Suppression of colorectal cancer liver metastasis and extension of survival by expression of apolipoprotein(a) kringles.
The formation of hepatic metastases in colorectal cancer is the main cause of patient death. Current therapies directed at hepatic metastasis of colorectal cancer have had minimal impact on outcome. Therefore, alternative treatment strategies for liver metastasis require development. The present study was performed to evaluate the application of cDNA of LK68 encoding apolipoprotein(a) kringles IV-9, IV-10, and V as possible candidates for gene therapy treatment of this life-threatening disease. The murine colorectal cancer cell line CT26 was transduced ex vivo with LK68 cDNA via retroviral gene transfer, and an experimental model of hepatic metastasis was established by injecting LK68-expressing and control cells into the spleens of BALB/c mice. Expression of LK68 did not affect the growth characteristics and viability of transduced CT26 cells in vitro. LK68 produced from CT26 cells substantially inhibited the migration of endothelial cells in vitro. In vivo, substantial suppression of liver metastasis and prolonged survival were observed in mice bearing LK68-expressing CT26 cells, compared with controls. LK68-expressing liver metastases were restricted to smaller sizes and displayed decreased microvessel density and increased tumor cell apoptosis. Our data collectively indicate that LK68 suppresses angiogenesis-dependent progression of prevascular micrometastases to macroscopic tumors and their growth, which are clinically accessible and biologically relevant therapeutic targets. We propose that antiangiogenic gene therapy with LK68 is a promising strategy for the treatment of colorectal cancer liver metastasis.
Mogam Biotechnology Research Institute, Yongin-city, Kyonggi-do, Republic of Korea.
Hyun-Kyung
HK
Yu
Jang-Seong
JS
Kim
Ho-Jeong
HJ
Lee
Jin-Hyung
JH
Ahn
Suk-Keun
SK
Lee
Soon-Won
SW
Hong
Yeup
Y
Yoon
D000818:Animals; D001053:Apolipoproteins / Q000096:biosynthesis / Q000235:genetics*; D053241:Apoprotein(a); D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D018076:DNA, Complementary / Q000008:administration & dosage / Q000235:genetics; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000473:pathology; D015316:Genetic Therapy / Q000379:methods*; D018082:Kringles / Q000235:genetics*; D017270:Lipoprotein(a) / Q000096:biosynthesis / Q000235:genetics*; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000628:therapy
D001053:Apolipoproteins; D018076:DNA, Complementary; D017270:Lipoprotein(a); D053241:Apoprotein(a)