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. 2009 Jan;24(1):57-67. doi: 10.1007/s00384-008-0550-9. Epub 2008 Aug 31.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Northern
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Immunohistochemistry
  • Insulin-Like Growth Factor I / metabolism
  • Interleukin-13 / metabolism
  • Interleukin-13 / pharmacology*
  • Lymphatic Metastasis*
  • Mitogen-Activated Protein Kinases / metabolism
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Phosphorylation
  • Receptors, Interleukin-4 / metabolism

Substances

  • Interleukin-13
  • Receptors, Interleukin-4
  • Insulin-Like Growth Factor I
  • Mitogen-Activated Protein Kinases