Nerves are important pathological elements of the microenvironment of tumors, including those in pancreatic, colon and rectal, prostate, head and neck, and breast cancers. Recent studies have associated perineural invasion with tumor progression and poor outcomes. In turn, tumors drive the reprogramming of neurons to recruit new nerve fibers. Therefore, the crosstalk between nerves and tumors is the hot topic and trend in current cancer investigations. Herein, we reviewed recent studies presenting direct supporting evidences for a better understanding of nerve–tumor interactions.
Background Adipose tissue remodeling plays a significant role in obesity-induced insulin resistance. Published studies reported that level of trigger receptor expressed on myeloid cells 2 (TREM2) in adipose tissue is up-regulated in animal models of obesity. This study aims to investigate whether TREM2 regulates obesity-induced insulin resistance via modulating adipose tissue remodeling in mice of high-fat diet (HFD). Methods Wild-type (WT) and TREM2 −/− mice were both fed with a controlled-fat diet (CFD) or HFD for 12 weeks and studied for obesity and insulin resistance. Meanwhile, epididymal adipose tissue (EAT) was examined for morphological and pathological changes to determine adipose tissue remodeling. After that, adipocyte-derived MCP-1 was measured in adipocytes, adipose tissue and circulation. Next, inflammatory cytokines were determined in adipose tissue macrophages (ATM). At last, livers were analyzed for hepatic steatosis. Results TREM2 −/− mice on HFD had increased obesity and insulin resistance compared with WT counterparts. Adipose tissue from TREM2 −/− mice exhibited reduced mass but greater adipocyte hypertrophy and increased adipocyte death. Besides, adipocyte-derived MCP-1 was down-regulated in TREM2 −/− mice, and circulating MCP-1 level was lower than that of WT mice. Furthermore, TREM2 −/− mice displayed reduced infiltration of F4/80 + CD11c + macrophages into adipose tissue, which was unable to form crown-like structures (CLS) to clean dead adipocytes and cellular contents. Also, TREM2 deficiency augmented inflammatory response of adipose tissue macrophages in HFD mice. In addition, TREM2 −/− mice demonstrated more severe hepatic steatosis than WT counterparts under HFD feeding. Conclusions Trigger receptor expressed on myeloid cells 2 may function as a feedback mechanism to curb obesity-induced insulin resistance via regulating adipose tissue remodeling.
Background Sunitinib resistance can be classified into primary and secondary resistance. While accumulating research has indicated several underlying factors contributing to sunitinib resistance, the precise mechanisms in renal cell carcinoma are still unclear. Methods RNA sequencing and m6A sequencing were used to screen for functional genes involved in sunitinib resistance. In vitro and in vivo experiments were carried out and patient samples and clinical information were obtained for clinical analysis. Results We identified a tumor necrosis factor receptor-associated factor, TRAF1, that was significantly increased in sunitinib-resistant cells, resistant cell-derived xenograft (CDX-R) models and clinical patients with sunitinib resistance. Silencing TRAF1 increased sunitinib-induced apoptotic and antiangiogenic effects. Mechanistically, the upregulated level of TRAF1 in sunitinib-resistant cells was derived from increased TRAF1 RNA stability, which was caused by an increased level of N6-methyladenosine (m6A) in a METTL14-dependent manner. Moreover, in vivo adeno-associated virus 9 (AAV9) -mediated transduction of TRAF1 suppressed the sunitinib-induced apoptotic and antiangiogenic effects in the CDX models, whereas knockdown of TRAF1 effectively resensitized the sunitinib-resistant CDXs to sunitinib treatment. Conclusions Overexpression of TRAF1 promotes sunitinib resistance by modulating apoptotic and angiogenic pathways in a METTL14-dependent manner. Targeting TRAF1 and its pathways may be a novel pharmaceutical intervention for sunitinib-treated patients.
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