Expression of human apolipoprotein(a) kringles in colon cancer cells suppresses angiogenesis-dependent tumor growth and peritoneal dissemination.
BACKGROUND
Anti-angiogenesis therapy has been regarded as a promising treatment of cancer based on the fact that most tumors and their metastasis are angiogenesis-dependent. Gene therapy can potentially expand the horizons of tumor angiogenesis therapy by virtue of its ability to produce high concentrations of therapeutic agents in a local area for a sustained period. The present study was performed to evaluate the therapeutic potential of gene therapy for the treatment of cancer and metastasis.


METHODS
The murine colon carcinoma cell line CT26 was manipulated ex vivo to express an anti-angiogenic molecule, LK68, consisting of human apolipoprotein(a) kringle domains, KIV(9)-KIV(10)-KV, using retrovirus-mediated gene transfer. Its effects on colon tumor growth and metastasis were evaluated in experimental animal models established by injecting LK68-expressing and control CT26 cells subcutaneously or into the peritoneal cavity of BALB/c mice, respectively.


RESULTS
Expression of LK68 significantly suppressed colon tumor growth in mice, but did not influence the growth of tumor cells in vitro. Immunohistochemical analysis of tumor tissues revealed a significant reduction in microvessel density in LK68-expressing tumors. Thus, the suppression of tumor growth appears to result mainly from inhibition of tumor angiogenesis. This decrease in vessel density is correlated with a notable increase in tumor cell apoptosis in vivo, but has no influence on proliferation. Moreover, expression of LK68 prevents peritoneal dissemination, and consequently improves overall host survival.


CONCLUSIONS
These results collectively indicate that a gene therapy strategy using LK68 cDNA is useful for the treatment for both colon tumor growth and peritoneal dissemination.
Yu
Hyun-Kyung
HK
Mogam Biotechnology Research Institute, Yongin-city, Kyonggi-do 449-910, Korea.
Ahn
Jin-Hyung
JH
Lee
Ho-Jeong
HJ
Lee
Suk-Keun
SK
Hong
Soon-Won
SW
Yoon
Yeup
Y
Kim
Jang-Seong
JS
D000818:Animals; D001054:Apolipoproteins A / Q000235:genetics / Q000378:metabolism*; D002277:Carcinoma / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D015316:Genetic Therapy; D006801:Humans; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D018082:Kringles / Q000235:genetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000628:therapy; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010529:Peritoneal Cavity / Q000473:pathology*; D012190:Retroviridae / Q000235:genetics
D001054:Apolipoproteins A