This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Marchesi, F. Articles by Allavena, P. Search for Related Content PubMed PubMed Citation Articles by Marchesi, F. Articles by Allavena, P.

Increased Survival, Proliferation, and Migration in Metastatic Human Pancreatic Tumor Cells Expressing Functional CXCR4

¹ Department of Immunology and Cell Biology, "Mario Negri" Institute, Milan; ² Telethon-Juvenile Diabetes Research Foundation Center for Cell Replacement, San Raffaele Scientific Institute, Milan; ³ Department of Surgery, University of Milano-Bicocca, Milan; and ⁴ Centro IDET, Institute of General Pathology, University of Milan, Milan, Italy

In this study, we have evaluated 11 pancreatic tumor cell lines and tumor cells from surgical samples of patients with pancreatic adenocarcinoma for expression of the chemokine receptor CXCR4. Six of 11 cell lines expressed detectable mRNA of CXCR4, with three cell lines (AsPC1, Capan1, and Hs766T) having substantial amounts of transcripts. Expression was higher in lines derived from metastatic lesions compared with those derived from primary tumors. Different inflammatory cytokines did not modify expression, whereas IFN- down-regulated and hypoxia up-regulated CXCR4 transcripts. Transcript expression was associated with surface expression in pancreatic carcinoma cell lines. All surgical carcinoma samples tested expressed higher levels of CXCR4 than normal pancreatic ducts, which were used as reference tissue. The chemokine CXCL12 induced chemotaxis in CXCR4-positive pancreatic carcinoma cell lines, which was inhibited by anti-CXCR4 monoclonal antibody and by the antagonist AMD3100. Transendothelial migration, Matrigel invasion, and activation of matrix metalloproteases were also enhanced by CXCL12. In CXCR4-positive cell lines, CXCL12 stimulated cell proliferation. The cell line Hs766T produces high levels of CXCL12, and addition of the CXCR4 antagonist AMD3100 partially inhibited proliferation, indicating an autocrine loop. Moreover, the addition of exogenous CXCL12 inhibited apoptosis induced by serum starvation. These results indicate that the CXCR4 receptor is frequently expressed in metastatic pancreatic tumor cells. CXCR4 not only stimulates cell motility and invasion but also promotes survival and proliferation. Strategies to target CXCR4 expressed on tumor cells may be of benefit in patients with pancreatic cancer.

This article has been cited by other articles:

				B. Sung, S. Jhurani, K. S. Ahn, Y. Mastuo, T. Yi, S. Guha, M. Liu, and B. B. Aggarwal Zerumbone Down-regulates Chemokine Receptor CXCR4 Expression Leading to Inhibition of CXCL12-Induced Invasion of Breast and Pancreatic Tumor Cells Cancer Res., November 1, 2008; 68(21): 8938 - 8944. [Abstract] [Full Text] [PDF]

				F. Marchesi, L. Piemonti, G. Fedele, A. Destro, M. Roncalli, L. Albarello, C. Doglioni, A. Anselmo, A. Doni, P. Bianchi, et al. The Chemokine Receptor CX3CR1 Is Involved in the Neural Tropism and Malignant Behavior of Pancreatic Ductal Adenocarcinoma Cancer Res., November 1, 2008; 68(21): 9060 - 9069. [Abstract] [Full Text] [PDF]

				R M Thomas, J Kim, M P Revelo-Penafiel, R Angel, D W Dawson, and A M Lowy The chemokine receptor CXCR4 is expressed in pancreatic intraepithelial neoplasia Gut, November 1, 2008; 57(11): 1555 - 1560. [Abstract] [Full Text] [PDF]

				E. J. Cheadle, K. Riyad, D. Subar, D. G. Rothwell, G. Ashton, H. Batha, D. J. Sherlock, R. E. Hawkins, and D. E. Gilham Eotaxin-2 and Colorectal Cancer: A Potential Target for Immune Therapy Clin. Cancer Res., October 1, 2007; 13(19): 5719 - 5728. [Abstract] [Full Text] [PDF]

				E. L. Hsu, D. Yoon, H. H. Choi, F. Wang, R. T. Taylor, N. Chen, R. Zhang, and O. Hankinson A Proposed Mechanism for the Protective Effect of Dioxin against Breast Cancer Toxicol. Sci., August 1, 2007; 98(2): 436 - 444. [Abstract] [Full Text] [PDF]

