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Vasohibin-1 suppresses colon cancer.

Liu S, Han B, Zhang Q, Dou J, Wang F, Lin W, Sun Y, Peng G - Oncotarget (2015)

Bottom Line: Here we showed that stromal VASH1 levels were negatively correlated with tumor size, advanced clinical stage and distant metastases in colon cancer patients.Overexpression of VASH1 in colon cancer cells induced apoptosis and senescence, inhibiting cancer cell growth and colony formation in vitro and tumor growth in vivo.In addition, knockdown of VASH1 in cancer cells promoted cell growth, adhesion and migration in vitro, and enhanced tumorigenesis and metastasis in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Jinan Central Hospital, Affiliated to Shandong University, Jinan, P. R. China.

ABSTRACT
Vasohibin-1 (VASH1) is an endogenous angiogenesis inhibitor.However, the clinical relevance of VASH1 in colon cancer and its regulations on cancer angiogenesis and cancer cell biological characteristics are still unknown. Here we showed that stromal VASH1 levels were negatively correlated with tumor size, advanced clinical stage and distant metastases in colon cancer patients. Overexpression of VASH1 in colon cancer cells induced apoptosis and senescence, inhibiting cancer cell growth and colony formation in vitro and tumor growth in vivo. In addition, knockdown of VASH1 in cancer cells promoted cell growth, adhesion and migration in vitro, and enhanced tumorigenesis and metastasis in vivo.

No MeSH data available.


Related in: MedlinePlus

Overexpression of VASH1 in human colon cancer HT29 cells inhibited tumor growth and tumorigenesis in vivo(A) Overexpression of VASH1-A and VASH1-B in HT29 cells dramatically inhibited tumor growth in nude mice. (B) Representative image of the xenograft tumors shown are obtained from the 3 groups at the endpoint of the experiments (day 24). (C) The mean weights of xenograft tumors obtained from the 3 groups at the endpoint of the experiments (day 24). Human colon cancer HT29 cells (5 × 106/mouse) transfected with VASH1-A, VASH1-B or control vector, were subcutaneously injected into nude mice (n=5). Tumor growth was evaluated (in A). At the end of experiments, tumors were isolated from the sacrificed mice and weighted (B). **p<0.01 compared with the control vector group (in B). (D) & (E) Transfection of VASH1-A or VASH1-B in HT29 cells significantly decreased Ki-67+ cell populations compared with vector-transfected group in the tumor tissues. Representative pictures for the expression of Ki-67 in tumor tissue sections determined using the immunohistochemical staining (in D). **p<0.01 compared with the control vector group. (F) & (G) Transfection of VASH1-A significantly increased SA-β-Gal positive cell populations in the tumor tissues. Representative pictures for the expression of SA-β-gal in tumor tissue sections determined using the SA-β-gal staining. **p<0.01 compared with the control vector group. (H) & (I) Transfection of VASH1-A and VASH1-B markedly increased Cleaved-Caspase 3+ cells in the tumor tissues. Representative pictures for the expression of Cleaved-Caspase 3 in tumor tissue sections determined using the immunohistochemical staining. #p<0.05 and **p<0.01 compared with the control vector group. Results shown in (C), (E), (G) and (I) are mean ± SD from 5 mice per group.
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Figure 6: Overexpression of VASH1 in human colon cancer HT29 cells inhibited tumor growth and tumorigenesis in vivo(A) Overexpression of VASH1-A and VASH1-B in HT29 cells dramatically inhibited tumor growth in nude mice. (B) Representative image of the xenograft tumors shown are obtained from the 3 groups at the endpoint of the experiments (day 24). (C) The mean weights of xenograft tumors obtained from the 3 groups at the endpoint of the experiments (day 24). Human colon cancer HT29 cells (5 × 106/mouse) transfected with VASH1-A, VASH1-B or control vector, were subcutaneously injected into nude mice (n=5). Tumor growth was evaluated (in A). At the end of experiments, tumors were isolated from the sacrificed mice and weighted (B). **p<0.01 compared with the control vector group (in B). (D) & (E) Transfection of VASH1-A or VASH1-B in HT29 cells significantly decreased Ki-67+ cell populations compared with vector-transfected group in the tumor tissues. Representative pictures for the expression of Ki-67 in tumor tissue sections determined using the immunohistochemical staining (in D). **p<0.01 compared with the control vector group. (F) & (G) Transfection of VASH1-A significantly increased SA-β-Gal positive cell populations in the tumor tissues. Representative pictures for the expression of SA-β-gal in tumor tissue sections determined using the SA-β-gal staining. **p<0.01 compared with the control vector group. (H) & (I) Transfection of VASH1-A and VASH1-B markedly increased Cleaved-Caspase 3+ cells in the tumor tissues. Representative pictures for the expression of Cleaved-Caspase 3 in tumor tissue sections determined using the immunohistochemical staining. #p<0.05 and **p<0.01 compared with the control vector group. Results shown in (C), (E), (G) and (I) are mean ± SD from 5 mice per group.

