Constitutive and Inducible Interleukin 8 Expression by Hypoxia and Acidosis Renders Human Pancreatic Cancer Cells More Tumorigenic and Metastatic1

1. Qian Shi, 
2. James L. Abbruzzese, 
3. Suyun Huang, 
4. Isaiah J. Fidler, 
5. Qinghua Xiong and
6. Keping Xie2

+Author Affiliations

1. Departments of Gastrointestinal Medical Oncology and Digestive Diseases [Q. S., J. L. A., Q. X., K. X.] and Cancer Biology [Q. S., S. H., I. J. F., K. X.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Abstract

The role and regulation of interleukin 8 (IL-8) in the growth and metastasis of SG, FG, and L3.3 variants derived from COLO 357 human pancreatic cancer cells were determined. After orthotopic implantation in the pancreas of nude mice, SG cells produced the smallest tumors, whereas L3.3 cells produced the largest tumors. SG cells produced no liver metastasis, whereas FG cells produced numerous liver metastases, and L3.3 cells produced more and larger liver metastases. In vitro analysis of IL-8 expression indicated that SG cells expressed the lowest level of IL-8 gene expression as determined by both Northern blot analysis and ELISA, whereas L3.3 cells expressed the highest level of IL-8. Immunohistochemical analysis of tumor lesions indicated that IL-8 overexpression was predominant in the regions surrounding necrotic areas, where cells were exposed to low oxygen tension (hypoxia) and acidic pH. In vitro treatment of FG tumor cells with hypoxia or acidosis led to an increased expression of IL-8. To directly determine the role of IL-8 in the growth and metastasis of pancreatic cancer, FG cells were transfected with IL-8 sense or antisense oligonucleotide expression vectors. Theneo-resistance gene-transfected FG cells were used as controls. Decreased IL-8 expression after transfection with IL-8 antisense oligonucleotide expression vector retarded the growth of FG cells in mice after intrapancreatic implantation, which correlated with decreased tumor angiogenesis. Our data demonstrated that hypoxia and acidosis contribute to the overexpression of IL-8, which in turn plays an important role in tumor angiogenesis and contributes significantly to the aggressive biology of human pancreatic cancer.

Footnotes

• The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
• ↵1 This work was supported in part by the Multidisciplinary Pancreatic Program Research Grant and Cancer Center Support Core Grant CA 16672 (to K. X.). Q. S. is supported by the Smith Education Fund of The University of Texas M. D. Anderson Cancer Center.
• ↵2 To whom requests for reprints should be addressed, at Departments of Gastrointestinal Oncology and Cancer Biology, Box 078, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030. Phone: (713) 792-2013; Fax: (713) 745-1163; E-mail: kepxie@notes.mdacc.tmc.edu.
• ↵3 The abbreviations used are: IL, interleukin; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor; HIF, hypoxia-inducible factor; NF, nuclear factor.
• • Accepted August 18, 1999.
  • Received May 20, 1999.
  • Revision received August 13, 1999.