Integrin alpha v beta 6 mediates the potential for colon cancer cells to colonize in and metastasize to the liver.
Integrin alpha v beta 6 (alpha v beta 6) is correlated with colon cancer progression. To detect the effects of alpha v beta 6 on liver metastasis, the specificity of alpha v beta 6 against the monoclonal antibody (mAb) 2G2 was examined by immunoprecipitation. Integrin alpha v beta 6-immunoreactivity (IR) in liver metastasis tissues (63 cases) and colon carcinoma (358 cases) were examined. These results showed that alpha v beta 6 was specifically recognized by the mAb 2G2, and that rates of alpha v beta 6 positivity in liver metastatic tissues (71.4%, 45/63) were higher than that for primary colon cancer (34.0%, 122/358) (P < 0.01). Patients who were alpha v beta 6-positive had higher liver metastasis rates (17%, 21/122) than those who were alpha v beta 6-negative (only 3%, 7/236) (P < 0.01). To examine the underlying mechanisms associated with alpha v beta 6 regulating colonic metastasis in the liver, experimental liver metastasis (intrasplenic injection of HT29 transfectants) and liver colonization assays (direct injection of WiDr transfectants into the liver) in nude mice were performed; these demonstrated that alpha v beta 6 contributed to the promotion of the metastatic potential and the survival of cancer cells in the liver. Matrix metalloproteinase-9 (MMP-9) levels in the cultures of both HT29 and WiDr cells were detected by the Biotrak MMP-9 activity assay system and gelatin zymography assay, and showed that suppression of alpha v beta 6-IR inhibited MMP-9 activity and secretion. Transwell migration assay in vitro also showed that alpha v beta 6 promoted migration on fibronectin for HT29/WiDr mock compared with HT29/WiDr antisense beta 6 transfects (P < 0.01). We concluded that alpha v beta 6 may mediate the potential for colon cancer cells to colonize in and metastasize to the liver. The mechanisms that alpha v beta 6 may be involved in include the promotion of MMP-9 secretion, the enhancement of migration on fibronectin, and the survival of cancer cells in the liver.
Yang
Guang-Yun
GY
General Surgical Department of Qilu Hospital and Institute of Hepatobiliary and Vascular Surgery, Shandong University, Jinan, China.
Xu
Ke-Sen
KS
Pan
Zhong-Qing
ZQ
Zhang
Zhao-Yang
ZY
Mi
Yue-Tang
YT
Wang
Jin-Shen
JS
Chen
Rong
R
Niu
Jun
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000473:pathology*; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000276:immunology / Q000378:metabolism*; D008113:Liver Neoplasms / Q000556:secondary*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D005353:Fibronectins; D016023:Integrins; D061965:Matrix Metalloproteinase Inhibitors; C073878:integrin alphavbeta6; D020780:Matrix Metalloproteinase 9