Production of interleukin 15 by human colon cancer cells is associated with induction of mucosal hyperplasia, angiogenesis, and metastasis.
OBJECTIVE
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.


METHODS
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 alpha. 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 alpha, 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 alpha and IL-2 receptor beta and gamma subunits and by a binding assay using (125)I-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.
Kuniyasu
Hiroki
H
Department of Oncological Pathology, Nara Medical University Cancer Center, Kashihara, Nara 634-8521, Japan. cooninh@zb4.so-net.ne.jp
Ohmori
Hitoshi
H
Sasaki
Takamistu
T
Sasahira
Tomonori
T
Yoshida
Kazuhiro
K
Kitadai
Yasuhiko
Y
Fidler
Isaiah J
IJ
D000818:Animals; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D053938:DNA Fragmentation; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia / Q000473:pathology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D019409:Interleukin-15 / Q000096:biosynthesis* / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009092:Mucous Membrane / Q000473:pathology*; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D016211:Transforming Growth Factor alpha / Q000378:metabolism
D017077:Culture Media, Conditioned; D019409:Interleukin-15; D018809:Proliferating Cell Nuclear Antigen; D015375:Receptors, Interleukin-2; D016211:Transforming Growth Factor alpha