Abstract
Chemokine receptors mediate cancer progression and metastasis. We have previously examined chemokine receptor CCR9 expression in pancreatic cancer. Here, our objective was to evaluate pancreatic stellate cells (PSCs) as a source of CCL25, the CCR9 ligand, and as an activator of CCL25-CCR9 signaling in pancreatic cancer cells. CCL25 and CCR9 expression levels in human pancreatic cancer tissues and normal human pancreas were assessed by immunohistochemsitry. In vitro secretion of CCL25 in PSCs and PANC-1 cells was verified by enzyme-linked immunosorbent assay. Pancreatic cancer cell invasion was measured using a modified Boyden chamber assay with CCL25, PSC secreted proteins, and PANC-1 secreted proteins as the chemoattractant. There was immunostaining for CCR9 expression in human pancreatic tumor tissues, but not in normal pancreatic tissue. CCL25 expression was absent in the normal pancreatic tissue sample, but was observed in cancer cells and in the stromal cells surrounding the tumor. In vitro, both PANC-1 cells and PSCs secreted CCL25. In an invasion assay, exposure to CCL25, PSC- and PANC-1-conditioned media significantly increased the invasiveness of PANC-1 cells. Inclusion of a CCR9-neutralizing antibody in the invasion assay blocked the increase in invading cells elicited by the chemoattractants. Our studies show that pancreatic cancer invasiveness is enhanced by autocrine and paracrine stimulation of CCR9. PSCs in the tumor microenvironment appear to contribute to paracrine activation of CCR9. Investigations into CCR9 as a potential therapeutic target in pancreatic cancer must consider cancer cell autocrine signaling and also paracrine signaling from interactions in the tumor microenvironment.
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References
Siegel R et al (2011) Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61:212–236
Colucci G et al (2010) Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study. J Clin Oncol 28:1645–1651
Cunningham D et al (2009) Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol 27:5513–5518
Moore MJ et al (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960–1966
Bachem MG et al (2005) Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 128:907–921
Hidalgo M (2010) Pancreatic cancer. N Engl J Med 362:1605–1617
Apte MV et al (2004) Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells. Pancreas 29:179–187
Farrow B, Albo D, Berger DH (2008) The role of the tumor microenvironment in the progression of pancreatic cancer. J Surg Res 149:319–328
Hwang RF et al (2008) Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res 68:918–926
Vonlaufen A et al (2008) Pancreatic stellate cells: partners in crime with pancreatic cancer cells. Cancer Res 68:2085–2093
Vonlaufen A et al (2008) Pancreatic stellate cells and pancreatic cancer cells: an unholy alliance. Cancer Res 68:7707–7710
Xu Z et al (2010) Role of pancreatic stellate cells in pancreatic cancer metastasis. Am J Pathol 177:2585–2596
Muerkoster S et al (2004) Tumor stroma interactions induce chemoresistance in pancreatic ductal carcinoma cells involving increased secretion and paracrine effects of nitric oxide and interleukin-1beta. Cancer Res 64:1331–1337
Svensson M, Agace WW (2006) Role of CCL25/CCR9 in immune homeostasis and disease. Expert Rev Clin Immunol 2:759–773
Svensson M et al (2008) Involvement of CCR9 at multiple stages of adult T lymphopoiesis. J Leukoc Biol 83:156–164
Amersi FF et al (2008) Activation of CCR9/CCL25 in cutaneous melanoma mediates preferential metastasis to the small intestine. Clin Cancer Res 14:638–645
Johnson EL et al (2010) CCL25-CCR9 interaction modulates ovarian cancer cell migration, metalloproteinase expression, and invasion. World J Surg Oncol 8:62–72
Singh S et al (2004) Expression and functional role of CCR9 in prostate cancer cell migration and invasion. Clin Cancer Res 10:8743–8750
Shen X et al (2009) CC chemokine receptor 9 enhances proliferation in pancreatic intraepithelial neoplasia and pancreatic cancer cells. J Gastrointest Surg 13:1955–1962
Johnson EL et al (2010) CCR9 interactions support ovarian cancer cell survival and resistance to cisplatin-induced apoptosis in a PI3K-dependent and FAK-independent fashion. J Ovarian Res 3:15–23
Johnson-Holiday C et al (2011) CCR9-CCL25 interactions promote cisplatin resistance in breast cancer cell through Akt activation in a PI3K-dependent and FAK-independent fashion. World J Surg Oncol 9:46–53
Sharma PK et al (2010) CCR9 mediates PI3K/AKT-dependent antiapoptotic signals in prostate cancer cells and inhibition of CCR9-CCL25 interaction enhances the cytotoxic effects of etoposide. Int J Cancer 127:2020–2030
Farrow B et al (2009) Characterization of tumor-derived pancreatic stellate cells. J Surg Res 157:96–102
Muller A et al (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410:50–56
Koizumi K et al (2007) CCL21 promotes the migration and adhesion of highly lymph node metastatic human non-small cell lung cancer Lu-99 in vitro. Oncol Rep 17:1511–1516
Nakamura ES et al (2006) RANKL-induced CCL22/macrophage-derived chemokine produced from osteoclasts potentially promotes the bone metastasis of lung cancer expressing its receptor CCR4. Clin Exp Metastasis 23:9–18
Yasumoto K et al (2006) Role of the CXCL12/CXCR4 axis in peritoneal carcinomatosis of gastric cancer. Cancer Res 66:2181–2187
Akashi T et al (2006) Androgen receptor negatively influences the expression of chemokine receptors (CXCR4, CCR1) and ligand-mediated migration in prostate cancer DU-145. Oncol Rep 16:831–836
Takeuchi H et al (2004) CCL21 chemokine regulates chemokine receptor CCR7 bearing malignant melanoma cells. Clin Cancer Res 10:2351–2358
Letsch A et al (2004) Functional CCR9 expression is associated with small intestinal metastasis. J Invest Dermatol 122:685–690
Zhang L et al (2011) Role of Rho-ROCK signaling in MOLT4 cells metastasis induced by CCL25. Leuk Res 35:103–109
Krantz SB et al (2011) MT1-MMP cooperates with Kras(G12D) to promote pancreatic fibrosis through increased TGF-β signaling. Mol CancRes 10:1294–1304
Hamada S et al (2012) Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells. Biochem Biophys Res Commun 421:349–354
Acknowledgments
Presented in part at the American College of Surgeons Surgical Forum Meeting on October 24, 2011 in San Francisco, CA.
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The authors declare they have no conflict of interest.
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This work was supported in part by a Research Scholar Grant (120687-RSG-11-070-01-TBE) from the American Cancer Society. Additional financial support was provided by the City of Hope Comprehensive Cancer Center (P30CA33572-27), The National Institutes of Health (5K22CA134637-2), and the Leo and Anne Albert Charitable Trust.
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Heinrich, E.L., Arrington, A.K., Ko, M.E. et al. Paracrine Activation of Chemokine Receptor CCR9 Enhances The Invasiveness of Pancreatic Cancer Cells. Cancer Microenvironment 6, 241–245 (2013). https://doi.org/10.1007/s12307-013-0130-6
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DOI: https://doi.org/10.1007/s12307-013-0130-6