This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Monti, P. Articles by Piemonti, L. Search for Related Content PubMed PubMed Citation Articles by Monti, P. Articles by Piemonti, L.

The CC Chemokine MCP-1/CCL2 in Pancreatic Cancer Progression

Regulation of Expression and Potential Mechanisms of Antimalignant Activity¹

Laboratory of Experimental Surgery, Department of Surgery II, Fondazione Centro S Raffaele del Monte Tabor, 20132 Milan [P. M., L. P.]; Università degli Studi di Milano-Bicocca, Milan [B. E. L.]; Department of Immunology, Istituto di Ricerche Farmacologiche "Mario Negri," Milan [F. M., P. A.]; Department of Surgery II, Università Vita-Salute San Raffaele, Milan [G. B., A. Z., F. S., F. P., V. D. C.]; Department of Medical and Surgical Sciences, University of Padova, Padova [C. P.]; and Epidemiology Unit, Scientific Institute H San Raffaele, Milan [G. C.], Italy

The aim of this study was to discover whether MCP-1/CCL2, a CC chemokine able to attract macrophages, is expressed in human pancreatic cancer and how it modulates cancer progression. All primary tumors were tested, and 6 of 14 pancreatic cancer cell lines were constitutively secreted CCL2. Analysis of the regulation demonstrated that the expression of CCL2 was significantly elevated and in a synergistic manner by IFN-, tumor necrosis factor , and interleukin 1ß. By immunohistochemistry and in situ hybridization, CCL2 production was confirmed in neoplastic ducts from surgical specimens. Serum levels of CCL2 in pancreatic cancer patients were significantly higher than in normal healthy subjects (P < 0.0001). Patients with high circulating levels of CCL2 had significantly higher survival rate than low CCL2 producers. Serum CCL2 levels positively correlated with tumor macrophage infiltration and inversely correlated with tumor proliferative activity (Ki67 expression). A direct effect of CCL2 on tumor cells is to be excluded, either because primary tumors as well as cell lines have no detectable CCL2 receptor (CCR2) and because addition of CCL2 on tumor cells in vitro did not modify cell cycle progression or apoptosis. In vitro, a model of tumor microenvironment showed a direct antiproliferative and proapoptotic activity of monocytes toward pancreatic cancer cell, which is mediated at least in part by interleukin 1ß. Moreover, other proinflammatory cytokines such as tumor necrosis factor and IFN- appeared able to induce apoptosis and to reduce the proliferative rate of pancreatic cancer. On the whole, the results presented in our investigation suggest that CCL2 could be a relevant negative regulator of pancreatic cancer progression.

This article has been cited by other articles:

				J. M. Weiss, T. C. Back, A. J. Scarzello, J. J. Subleski, V. L. Hall, J. K. Stauffer, X. Chen, D. Micic, K. Alderson, W. J. Murphy, et al. Successful immunotherapy with IL-2/anti-CD40 induces the chemokine-mediated mitigation of an immunosuppressive tumor microenvironment PNAS, November 17, 2009; 106(46): 19455 - 19460. [Abstract] [Full Text] [PDF]

				E. Diaz-Guerra, R. Vernal, M. J. del Prete, A. Silva, and J. A. Garcia-Sanz CCL2 Inhibits the Apoptosis Program Induced by Growth Factor Deprivation, Rescuing Functional T Cells J. Immunol., December 1, 2007; 179(11): 7352 - 7357. [Abstract] [Full Text] [PDF]

				E. Ziegler, M. Oberbarnscheidt, S. Bulfone-Paus, R. Forster, U. Kunzendorf, and S. Krautwald CCR7 Signaling Inhibits T Cell Proliferation J. Immunol., November 15, 2007; 179(10): 6485 - 6493. [Abstract] [Full Text] [PDF]

				K.-P. Tse, N.-M. Tsang, K.-D. Chen, H.-P. Li, Y. Liang, C. Hsueh, K.-P. Chang, J.-S. Yu, S.-P. Hao, L.-L. Hsieh, et al. MCP-1 Promoter Polymorphism at 2518 Is Associated with Metastasis of Nasopharyngeal Carcinoma after Treatment Clin. Cancer Res., November 1, 2007; 13(21): 6320 - 6326. [Abstract] [Full Text] [PDF]

				J.-S. Nam, M.-J. Kang, A. M. Suchar, T. Shimamura, E. A. Kohn, A. M. Michalowska, V. C. Jordan, S. Hirohashi, and L. M. Wakefield Chemokine (C-C motif) ligand 2 mediates the prometastatic effect of dysadherin in human breast cancer cells. Cancer Res., July 15, 2006; 66(14): 7176 - 7184. [Abstract] [Full Text] [PDF]

				B. Dave, R. R. Eason, Y. Geng, Y. Su, T. M. Badger, and R. C. M. Simmen Tp53-Associated Growth Arrest and DNA Damage Repair Gene Expression Is Attenuated in Mammary Epithelial Cells of Rats Fed Whey Proteins J. Nutr., May 1, 2006; 136(5): 1156 - 1160. [Abstract] [Full Text] [PDF]

				Z. A. Dehqanzada, C. E. Storrer, M. T. Hueman, R. J. Foley, K. A. Harris, Y. H. Jama, T.-C. Kao, C. D. Shriver, S. Ponniah, and G. E. Peoples Correlations between Serum Monocyte Chemotactic Protein-1 Levels, Clinical Prognostic Factors, and HER-2/neu Vaccine-Related Immunity in Breast Cancer Patients Clin. Cancer Res., January 15, 2006; 12(2): 478 - 486. [Abstract] [Full Text] [PDF]

				M. Gronborg, T. Z. Kristiansen, A. Iwahori, R. Chang, R. Reddy, N. Sato, H. Molina, O. N. Jensen, R. H. Hruban, M. G. Goggins, et al. Biomarker Discovery from Pancreatic Cancer Secretome Using a Differential Proteomic Approach Mol. Cell. Proteomics, January 1, 2006; 5(1): 157 - 171. [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]

				F. Marchesi, P. Monti, B. E. Leone, A. Zerbi, A. Vecchi, L. Piemonti, A. Mantovani, and P. Allavena Increased Survival, Proliferation, and Migration in Metastatic Human Pancreatic Tumor Cells Expressing Functional CXCR4 Cancer Res., November 15, 2004; 64(22): 8420 - 8427. [Abstract] [Full Text] [PDF]

				Y. Hu, H. Sun, J. Drake, F. Kittrell, M. C. Abba, L. Deng, S. Gaddis, A. Sahin, K. Baggerly, D. Medina, et al. From Mice to Humans: Identification of Commonly Deregulated Genes in Mammary Cancer via Comparative SAGE Studies Cancer Res., November 1, 2004; 64(21): 7748 - 7755. [Abstract] [Full Text] [PDF]