Increased expression of Cyr61 (CCN1) identified in peritoneal metastases from human pancreatic cancer

BACKGROUND: Identification Identification of extracellular matrix proteins (ECM) associated with tumor cell metastasis may generate targets for future therapy against pancreatic cancer metastases. We hypothesized that comparison of ECM-associated gene expression in primary and metastatic pancreatic tumors would identify ECM proteins associated with pancreatic metastasis. STUDY DESIGN: A clinically relevant model of pancreatic cancer was used to generate RNA from primary and metastatic tumors; it was evaluated by microarray analysis with subsequent cluster analysis. Target genes (Cyr61 and integrins α_v and β₃) identified by microarray analysis were confirmed by reverse transcription polymerase chain reaction and immunohistochemistry analysis. RESULTS: Peritoneal metastases at sites distant from the primary tumor were present in all animals bearing orthotopic tumors. High-density microarray comparison of gene expression in metastases versus primary pancreatic tumors identified a greater than twofold increase in the expression of Cyr61, a secreted matricellular protein that binds to integrins. Reverse transcription polymerase chain reaction confirmed the microarray results, and immunohistochemistry analysis demonstrated increased Cyr61 protein and persistent α_vβ₃ expression in peritioneal metastases. Additionally, immunohistochemistry demonstrated increased collocalization of Cyr61 and α_v in metastases relative to primary tumor. CONCLUSIONS: The ECM protein Cyr61 shows increased expression in metastatic lesions in a clinically relevant model of pancreatic adenocarcinoma. Protein analysis confirms the microarray results and collocalization of Cyr61, and α_v suggests that interaction between Cyr61 and α_vβ₃ promotes formation of peritoneal metastases.