recent studies show that highly proliferative cancer cells have lipogenic activity by uptake of exogenous lipids and activating endogenous lipid biosynthesis (Beloribi-Djefaflia et al., 2016). Utilization of exogenous free fatty acids (FFAs) for energy production through the fatty Azaserine synthesis oxidation (FAO) metabolic pathway is prominent in non-glycolytic cancers such as prostate cancer and B cell lymphoma (Caro et al., 2012, Liu et al., 2010). Several lipogenic enzymes, including acetyl coenzyme A carboxylase and fatty acid synthase (FASN), are often increased in invasive tumors and their expression levels correlate with poor prognosis (Kuhajda, 2006). The FAO-limiting enzyme, CPT1 (A and C types), is often overexpressed in many human tumors (Reilly and Mak, 2012). It is known that adipose tissue and FFA significantly contribute to cancer cell survival, proliferation, and migration (Lazar et al., 2016, Nieman et al., 2011). Previously published work also showed that anti-VEGF treatment and tissue hypoxia increase lipid transport and storage through an HIF-1α-dependent mechanism in cancer cells (Bensaad et al., 2014).
Discussion Drug resistance poses the greatest hurdle of achieving high efficacy with AADs in cancer patients. AAD-treated cancer patients often encounter intrinsic and evasive drug resistance that diminishes the therapeutic efficacy to only minor survival benefits in most cancer types. Despite this known clinical fact, molecular mechanisms that underlie AAD resistance are largely unknown. Most studies devote their efforts to compensative mechanisms (i.e., drug-induced switch to angiogenic signaling pathways that are not targeted by original drugs; Cao and Langer, 2010). However, AADs targeting multiple angiogenic signaling pathways, including tyrosine kinase inhibitors, may not necessarily produce greater beneficial effects compared with monospecific drugs such as bevacizumab (Kerbel, 2008). In addition, targeting multiple signaling pathways markedly increases toxicity profiles in cancer patients and thus is less desirable for clinical practice (Bretagne et al., 2016). These clinical findings suggest the existence of alternative mechanisms of AAD resistance in cancer patients. One of the most surprising findings of our present study is that the antiangiogenic effect by AADs is uncoupled from tumor growth in tissues adjacent to adipose depots and in fatty liver. According to the gold-standard principles, solid tumor growth is dependent on angiogenesis (Folkman, 1971) and drug-triggered antiangiogenic effects should be correlated with the degree of tumor suppression. In both adipose tissue- and steatotic liver-implanted tumor models, we show that treatments with anti-VEGF-based AADs display marked antiangiogenic effects that are virtually indistinguishable from AAD-treated non-adipose tumors. What are the alternative mechanisms compensating energy supply in vascular depleted tumors? Under pathophysiological conditions, tumors show exacerbated glucose uptake and glycolysis-dependent metabolism for their growth and expansion, the celebrated Warburg effect (Warburg, 1956). The source of glucose supply is mainly from the circulation, and suppression of tumor angiogenesis severely depletes glucose supply (Nardo et al., 2011). Without sufficient glucose supply, tumors would starve and be unable to sustain their uncontrollable growth.