Expression of human apolipoprotein(a) kringles in colon cancer cells suppresses angiogenesis‐dependent tumor growth and peritoneal dissemination

Yu, Hyun Kyung; Ahn, Jung Yong; Lee, Ho Jeong; Lee, Suk Keun; Hong, Soon Won; Yoon, Yeup; Kim, Jang Seong

doi:10.1002/jgm.638

Cited by 25 publications

(9 citation statements)

References 35 publications

(49 reference statements)

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“…A recombinant protein (LK68) of LPA Kringle type IV and V experimentally suppressed tumor growth and capillary density within tumors in mice [11]. Gene therapy inducing an LK68 recombinant gene suppressed the tumor growth of transplanted hepatocellular carcinoma in mice [12] and liver metastasis and peritoneal dissemination in a murine colon cancer model [13], [14]. Tumor growth and angiogenesis were also suppressed in apo(a)-transgenic mice [15].…”

Section: Introductionmentioning

confidence: 99%

Low Lipoprotein(a) Concentration Is Associated with Cancer and All-Cause Deaths: A Population-Based Cohort Study (The JMS Cohort Study)

et al. 2012

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Background Experimental studies support the anti-neoplastic effect of apo(a), but several clinical studies have reported contradictory results. The purpose of this study was to determine whether a low lipoprotein(a) [Lp(a)] concentration is related to mortality from major causes of death, especially cancer. Methods The subjects were 10,413 participants (4,005 men and 6,408 women) from a multi-center population-based cohort study in Japan (The Jichi Medical School cohort study). The average age at registration was 55.0 years, and the median observation period was 4,559 days. As the estimated hazard ratio was high for both the low and very high Lp(a) levels, we defined two Lp(a) groups: a low Lp(a) group [Lp(a)<80 mg/L] and an intermediate-to-high Lp(a) group [Lp(a)≥80]. Participants who died from malignant neoplasms (n = 316), cardiovascular disease (202), or other causes (312) during the observation period were examined. Results Cumulative incidence plots showed higher cumulative death rates for the low Lp(a) group than for the intermediate-to-high Lp(a) group for all-cause, cancer, and miscellaneous-cause deaths (p<0.001, p = 0.03, and p = 0.03, respectively). Cox proportional hazards analyses with the sex and age of the participants, body mass index, and smoking and drinking histories as covariates showed that a low Lp(a) level was a significant risk for all-cause, cancer, and miscellaneous-cause deaths (p<0.001, p = 0.003, and p = 0.01, respectively). The hazard ratio (95% CI) [1.48, 1.15–1.92] of a low Lp(a) level for cancer deaths was almost the same as that for a male sex (1.46, 1.00–2.13). Conclusions This is the first report to describe the association between a low Lp(a) level and all-cause or cancer death, supporting the anti-neoplastic effect of Lp(a). Further epidemiological studies are needed to confirm the present results.

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Section: Introductionmentioning

confidence: 99%

Low Lipoprotein(a) Concentration Is Associated with Cancer and All-Cause Deaths: A Population-Based Cohort Study (The JMS Cohort Study)

et al. 2012

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“…At the protein level, Kim et al 10 and Yu et al 11,12 demonstrated that the vascularity in LK68-treated tumor tissues was greatly reduced, and the expression of angiogenin, VEGF, and basic fibroblast growth factor (bFGF), which switch on the angiogenic phenotype in tumor tissues, was dramatically decreased at peripheral regions of the tumors. Similarly, LK8 was found to inhibit the migration of HUVECs in a dose-dependent manner in vitro and new capillary formation in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…LK68-expressing murine colorectal cancer cells (CT26) restricted hepatic metastases to smaller sizes, prevented peritoneal dissemination, and significantly suppressed colon tumor growth in different experimental models. 11,12 These investigators also demonstrated that apo(a) kringle KV, also referred to as LK8, inhibits the migration of HUVECs in a dose-dependent manner, and inhibits new capillary formation in vivo. 13 However, anti-angiogenic cancer therapy requires long-term administration of relatively high concentrations of anti-angiogenic proteins to ensure tumor growth suppression in vivo.…”

mentioning

confidence: 95%

Adeno-associated virus-mediated expression of apolipoprotein (a) kringles suppresses hepatocellular carcinoma growth in mice

