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Interleukin-13 exerts autocrine growth-promoting effects on human pancreatic cancer, and its expression correlates with a propensity for lymph node metastases

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International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Background and aims

Interleukin-13 (IL-13) is an anti-inflammatory cytokine produced in cells of hematopoetic origin. It is not known whether pancreatic cancer cells produce IL-13 or whether IL-13 can modulate pancreatic cancer cell growth and influence the frequency of lymph node metastases.

Materials and methods

Cell growth and signaling were analyzed by cell counting, colorimetric proliferation assays, fluorescent-activated cell sorting, and in vitro kinase activity assays. IL-13 expression and secretion were determined by Northern blot analysis and enzyme-linked immunosorbent assay, respectively. Localization of IL-13 and its transmembrane receptor (IL-4R) in primary pancreatic ductal adenocarcinoma (PDAC) was characterized by immunohistochemistry.

Results

IL-13 enhanced the growth of ASPC-1, CAPAN-1, and COLO-357 cells. This was associated with enhanced p44/42 mitogen-activated protein kinase (MAPK) phoshorylation. In contrast to p44/42 MAPK, phosphatidylinositol 3-kinase activity was also induced in IL-13-unresponsive MIA PaCa-2, PANC-1, and T3M4 cells. All cells expressed and secreted IL-13. Neutralizing IL-13 antibodies inhibited the growth of ASPC-1 and CAPAN-1 cells. Immunohistochemical analysis of resected primary ductal adenocarcinoma specimens revealed high levels of IL-13 in 30 of 70 cases and its transmembrane receptor (IL-4R) in 28 of 70 cases, respectively. Fifteen of 16 specimens (94%) exhibiting high IL-13 and IL-4R coexpression had lymph node metastases, while only 30 of the remaining 54 samples (56%) had positive lymph nodes (p = 0.0134).

Conclusion

IL-13 can act as an autocrine growth factor in PDAC. Endogenous expression of IL-13 in conjunction with IL-4R in the cancer cells seems to facilitate lymph node metastasis.

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Acknowledgments

This study was supported by a Ph.D. grant from the IZKF Ulm to O. Prokopschuk and Public Health Service Grant CA-75059 awarded by the National Cancer Institute to Mu. K. We thank I. Schneider for performing parts of the cell growth assays, FACS, and immunoblot analysis, E. Schmidt for assisting in IL-13 immunohistochemistry, R.S. Metzgar (Duke University, Durham, NC, USA) for the generous gift of the human pancreatic cancer cell lines COLO-357 and T3M4, and M. Buchholz for performing densitometric analysis.

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Authors and Affiliations

  1. Clinic of General, Visceral, and Transplantation Surgery, University of Ulm, Steinhoevelstrasse 9, 89075, Ulm, Germany

    Andrea Formentini, Olga Prokopchuk, Lukasz Filip Grochola, Gerd Leder, Doris Henne-Bruns & Marko Kornmann

  2. Department of Pathology, University of Ulm, 89075, Ulm, Germany

    Joern Sträter

  3. Department of General Surgery, University of Heidelberg, 69120, Heidelberg, Germany

    Joerg Kleeff

  4. Departments of Medicine, Pharmacology, and Toxicology, Dartmouth Hitchcock Medical Center and Dartmouth Medical School, Hanover, NH, 03755, USA

    Murray Korc

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  1. Andrea Formentini
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Correspondence to Marko Kornmann.

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Andrea Formentini and Olga Prokopchuk have equally contributed to this work.

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Formentini, A., Prokopchuk, O., Sträter, J. et al. Interleukin-13 exerts autocrine growth-promoting effects on human pancreatic cancer, and its expression correlates with a propensity for lymph node metastases. Int J Colorectal Dis 24, 57–67 (2009). https://doi.org/10.1007/s00384-008-0550-9

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