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

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Abstract
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. 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 αv and β3) identified by microarray analysis were confirmed by reverse transcription polymerase chain reaction and immunohistochemistry analysis. 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 αvβ3 expression in peritioneal metastases. Additionally, immunohistochemistry demonstrated increased collocalization of Cyr61 and αv in metastases relative to primary tumor. 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 αv suggests that interaction between Cyr61 and αvβ3 promotes formation of peritoneal metastases.