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  • br Results br Discussion Drug resistance poses

    2019-09-19


    Results
    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 amanitin 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. Our surprising results show that AAD-treated tumors adjacent to adipose tissues and in steatotic liver continue to grow in the presence of a minimal number of microvessels. In non-adipose tumor models, the similar degree of vascular suppression is translated into marked suppression of tumor growth. The anti-cancer resistance, but not antiangiogenesis resistance, poses challenges of the classic dogma of angiogenesis-dependent tumor growth. Perhaps, this concept should be revised in line with a host tissue context-dependent paradigm. What then would be the reasons to make tumors become resistant in relation to the adipose environment? To tackle this issue, both malignant cell intrinsic properties and tissue/organ environmental factors should be taken into consideration. amanitin Tumor cells have the intrinsic properties of genome instability, heterogeneity of cellular populations, and high rates of glycolysis-dependent metabolism under aerobic conditions. The relentless genetic alterations of malignant cells determine their intrinsic abilities of switching signaling and metabolic pathways (Beloribi-Djefaflia et al., 2016). Adipose tissues are highly vascularized and contain an exceptionally high number of microvessels that essentially engulf each adipocyte (Cao, 2007, Cao, 2010, Cao, 2013). Moreover, recent work from our laboratory and others shows that maintenance of microvascular density and integrity in WAT is largely dependent on VEGF (Honek et al., 2014, Kamba et al., 2006, Yang et al., 2013b). Particularly, the sinusoidal hepatic microvessels are dependent on VEGF for survival and structural integrity (Yang et al., 2013b, Yang et al., 2016). It is plausible that elevated inflammation may play an important role in modulating tumor growth. However, several lines of experimental evidence largely exclude this possibility in our current experimental settings. These include (1) the total inflammatory cell populations in steatotic and non-steatotic livers remain indistinguishable; (2) inflammatory cell numbers in subcutaneous tumors of lean and HFD-induced mice were the same; (3) ablation of inflammatory cells by pharmacological treatment with clodronate did not significantly affect tumor growth in non-adipose and adipose environments; and (4) treatment with a CPT1 inhibitor potentiated anti-tumor effects of anti-VEGF drugs without affecting inflammation. It seems that infiltration of inflammatory cells in tumors mainly contribute to cancer invasion and metastasis without significantly impairing tumor growth. In supporting this view, several independent studies show that tumor-associated inflammatory cells stimulate cancer metastasis without affecting primary tumor growth (Lin et al., 2001, Qian et al., 2015). A recent retrospective meta-analysis study shows that patients with chronically diseased livers, including fatty liver, have lower incidences of colorectal liver metastases (Cai et al., 2014). At this time of writing, the molecular mechanism underlying this interesting clinical phenomenon is unclear.