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    • Our surprising results show that AAD treated tumors

    2023-11-23

    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. Tumor haspin inhibitor 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. VEGF inhibition causes vascular regression and tissue hypoxia in tumor tissues and their surrounding healthy adipose tissues. In this regard, tumors in steatotic livers and adjacent to adipose tissues would experience more hypoxia than non-adipose tumors. Indeed, our present experimental results support this notion, showing the existence of tissue hypoxia in adipose tumors. In both in vitro and in vivo experimental settings, we show that AAD-triggered hypoxia is the primary driving force for switching to the lipid-dependent metabolic reprogramming in tumor cells. FAO-committing crucial molecular components, including AMPK, are significantly upregulated, indicating activation of the FAO pathway in cancer cells in AAD-treated adipose tumors. Hypoxia might also trigger lipolysis in tumor adjacent adipose tissues that release more FFA. This interesting possibility warrants future investigation. In addition, hypoxia markedly increases expression levels of FFA uptake, transportation, and metabolism machineries in malignant cells to ensure the availability of FFA as a fuel for the FAO-committed energy production. Paradoxically, activation of FAO also requires oxygen for energy production and tissue hypoxia would be counterintuitive to this dogma. It is likely that mild and intermittent hypoxia induced by AAD still allows sufficient oxygen for fuel. We provide crucial evidence of the functional impact of FFA on cell proliferation under hypoxic conditions. Under the normoxic condition, FFA has no impact on cancer cell proliferation. Perhaps there is no need for cancer cell to utilize FFA for energy production because of the predominant glycolysis metabolic pathway (i.e., the Warburg effect). Under hypoxic conditions, however, both FFA uptake and metabolism pathways are activated and FFA is able to further stimulate cancer cell growth. Consistent with these in vitro findings, our recent work demonstrates that tumors in adipose tissues grow at exacerbated rates relative to non-adipose tissues (Lim et al., 2016). These data also imply that the FAO-committed bioenergetic pathway also significantly contributes to tumor expansion under hypoxic conditions.