Abstract
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.
Highlights
Colorectal cancer is the third most common cancer and the second leading cause of cancer death in the United States
We have demonstrated that recombinant apo(a) kringle V, named rhLK8, inhibits the migration of human umbilical vein endothelial cells (HUVECs) in vitro, in part by interfering with the activation of focal adhesion kinases and the subsequent formation of actin stress fibers/focal adhesions [18]. rhLK8 inhibited the neovascularization of chick chorioallantoic membranes and capillary infiltration into the Matrigel plugs in vivo
Effects of rhLK8 on Endothelial Cell Apoptosis in vitro To determine the effects of rhLK8 on endothelial cell apoptosis, HUVEC monolayers were incubated in EBM-2 containing 1% FBS in the presence or absence of 3 ng/ml basic fibroblast growth factor (bFGF) and treated with various concentrations of rhLK8 (0.1–5 mM) for 12 or 24 h
Summary
It is estimated that in the year 2013, nearly 142,820 new cases of colorectal cancer were diagnosed and 50,830 patients died from this disease [1]. 25% of patients present with metastatic disease at diagnosis. The remaining 75% are treated surgically with cure as the objective [2], but even with complete resection the disease eventually recurs in 50% of these patients. The liver is the primary site of metastases in patients with colorectal cancer, before and after surgical removal of the primary tumor, and the formation of liver metastases constitutes a major cause of death from the disease [3]. Surgery is the primary treatment option for isolated metastases, but only 20–25% of patients are suitable for resection [4], and recurrence after surgery is frequent. The development of a new treatment modality for this life-threatening disease is urgently needed
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