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Production of Interleukin 15 by Human Colon Cancer Cells Is Associated with Induction of Mucosal Hyperplasia, Angiogenesis, and Metastasis

Department of Oncological Pathology, Nara Medical University Cancer Center, Kashihara, Nara 634-8521, Japan [H. K., H. O., T. Sasak., T. Sasah.]; Department of Tumor Surgery, Research Institute for Nuclear Medicine [K. Y.], and Department of Medicine and Molecular Science, Graduate School of Biomedical Sciences [Y. K.], Hiroshima University, Hiroshima, 734-8551 Japan; and Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [I. J. F.]

Purpose: The purpose of this study was to identify a mediator produced by human colon cancer cells that is responsible for the induction of hyperplasia in the adjacent mucosa.

Experimental Design: Seventy human colon cancer surgical specimens were immunostained to determine the presence of cytokines that can induce hyperplasia in the adjacent mucosal. Human colon cancer cells with low and high metastatic potential were implanted into the cecal wall of nude mice. The resulting lesions were studied by immunohistochemistry to detect possible mediators of mucosal hyperplasia.

Results: Immunostaining of 70 colon cancer specimens from 70 patients suggested that mucosal hyperplasia and distant metastasis were associated with the expression of interleukin (IL)-15 and, to a lesser extent, transforming growth factor . The production of IL-15 by colon cancer cells was not associated with the infiltration of natural killer cells into the tumors. Cecal tumors produced in nude mice by human colon cancer cells with low and high metastatic potential (KM12C and KM12SM cells, respectively) expressed similar levels of transforming growth factor , and expression of IL-15 was detected only in the metastatic KM12SM cells and was associated with hyperplasia of the surrounding mucosa. The expression of the IL-15 receptor in rat intestinal epithelial cells (IEC6 cells) was confirmed by immunoblotting with antibodies against IL-15 receptor and IL-2 receptor ß and subunits and by a binding assay using ¹²⁵I-labeled IL-15 (K_d = 0.011 nM). IL-15 stimulated proliferation of the IEC6 cells, even under serum starvation. Treatment of IEC6 cells with IL-15 decreased doxorubicin-mediated cytotoxicity. In IEC6 cells treated with either IL-15- or KM12SM-conditioned medium, immunoblotting revealed a decrease in the production of p21Waf1, Bax, and Bak and an increase in the production of cyclin E, proliferating cell nuclear antigen, the phosphorylated active form of AKT, basic fibroblast growth factor, and vascular endothelial growth factor, changes associated with cell growth, survival, and induction of angiogenesis.

Conclusions: These data indicate that IL-15 produced by metastatic colon carcinoma cells can induce hyperplasia in the mucosa adjacent to colon cancer, thus contributing to angiogenesis and progression of the disease.

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