Lee¹,

Yun²,

Kim³

et al. 2006

Hepatology

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Hepatocellular carcinoma (HCC) constitutes more than 90% of all primary liver cancers. HCC is a hypervascular tumor that develops from dedifferentiation of small avascular HCC and is therefore a good target for anti-angiogenic gene therapy. Recent studies have identified apolipoprotein(a) [apo(a)] kringles LK68 and LK8 (LKs) as having a potential antiangiogenic and anti-tumor activity, and the current study evaluates the therapeutic potential of gene therapy with recombinant adeno-associated virus carrying genes encoding LKs (rAAV-LK) in the treatment of hypervascular HCC. We generated rAAV-LK to obtain persistent transgene expression in vivo, which is essential for anti-angiogenic therapy. The rAAV-produced LKs substantially inhibited proliferation and migration of human umbilical vein endothelial cells (HUVECs) in vitro, validating their anti-angiogenic potential. Intramuscular administration of rAAV-LK gave 60% to 84% suppression (P < .05) of tumor growth in mice bearing subcutaneously transplanted HCC derived from Huh-7 and Hep3B cells, respectively. Histological and immunohistochemical analyses of HCC tumor sections showed that a single administration of rAAV-LK gave rise to persistent expression of LKs that inhibited tumor angiogenesis and triggered tumor apoptosis, and, thus, significantly suppressed tumor growth. The administration of rAAV-LK provided a significant survival benefit (P < .05), and 3 of 10 rAAV-LK-treated mice were still alive without visible tumors and without clinical symptoms 188 days after treatment. In conclusion, rAAV-LK is a potential candidate for anti-angiogenic gene therapy in the treatment of HCC.

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“…disseminated tumors resulted from malignancies, such as gastric, ovarian, colon or pancreatic cancer, conventional treatment modalities have yet to demonstrate satisfactory efficacy [1][2][3]. With better understanding of the molecular mechanisms and genetic lesions involving malignancy, a growing number of novel therapies targeting metastasis have been under development [4][5][6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Mutant Bik gene transferred by cationic liposome inhibits peritoneal disseminated murine colon cancer

Lan

Yen

Liu

et al. 2007

Clin Exp Metastasis

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Peritoneal carcinomatosis of intraabdominal malignancies, such as pancreatic, ovarian, gastric, and colorectal cancers, represents an unmet medical need as conventional cancer treatments rarely eliminate these tumors. Satisfactory treatment for either peritoneally disseminated tumors or prevention of local recurrence after surgery is yet to be developed. To improve the efficacy of novel strategies against peritoneal metastasis, a sensitive, and less invasive model is needed to scrutinize the in vivo tumor growth and response to experimental therapeutics. To study this we intraperitoneally inoculated CT-26 stably expressing luciferase (CT-26-Luc) to mimic tumor spreading within the abdomen. Bioluminescent signals emitted from the living experimental mice correlate well with the injected cell numbers as well as the weights of dissected tumors. Since a nonviral cationic liposome coupled mutant pro-apoptotic gene, Bik(T33D/S35D) (BikDD), was previously shown to have potent anti-cancer effects on an orthotopic breast cancer animal model (Li et al., Cancer Res 63(22):7630-7633, 2003), we evaluated the inhibitory effect of BikDD on the growth kinetics of intraperitoneally inoculated CT-26-Luc. We found that intraperitoneal (i.p.) injection of liposome coupled BikDD suppressed the expansion of CT-26-Luc and prolonged life span of experimental mice. These results suggest a therapeutic effect of BikDD gene therapy on peritoneal carcinomatosis of colon cancer.

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Expression of human apolipoprotein(a) kringles in colon cancer cells suppresses angiogenesis‐dependent tumor growth and peritoneal dissemination

Abstract: 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.

Cited by 25 publications

References 35 publications

Low Lipoprotein(a) Concentration Is Associated with Cancer and All-Cause Deaths: A Population-Based Cohort Study (The JMS Cohort Study)

Low Lipoprotein(a) Concentration Is Associated with Cancer and All-Cause Deaths: A Population-Based Cohort Study (The JMS Cohort Study)

Adeno-associated virus-mediated expression of apolipoprotein (a) kringles suppresses hepatocellular carcinoma growth in mice

Mutant Bik gene transferred by cationic liposome inhibits peritoneal disseminated murine colon cancer

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