				Y. Wang, A. Thakur, Y. Sun, J. Wu, H. Biliran, A. Bollig, and D. J. Liao Synergistic Effect of Cyclin D1 and c-Myc Leads to More Aggressive and Invasive Mammary Tumors in Severe Combined Immunodeficient Mice Cancer Res., April 15, 2007; 67(8): 3698 - 3707. [Abstract] [Full Text] [PDF]

				I. Kryczek, S. Wei, E. Keller, R. Liu, and W. Zou Stroma-derived factor (SDF-1/CXCL12) and human tumor pathogenesis Am J Physiol Cell Physiol, March 1, 2007; 292(3): C987 - C995. [Abstract] [Full Text] [PDF]

				J. Meijer, I. S. Zeelenberg, B. Sipos, and E. Roos The CXCR5 Chemokine Receptor Is Expressed by Carcinoma Cells and Promotes Growth of Colon Carcinoma in the Liver Cancer Res., October 1, 2006; 66(19): 9576 - 9582. [Abstract] [Full Text] [PDF]

				J. D. Holland, M. Kochetkova, C. Akekawatchai, M. Dottore, A. Lopez, and S. R. McColl Differential functional activation of chemokine receptor CXCR4 is mediated by g proteins in breast cancer cells. Cancer Res., April 15, 2006; 66(8): 4117 - 4124. [Abstract] [Full Text] [PDF]

				S. Scala, P. Giuliano, P. A. Ascierto, C. Ierano, R. Franco, M. Napolitano, A. Ottaiano, M. L. Lombardi, M. Luongo, E. Simeone, et al. Human Melanoma Metastases Express Functional CXCR4 Clin. Cancer Res., April 15, 2006; 12(8): 2427 - 2433. [Abstract] [Full Text] [PDF]

				T. Kakinuma and S. T. Hwang Chemokines, chemokine receptors, and cancer metastasis J. Leukoc. Biol., April 1, 2006; 79(4): 639 - 651. [Abstract] [Full Text] [PDF]

				S. Ohira, M. Sasaki, K. Harada, Y. Sato, Y. Zen, K. Isse, K. Kozaka, A. Ishikawa, K. Oda, Y. Nimura, et al. Possible Regulation of Migration of Intrahepatic Cholangiocarcinoma Cells by Interaction of CXCR4 Expressed in Carcinoma Cells with Tumor Necrosis Factor-{alpha} and Stromal-Derived Factor-1 Released in Stroma Am. J. Pathol., April 1, 2006; 168(4): 1155 - 1168. [Abstract] [Full Text] [PDF]

				K. Yasumoto, K. Koizumi, A. Kawashima, Y. Saitoh, Y. Arita, K. Shinohara, T. Minami, T. Nakayama, H. Sakurai, Y. Takahashi, et al. Role of the CXCL12/CXCR4 Axis in Peritoneal Carcinomatosis of Gastric Cancer Cancer Res., February 15, 2006; 66(4): 2181 - 2187. [Abstract] [Full Text] [PDF]

				I. Airoldi, L. Raffaghello, E. Piovan, C. Cocco, B. Carlini, A. Amadori, M. V. Corrias, and V. Pistoia CXCL12 Does Not Attract CXCR4+ Human Metastatic Neuroblastoma Cells: Clinical Implications Clin. Cancer Res., January 1, 2006; 12(1): 77 - 82. [Abstract] [Full Text] [PDF]

				D Wang and R N DuBois PROSTAGLANDINS AND CANCER Gut, January 1, 2006; 55(1): 115 - 122. [Full Text] [PDF]

				C. Akekawatchai, J. D. Holland, M. Kochetkova, J. C. Wallace, and S. R. McColl Transactivation of CXCR4 by the Insulin-like Growth Factor-1 Receptor (IGF-1R) in Human MDA-MB-231 Breast Cancer Epithelial Cells J. Biol. Chem., December 2, 2005; 280(48): 39701 - 39708. [Abstract] [Full Text] [PDF]

				P. Allavena, M. Signorelli, M. Chieppa, E. Erba, G. Bianchi, F. Marchesi, C. O. Olimpio, C. Bonardi, A. Garbi, A. Lissoni, et al. Anti-inflammatory Properties of the Novel Antitumor Agent Yondelis (Trabectedin): Inhibition of Macrophage Differentiation and Cytokine Production Cancer Res., April 1, 2005; 65(7): 2964 - 2971. [Abstract] [Full Text] [PDF]