[Show abstract][Hide abstract] ABSTRACT: The RON receptor tyrosine kinase is overexpressed in premalignant pancreatic intraepithelial neoplasia (PanIN) and in the majority of pancreatic cancers. In pancreatic cells, RON is an important K-Ras effector and RON ligand can enhance migration/invasion and apoptotic resistance. However, the pathobiological significance of RON overexpression in pancreatic cancers has yet to be fully established. In this study, we demonstrate that RON signaling mediates a unique transcriptional program that is conserved between cultured cells derived from murine PanIN or human pancreatic cancer cells grown as subcutaneous tumor xenografts. In both systems, RON signaling regulates expression of genes implicated in cancer-cell survival, including Bcl-2 and the transcription factors signal transducer and activator of transcription 3 (STAT 3) and c-Jun. shRNA-mediated silencing of RON in pancreatic cancer xenografts inhibited their growth, primarily by increasing susceptibility to apoptosis and by sensitizing them to gemcitabine treatment. Escape from RON silencing was associated with re-expression of RON and/or expression of phosphorylated forms of the related c-Met or epidermal growth factor receptors. These findings indicate that RON signaling mediates cell survival and in vivo resistance to gemcitabine in pancreatic cancer, and they reveal mechanisms through which pancreatic cancer cells may circumvent RON-directed therapies.
Cancer Research 02/2010; 70(3):1130-40. DOI:10.1158/0008-5472.CAN-09-0761 · 9.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: High levels of vascular endothelial growth factor (VEGF) in ovarian cancer metastases are associated with a worse prognosis in patients treated with chemotherapy. VEGF-directed therapy improves survival for those with metastatic colorectal cancer. Patients with mucinous adenocarcinomas metastatic to the peritoneal surfaces can be treated with cytoreductive surgery, and both tumor grade and cytoreduction status are prognostic. We hypothesized that angiogenic indices may be prognostic in patients undergoing cytoreductive surgery for mucinous adenocarcinoma of the appendix and colon.
Cytoreductive cases from a 5-year period from the University of Cincinnati peritoneal malignancy database were reviewed. CD 34 counts (blood vessels) and VEGF expression was evaluated by means of immunohistochemistry on specimens from patients undergoing cytoreductive surgery and intraperitoneal hyperthermic perfusion (IPHP) for mucinous adenocarcinoma.
A total of 26 males and 9 females, with a mean age of 50 years, underwent cytoreductive surgery and IPHP for mucinous adenocarcinoma of appendiceal (n = 32) or colonic (n = 3) origin. With a mean follow-up of 18 months (range 1-63 months), 23 had disease recurrence and 12 were alive without recurrence. The mean survival was 19 months (range 1-63 months). CD34 counts did not correlate with recurrence or survival; however, average VEGF counts correlated with survival (P = 0.017), and, for patients with recurrence, this correlation was stronger (P = 0.002).
These results suggest that markers of tumor angiogenesis may predict survival in patients with peritoneal surface metastases from mucinous adenocarcinoma. These findings provoke the hypothesis that antiangiogenic therapies may be effective in patients with this devastating disease.