CXCL4 chemokines in tumor development

The CXCL4 paralog CXCL4L1 is a little studied chemokine that has been suggested to exert an anti-angiogenic function. However, CXCL4L1 is also expressed in patient tumors, tumor cell lines and murine xenografts, prompting a more detailed analysis of its role in cancer pathogenesis. We used genetic and antibody-based approaches to attenuate CXCL4L1 in models of pancreatic adenocarcinoma (PDAC). Mechanisms of expression were assessed in cell co-culture experiments, murine and avian xenotransplants, including through an evaluation of CpG methylation and mutation of critical CpG residues. CXCL4L1 gene expression was increased greatly in primary and metastatic PDAC. We found that myofibroblasts triggered cues in the tumor microenvironment which led to induction of CXCL4L1 in tumor cells. CXCL4L1 expression was also controlled by epigenetic modifications at critical CpG islands which were mapped. CXCL4L1 inhibited vasculogenesis but also affected tumor development more directly depending on the tumor cell type. In vivo administration of a monoclonal antibody against CXCL4L1, we demonstrated a blockade in the growth of tumors positive for CXCR3, a critical receptor for CXCL4 ligands. Our findings define a pro-tumorigenic role in PDAC development for endogenous CXCL4L1, which is independent of its anti-angiogenic function.

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