Abstract 5378: Targeting CXCL12/CXCR4 signaling axis for pancreatic cancer therapy

Abstract

Abstract Pancreatic cancer is a lethal malignancy with an extremely poor prognosis. Furthermore, it is also highly resistant to currently available therapeutic modalities. Hence, it is very important to better understand the drug-resistance mechanisms and to develop novel and effective therapeutic strategies. Chemokine signaling has been shown to play an important role in cancer progression and metastasis. Importantly, a chemokine receptor, CXCR4, has been shown to be expressed in pancreatic cancer tissues, precancerous lesions, and cancer stem cells. CXCR4 signaling induced by binding to its ligand (CXCL12) potentiates pancreatic tumor cell growth, migration and invasion, and distant metastasis in an autocrine and/or paracrine fashion. CXCL12/CXCR4 signaling has also been shown to facilitate the tumor-microenvironment interaction and induce desmoplastic alterations in the stroma, which is a common feature of pancreatic adenocarcinoma. Therefore, targeting CXCR4, alone or in combination with cytotoxic drug, might be an effective strategy for pancreatic cancer therapy. Here, we examined the expression of CXCR4 in a panel of twelve pancreatic cancer cell lines and pancreatic cancer tissues. Our data document that CXCR4 is expressed by all pancreatic cancer cell lines and overexpressed in pancreatic cancer tissues as compared to corresponding normal pancreas. Furthermore, treatment with CXCL12 induced the growth of pancreatic cancer cells, indicating the functionality of the CXCL12/CXCR4 signaling axis and suggesting its potential suitability as a therapeutic target. Interestingly, pancreatic cancer cells treated with CXCL12 showed reduced cytotoxicity to the cytotoxic drug 5-fluoro-uracil (5-FU) as compared to cells treated with drug alone. Treatment with CXCR4 antagonist, AMD3100, arrested the CXCL12-induced pancreatic cancer cell growth, and resulted in a cooperative growth inhibitory effect with 5-FU treatment. Taken together, our findings suggest that targeting of CXCL12/CXCR4 signaling axis can be exploited as a novel and effective approach for pancreatic cancer therapy, alone or in combination with cytotoxic chemotherapeutic agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5378.