Cathelicidin suppresses colon cancer development by inhibition of cancer associated fibroblasts

被引：42

作者：

Cheng, Michelle ^{[1
]}

Ho, Samantha ^{[1
]}

Yoo, Jun Hwan ^{[1
,2
]}

Deanna Hoang-Yen Tran ^{[1
]}

Bakirtzi, Kyriaki ^{[1
]}

Su, Bowei ^{[1
]}

Diana Hoang-Ngoc Tran ^{[1
]}

Kubota, Yuzu ^{[1
]}

Ichikawa, R. Yan ^{[1
]}

Koon, Hon Wai ^{[1
]}

机构：

[1] Univ Calif Los Angeles, David Geffen Sch Med, Div Digest Dis, Ctr Inflammatory Bowel Dis, Los Angeles, CA 90095 USA

[2] Univ Bundang, Med Ctr, CHA, Digest Dis Ctr, Seongnam, South Korea

来源：

CLINICAL AND EXPERIMENTAL GASTROENTEROLOGY | 2015年 / 8卷

基金：

美国国家卫生研究院;

关键词：

colon cancer; epithelial-mesenchymal transition; fibroblasts;

D O I：

10.2147/CEG.S70906

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Background: Cathelicidin (LL-37 in humans and mCRAMP in mice) represents a family of endogenous antimicrobial and anti-inflammatory peptides. Cancer-associated fibroblasts can promote the proliferation of colon cancer cells and growth of colon cancer tumors. Methods: We examined the role of cathelicidin in the development of colon cancer, using subcutaneous human HT-29 colon-cancer-cell-derived tumor model in nude mice and azoxymethane-and dextran sulfate-mediated colon cancer model in C57BL/6 mice. We also determined the indirect antitumoral mechanism of cathelicidin via the inhibition of epithelialmesenchymal transition (EMT) of colon cancer cells and fibroblast-supported colon cancer cell proliferation. Results: Intravenous administration of cathelicidin expressing adeno-associated virus significantly reduced the size of tumors, tumor-derived collagen expression, and tumor-derived fibroblast expression in HT-29-derived subcutaneous tumors in nude mice. Enema administration of the mouse cathelicidin peptide significantly reduced the size and number of colonic tumors in azoxymethane-and dextran sulfate-treated mice without inducing apoptosis in tumors and the adjacent normal colonic tissues. Cathelicidin inhibited the collagen expression and vimentinpositive fibroblast expression in colonic tumors. Cathelicidin did not directly affect HT-29 cell viability, but did significantly reduce tumor growth factor-beta 1-induced EMT of colon cancer cells. Media conditioned by the human colonic CCD-18Co fibroblasts promoted human colon cancer HT-29 cell proliferation. Cathelicidin pretreatment inhibited colon cancer cell proliferation mediated by media conditioned by human colonic CCD-18Co fibroblasts. Cathelicidin disrupted tubulin distribution in colonic fibroblasts. Disruption of tubulin in fibroblasts reduced fibroblast-supported colon cancer cell proliferation. Conclusion: Cathelicidin effectively inhibits colon cancer development by interfering with EMT and fibroblast-supported colon cancer cell proliferation.

引用

页码：13 / 28

页数：16

共 40 条

[1] Cathelicidin gene therapy: a new therapeutic option in ulcerative colitis and beyond? [J].

Ahluwalia, A. ;

Tarnawski, A. S. .

GENE THERAPY, 2013, 20 (02) :119-120

[2] How Taxol® stabilises microtubule structure [J].

Amos, LA ;

Löwe, J .

CHEMISTRY & BIOLOGY, 1999, 6 (03) :R65-R69

[3] Aberrant expression of microRNAs involved in epithelial-mesenchymal transition of HT-29 cell line [J].

Cai, Zhi-Gang ;

Zhang, Shao-Ming ;

Zhang, Hang ;

Zhou, Yi-Yong ;

Wu, Hai-Bo ;

Xu, Xiao-Ping .

