Abstract
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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is anunrelenting form of human cancer, with no effective technique for early diagnosis or treatment, and an incidence nearly equal to mortality [1,2]
The functions of CXCR4, CXCR7 or CXCL12 in pancreatic cancer progression remain based on limited analyses without simultaneous analysis of all three chemokine signaling components in both normal and diseased tissue.Immunostaining of serial tissue sectionswith specific antibodies,revealedrobust CXCL12 staining on normal ductal epithelial cells, with those same epitheliaalso staining positive for CXCR4 and CXCR7(Fig.1A &Fig. 2A)
CXCL12 staining wasmore variable, with mixed tomarkedly decreased expression in pancreatic intestinal neoplasm (PanIN) compared to normal pancreatic ducts (Fig.2C–D)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is anunrelenting form of human cancer, with no effective technique for early diagnosis or treatment, and an incidence nearly equal to mortality [1,2]. Recent studies have determined the molecular factors involved in the progression of PDAC [5,6,7], little is known about the biologic mechanisms regulating cell motility and, in turn,metastasis. Chemotactic cytokines, or chemokines, play keyroles in cellular migration, and are capable of coordinating multiple aspects of the cell migration machinery. Through activation of their receptors, chemokinesregulate several facets of normal physiology, including leukocyte trafficking, epithelial cell migration necessary for wound closure, tissue vascularization, and organ development during embryogenesis [8,9,10]. Our lab revealedthe importance of the dual expression of the chemokine CXCL12 and its cognate receptor CXCR4 in enterocyte migration, wound healing, and angiogenesis [11,12,13,14,15,16]
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