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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.

Ahn JH, Yu HK, Lee HJ, Hong SW, Kim SJ, Kim JS - PLoS ONE (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Cancer Biology Team, Mogam Biotechnology Research Institute, Yongin, Republic of Korea.

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.

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Kaplan-Meier survival curve for mice bearing liver metastases.Athymic BALB/c nude mice were injected intrasplenically with 3×105 LS174T human colorectal carcinoma cells. Mice had daily i.p. administrations of 0 (•), 10 (▾) or 50 (○) mg/kg rhLK8, and the fraction of surviving mice was monitored over time. Differences in survival were statistically significant, as determined by log-rank analysis: p<0.005, control vs. the rhLK8-treated group (10 mg/kg); p<0.0001, control vs. the rhLK8-treated group (50 mg/kg). Data are representative of two independent experiments.
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pone-0093794-g005: Kaplan-Meier survival curve for mice bearing liver metastases.Athymic BALB/c nude mice were injected intrasplenically with 3×105 LS174T human colorectal carcinoma cells. Mice had daily i.p. administrations of 0 (•), 10 (▾) or 50 (○) mg/kg rhLK8, and the fraction of surviving mice was monitored over time. Differences in survival were statistically significant, as determined by log-rank analysis: p<0.005, control vs. the rhLK8-treated group (10 mg/kg); p<0.0001, control vs. the rhLK8-treated group (50 mg/kg). Data are representative of two independent experiments.

Mentions: To assess whether the suppression of metastasis by rhLK8 translates into a survival benefit, we conducted the following survival experiment. Mice were injected intrasplenically with LS174T human colon carcinoma cells and were then treated intraperitoneally with 10 or 50 mg/kg rhLK8. The fraction of surviving animals was monitored for ∼70 days. As depicted in Fig. 5, systemic treatment with 10 or 50 mg/kg/day rhLK8 significantly improved host survival in rhLK8-treated mice compared with control mice (log-rank test; p<0.005 and p<0.0001 for mice treated with 10 or 50 mg/kg rhLK8 vs. control, respectively). The median survival was 29, 41 and 46 days and the overall survival was 38, 50, and 68 days in control mice and mice treated with 10 or 50 mg/kg rhLK8, respectively (Fig. 5).


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.

Ahn JH, Yu HK, Lee HJ, Hong SW, Kim SJ, Kim JS - PLoS ONE (2014)

Kaplan-Meier survival curve for mice bearing liver metastases.Athymic BALB/c nude mice were injected intrasplenically with 3×105 LS174T human colorectal carcinoma cells. Mice had daily i.p. administrations of 0 (•), 10 (▾) or 50 (○) mg/kg rhLK8, and the fraction of surviving mice was monitored over time. Differences in survival were statistically significant, as determined by log-rank analysis: p<0.005, control vs. the rhLK8-treated group (10 mg/kg); p<0.0001, control vs. the rhLK8-treated group (50 mg/kg). Data are representative of two independent experiments.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3974802&req=5

pone-0093794-g005: Kaplan-Meier survival curve for mice bearing liver metastases.Athymic BALB/c nude mice were injected intrasplenically with 3×105 LS174T human colorectal carcinoma cells. Mice had daily i.p. administrations of 0 (•), 10 (▾) or 50 (○) mg/kg rhLK8, and the fraction of surviving mice was monitored over time. Differences in survival were statistically significant, as determined by log-rank analysis: p<0.005, control vs. the rhLK8-treated group (10 mg/kg); p<0.0001, control vs. the rhLK8-treated group (50 mg/kg). Data are representative of two independent experiments.
Mentions: To assess whether the suppression of metastasis by rhLK8 translates into a survival benefit, we conducted the following survival experiment. Mice were injected intrasplenically with LS174T human colon carcinoma cells and were then treated intraperitoneally with 10 or 50 mg/kg rhLK8. The fraction of surviving animals was monitored for ∼70 days. As depicted in Fig. 5, systemic treatment with 10 or 50 mg/kg/day rhLK8 significantly improved host survival in rhLK8-treated mice compared with control mice (log-rank test; p<0.005 and p<0.0001 for mice treated with 10 or 50 mg/kg rhLK8 vs. control, respectively). The median survival was 29, 41 and 46 days and the overall survival was 38, 50, and 68 days in control mice and mice treated with 10 or 50 mg/kg rhLK8, respectively (Fig. 5).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Cancer Biology Team, Mogam Biotechnology Research Institute, Yongin, Republic of Korea.

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.

Show MeSH
Related in: MedlinePlus