CELL BIOLOGY INTERNATIONAL, 2013, 37 (07) :669-674

[4]

Cirri P, 2011, AM J CANCER RES, V1, P482

[5] Ovarian cancers overexpress the antimicrobial protein hCAP-18 and its derivative LL-37 increases ovarian cancer cell proliferation and invasion [J].

Coffelt, Seth B. ;

Waterman, Ruth S. ;

Florez, Luisa ;

zu Bentrup, Kerstin Honer ;

Zwezdaryk, Kevin J. ;

Tomchuck, Suzanne L. ;

LaMarca, Heather L. ;

Danka, Elizabeth S. ;

Morris, Cindy A. ;

Scandurro, Aline B. .

INTERNATIONAL JOURNAL OF CANCER, 2008, 122 (05) :1030-1039

[6] Progastrin-Induced Secretion of Insulin-Like Growth Factor 2 From Colonic Myofibroblasts Stimulates Colonic Epithelial Proliferation in Mice [J].

Duckworth, Carrie A. ;

Clyde, Daniel ;

Worthley, Daniel L. ;

Wang, Timothy C. ;

Varro, Andrea ;

Pritchard, D. Mark .

GASTROENTEROLOGY, 2013, 145 (01) :197-+

[7] Antimicrobial protein hCAP18/LL-37 is highly expressed in breast cancer and is a putative growth factor for epithelial cells [J].

Heilborn, JD ;

Nilsson, MF ;

Jimenez, CIC ;

Sandstedt, B ;

Borregaard, N ;

Tham, E ;

Sorensen, OE ;

Weber, G ;

Ståhle, M .

INTERNATIONAL JOURNAL OF CANCER, 2005, 114 (05) :713-719

[8] Protumorigenic effects of Snail-expression fibroblasts on colon cancer cells [J].

Herrera, Alberto ;

Herrera, Mercedes ;

Alba-Castellon, Lorena ;

Silva, Javier ;

Garcia, Vanesa ;

Loubat-Casanovas, Jordina ;

Alvarez-Cienfuegos, Ana ;

Miguel Garcia, Jose ;

Rodriguez, Rufo ;

Gil, Beatriz ;

Jesus Citores, Ma ;

Jesus Larriba, Ma ;

Ignacio Casal, J. ;

Garcia de Herreros, Antonio ;

Bonilla, Felix ;

Pena, Cristina .

INTERNATIONAL JOURNAL OF CANCER, 2014, 134 (12) :2984-2990

[9] The antimicrobial peptide cathelicidin modulates Clostridium difficile-associated colitis and toxin A-mediated enteritis in mice [J].

Hing, Tressia C. ;

Ho, Samantha ;

Shih, David Q. ;

Ichikawa, Ryan ;

Cheng, Michelle ;

Chen, Jeremy ;

Chen, Xinhua ;

Law, Ivy ;

Najarian, Robert ;

Kelly, Ciaran P. ;

Gallo, Richard L. ;

Targan, Stephan R. ;

Pothoulakis, Charalabos ;

Koon, Hon Wai .

GUT, 2013, 62 (09) :1295-1305

[10] Low-dose paclitaxel inhibits the induction of epidermal-mesenchymal transition in the human cholangiocarcinoma CCKS-1 cell line [J].

Hirose, Atsushi ;

Tajima, Hidehiro ;

Ohta, Tetsuo ;

Tsukada, Tomoya ;

Okamoto, Koichi ;

Nakanuma, Shinichi ;

Sakai, Seisho ;

Kinoshita, Jun ;

Makino, Isamu ;

Furukawa, Hiroyuki ;

Hayashi, Hironori ;

Nakamura, Keishi ;

Oyama, Katsunobu ;

Inokuchi, Masafumi ;

Nakagawara, Hisatoshi ;

Miyashita, Tomoharu ;

Takamura, Hiroyuki ;

Ninomiya, Itasu ;

Kitagawa, Hirohisa ;

Fushida, Sachio ;

Fujimura, Takashi ;

Harada, Shinichi .

ONCOLOGY LETTERS, 2013, 6 (04) :915-920

← 1 2 3 4 →