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CC Chemokine Receptor 9 Enhances Proliferation in Pancreatic Intraepithelial Neoplasia and Pancreatic Cancer Cells

  • 2009 SSAT Plenary Presentation
  • Published:
Journal of Gastrointestinal Surgery Aims and scope

Abstract

Introduction

Chemokine receptors may regulate the progression and metastasis of invasive malignancies. There are little data, however, regarding their role in premalignant lesions. Our objective was to determine the role of CC chemokine receptor 9 (CCR9) in pancreatic intraepithelial neoplasia (PanIN).

Methods

Human and murine formalin-fixed paraffin-embedded (FFPE) PanIN specimens were assessed for CCR9 expression. The established murine PanIN, invasive pancreatic cancer (5143PDA) and liver metastasis (5143LM) cell lines, and human pancreatic cancer cell line (PANC-1) were obtained to verify CCR9 expression and function.

Results

Immunohistochemistry of FFPE specimens demonstrated CCR9 expression in both murine and human PanIN lesions. CCR9 expression in murine and human cell lines was verified by Western blot assay, immunofluorescence, and flow cytometry. CCR9 function was demonstrated by in vitro exposure to CCL25, the selective CCR9 ligand, which resulted in significantly increased cell proliferation in PanIN and pancreatic cancer cell lines.

Conclusions

This is the first report of chemokine receptor CCR9 expression in murine and human PanIN tissues. Our results demonstrate enhanced PanIN and pancreatic cancer cell proliferation with activation of CCR9 by its selective ligand CCL25. CCR9 may prove to be a novel therapeutic target for PanIN and its progression to invasive cancer.

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Acknowledgements

Presented at the 50th Annual Meeting of The Society for Surgery of the Alimentary Tract; Chicago IL, 2009.

Financial Support

Susan E. Riley Foundation and STOP Cancer Foundation.

Author information

Authors and Affiliations

  1. Department of Oncologic Surgery, City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA, 91010, USA

    Xiaoming Shen, Brian Mailey, Joshua D. I. Ellenhorn & Joseph Kim

  2. Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA

    Peiguo G. Chu

  3. Division of Surgical Oncology, Moores UCSD Cancer Center, La Jolla, CA, USA

    Andrew M. Lowy

Authors
  1. Xiaoming Shen
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  2. Brian Mailey
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  3. Joshua D. I. Ellenhorn
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  6. Joseph Kim
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Corresponding author

Correspondence to Joseph Kim.

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Discussion

Dr. Brian A. Mailey, Presenter (City of Hope, Duarte, CA, USA)

Discussant

Dr. Syed Ahmad (Cincinnati, OH, USA): Your group has previously presented on CXCR4 in PanIN cells and demonstrated advancing degree of expression as PanIN progresses from 1 to 3 and that activation of CXCR4 increased growth and proliferation. And in this current study, you’ve demonstrated that CCR9 is present in PanIN cells. With that background, I have a few questions.

Were you able to demonstrate a similar finding in terms of differential degree of expression from PanIN‑1 to PanIN‑3? Was there a difference in expression in primary pancreatic cancers versus liver metastases? Have you looked at that or is that something you are planning to do?

The second question I have is, how do you explain the presence of CCR9 on normal ductal epithelial cells? In fact in the western that you demonstrated, it appeared that the expression of CCR9 was higher in normal cells than in PanIN cells. Have you done any assays to see if ductal cells proliferate when exposed to the ligand for CCR9?

Finally, the last question I have is, if you are proposing this as a mechanism of progression, how do you explain that mechanism? Where does the ligand come from? And do you see this as more of a chemo preventive target or a chemotherapeutic target?

Closing Discussant

Dr. Brian Mailey: We are very interested in the CCR9 receptor, but we are still in the early stages of investigation. The question that you raised about the increase in progression of expression in CXCR4 and what we have seen in CCR9, is that it is not exactly the same. We don’t see a progression in CCR9 expression from PanIN‑1 to PanIN‑3, although there are pending studies which may help further define this.

The second question about the HPDE cell line; we did demonstrate that CCR9 is present in normal pancreatic ductal cells. The function of CCR9 in these cells? We can speculate on what it may potentially do, although we don’t have a firm answer for that yet. I think that the western blot demonstrates that CCR9 expression is at least as high in PanIN as it is in HPDE. It will be interesting to determine if CCR9 does play a function in normal cells, and if the downstream signaling functions differently in pathologic cells.

(Questioner from the floor not using a microphone.)

The ligand is one of the most interesting aspects of this receptor, which really stimulated our interest in investigating it further when we discovered CCR9 on the microarray analysis. It is produced by the small bowel as I mentioned, and this was part of our hypothesis, that the ligand may be released in a paracrine manner to stimulate pancreatic cancer cells.

(Questioner from the floor not using a microphone.)

It may be a possible explanation for the extremely poor survival in pancreatic cancer, even for patients with early stage lesions. I think that chemo‑preventive versus therapeutic measures are still forthcoming. I think it’s a little bit early for us to tell.

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Shen, X., Mailey, B., Ellenhorn, J.D.I. et al. CC Chemokine Receptor 9 Enhances Proliferation in Pancreatic Intraepithelial Neoplasia and Pancreatic Cancer Cells. J Gastrointest Surg 13, 1955–1962 (2009). https://doi.org/10.1007/s11605-009-1002-8

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  • DOI: https://doi.org/10.1007/s11605-009-1002-8

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