Suppression of colorectal cancer liver metastasis by apolipoprotein(a) kringle V in a nude mouse model through the induction of apoptosis in tumor-associated endothelial cells.
The formation of liver metastases in colorectal cancer patients is the primary cause of patient death. Current therapies directed at liver metastasis from colorectal cancer have had minimal impact on patient outcomes. Therefore, the development of alternative treatment strategies for liver metastasis is needed. In the present study, we demonstrated that recombinant human apolipoprotein(a) kringle V, also known as rhLK8, induced the apoptotic turnover of endothelial cells in vitro through the mitochondrial apoptosis pathway. The interaction of rhLK8 with glucose-regulated protein 78 (GRP78) may be involved in the induction of apoptosis because the inhibition of GRP78 by GRP78-specific antibodies or siRNA knockdown inhibited the rhLK8-mediated apoptosis of human umbilical vein endothelial cells in vitro. Next, to evaluate the effects of rhLK8 on angiogenesis and metastasis, an experimental model of liver metastasis was established by injecting a human colorectal cancer cell line, LS174T, into the spleens of BALB/c nude mice. The systemic administration of rhLK8 significantly suppressed liver metastasis from human colorectal cancer cells and improved host survival compared with controls. The combination of rhLK8 and 5-fluorouracil substantially increased these survival benefits compared with either therapy alone. Histological observation showed significant induction of apoptosis among tumor-associated endothelial cells in liver metastases from rhLK8-treated mice compared with control mice. Collectively, these results suggest that the combination of rhLK8 with conventional chemotherapy may be a promising approach for the treatment of patients with life-threatening colorectal cancer liver metastases.
Cancer Biology Team, Mogam Biotechnology Research Institute, Yongin, Republic of Korea.
Jin-Hyung
JH
Ahn
Cancer Biology Team, Mogam Biotechnology Research Institute, Yongin, Republic of Korea.
Hyun-Kyung
HK
Yu
Cancer Biology Team, Mogam Biotechnology Research Institute, Yongin, Republic of Korea; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Ho-Jeong
HJ
Lee
Department of Pathology, Gangnam Sevrance Hospital, Yonsei University, Seoul, Republic of Korea.
Soon Won
SW
Hong
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Sun Jin
SJ
Kim
Cancer Biology Team, Mogam Biotechnology Research Institute, Yongin, Republic of Korea; Research Center of Integrative Cellulomics, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
Jang-Seong
JS
Kim
D000818:Animals; D001054:Apolipoproteins A / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005472:Fluorouracil / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018082:Kringles; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism
D001054:Apolipoproteins A; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D005472:Fluorouracil