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The aggressive nature and metastatic potential of pancreatic cancer (PC) results in poor prognosis and high mortality. A better understanding of the underlying biology of PC and the ability of tumor cells to spread to distant sites is needed to advance the treatment of PC. The chemokine receptor CXCR4 has been heavily implicated in the spread and mobility of many solid cancers based on its role in cancer cell chemotaxis as well as increased metastatic potential. To better elucidate CXCR4's role in the metastatic spread of PC, we examined its expression on various tumor associated cells (TACs) in the peripheral blood of PC patients, including circulating tumor cells (CTCs), epithelial to mesenchymal transition cells (EMTs), and cancer associated macrophage-like cells (CAMLs). In this pilot study, blood samples were procured from 30 PC patients prior to the start of therapeutic intent. CXCR4 expression was analyzed on TACs captured from the blood samples and evaluated in relation to cell migration as well as patient clinical outcomes. In total, CTCs, EMTs, and CAMLs were found in 27%, 60%, and 97% of PC patients, respectively. High CXCR4 expression in CTCs, CAMLs, and EMTs was found to significantly relate to their increased numbers in circulation. Further, higher expression of CXCR4 in CAMLs and EMTs was significantly related to faster progression and worse survival. These data suggest that CXCR4 expression in PC is strongly related to the intravasation and presence of TACs into circulation, as well as being a possible biomarker for aggressive metastatic disease. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma is an unsolved health problem with nearly 75% of patients diagnosed with advanced disease and an overall 5-year survival rate near 5%. Despite the strong link between mortality and malignancy, the mechanisms behind pancreatic cancer dissemination and metastasis are poorly understood. Correlative pathological and cell culture analyses suggest the chemokine receptor CXCR4 plays a biological role in pancreatic cancer progression. In vivo roles for the CXCR4 ligand CXCL12 in pancreatic cancer malignancy were investigated. CXCR4 and CXCR7 were consistently expressed in normal and cancerous pancreatic ductal epithelium, established cell lines, and patient-derived primary cancer cells. Relative to healthy exocrine ducts, CXCL12 expression was pathologically repressed in pancreatic cancer tissue specimens and patient-derived cell lines. To test the functional consequences of CXCL12 silencing, pancreatic cancer cell lines stably expressingthe chemokine were engineered. Consistent with a role for CXCL12 as a tumor suppressor, cells producing the chemokine wereincreasingly adherent and migration deficient in vitro and poorly metastatic in vivo, compared to control cells. Further, CXCL12 reintroduction significantly reduced tumor growth in vitro, with significantly smaller tumors in vivo, leading to a pronounced survival advantage in a preclinical model. Together, these data demonstrate a functional tumor suppressive role for the normal expression of CXCL12 in pancreatic ducts, regulating both tumor growth andcellulardissemination to metastatic sites. [ABSTRACT FROM AUTHOR]