Paracrine activation of chemokine receptor CCR9 enhances the invasiveness of pancreatic cancer cells

Eileen L. Heinrich, Amanda K. Arrington, Michelle E. Ko, Carrie Luu, Wendy Lee, Jianming Lu, Joseph Kim

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)241-245
Number of pages5
JournalCancer Microenvironment
Volume6
Issue number3
DOIs
StatePublished - Dec 2013

Keywords

  • CCL25
  • CCR9
  • Pancreatic cancer
  • Pancreatic stellate cells

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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