Mentions: These in vitro studies provided us important information regarding the importance of VASH1 in controlling colon cancer tumor cell growth and metastasis. We next performed complementary in vivo studies, using human colon cancer cells in humanized nude and Rag1−/− immunodeficient mouse models, and explored whether VASH1 is critical for the tumorigenesis and metastasis of colon cancer in vivo [36, 37]. We first performed xenograft models to investigate whether overexpression of VASH1 in colon cancer cells can inhibit tumor growth and tumorigenesis. Human colon cancer HT29 cells transfected with VASH1-A, VASH1-B or control vector, were subcutaneously injected into nude mice. Tumor growth was evaluated. At the end of experiments, tumors were isolated from different groups of the sacrificed mice and weighted. HT29 tumor cells transfected with control vector grew progressively in nude mice. However, transfection of VASH1-A or VASH1-B in HT29 cells dramatically inhibited tumor growth (Figure 6A). Furthermore, tumor sizes collected from the VASH1-A or VASH1-B transfected HT29 groups on day 24 post inoculation were much smaller than those in the control vector-transfected group (Figure 6B). In addition, the average tumor weights obtained from the VASH1-A- and VASH1-B-transfected groups also showed much lower than that of control vector group (Figure 6C). Besides the tumor growth, we also verified the effects of VASH1 overexpression on tumor cell proliferation, apoptosis, senescence, and angiogenesis in tumor tissues. A large numbers of Ki-67+ cells were observed in HT29 tumor cells transfected with control vector. In contrast, transfection of VASH1-A or VASH1-B in HT29 cells significantly decreased Ki-67+ cell populations in the tumor tissues (Figure 6D and 6E). In addition, consistent to our in vitro observations (Figure 4), transfection of VASH1-A significantly induced tumor cell senescence evidencing by the increased SA-β-Gal positive cell populations (Figure 6F and 6G); and transfection of VASH1-B markedly increased the apoptotic cells (cleaved caspase 3+ cells) in the tumor tissues (Figure 6H and 6I). However, we did not find significantly inhibitory effects on tumor angiogenesis mediated by VASH1-A & B overexpression in tumor cells based on CD34+ blood vessel analyses in vessels in tumor tissues (Supplemental Figure 5). These results clearly suggest that VASH1 overexpression in colon cancer cells directly suppresses tumor growth and tumorigenesis, resulting from the induction of tumor cell apoptosis and senescence.


Vasohibin-1 suppresses colon cancer.

Liu S, Han B, Zhang Q, Dou J, Wang F, Lin W, Sun Y, Peng G - Oncotarget (2015)

Overexpression of VASH1 in human colon cancer HT29 cells inhibited tumor growth and tumorigenesis in vivo(A) Overexpression of VASH1-A and VASH1-B in HT29 cells dramatically inhibited tumor growth in nude mice. (B) Representative image of the xenograft tumors shown are obtained from the 3 groups at the endpoint of the experiments (day 24). (C) The mean weights of xenograft tumors obtained from the 3 groups at the endpoint of the experiments (day 24). Human colon cancer HT29 cells (5 × 106/mouse) transfected with VASH1-A, VASH1-B or control vector, were subcutaneously injected into nude mice (n=5). Tumor growth was evaluated (in A). At the end of experiments, tumors were isolated from the sacrificed mice and weighted (B). **p<0.01 compared with the control vector group (in B). (D) & (E) Transfection of VASH1-A or VASH1-B in HT29 cells significantly decreased Ki-67+ cell populations compared with vector-transfected group in the tumor tissues. Representative pictures for the expression of Ki-67 in tumor tissue sections determined using the immunohistochemical staining (in D). **p<0.01 compared with the control vector group. (F) & (G) Transfection of VASH1-A significantly increased SA-β-Gal positive cell populations in the tumor tissues. Representative pictures for the expression of SA-β-gal in tumor tissue sections determined using the SA-β-gal staining. **p<0.01 compared with the control vector group. (H) & (I) Transfection of VASH1-A and VASH1-B markedly increased Cleaved-Caspase 3+ cells in the tumor tissues. Representative pictures for the expression of Cleaved-Caspase 3 in tumor tissue sections determined using the immunohistochemical staining. #p<0.05 and **p<0.01 compared with the control vector group. Results shown in (C), (E), (G) and (I) are mean ± SD from 5 mice per group.
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Figure 6: Overexpression of VASH1 in human colon cancer HT29 cells inhibited tumor growth and tumorigenesis in vivo(A) Overexpression of VASH1-A and VASH1-B in HT29 cells dramatically inhibited tumor growth in nude mice. (B) Representative image of the xenograft tumors shown are obtained from the 3 groups at the endpoint of the experiments (day 24). (C) The mean weights of xenograft tumors obtained from the 3 groups at the endpoint of the experiments (day 24). Human colon cancer HT29 cells (5 × 106/mouse) transfected with VASH1-A, VASH1-B or control vector, were subcutaneously injected into nude mice (n=5). Tumor growth was evaluated (in A). At the end of experiments, tumors were isolated from the sacrificed mice and weighted (B). **p<0.01 compared with the control vector group (in B). (D) & (E) Transfection of VASH1-A or VASH1-B in HT29 cells significantly decreased Ki-67+ cell populations compared with vector-transfected group in the tumor tissues. Representative pictures for the expression of Ki-67 in tumor tissue sections determined using the immunohistochemical staining (in D). **p<0.01 compared with the control vector group. (F) & (G) Transfection of VASH1-A significantly increased SA-β-Gal positive cell populations in the tumor tissues. Representative pictures for the expression of SA-β-gal in tumor tissue sections determined using the SA-β-gal staining. **p<0.01 compared with the control vector group. (H) & (I) Transfection of VASH1-A and VASH1-B markedly increased Cleaved-Caspase 3+ cells in the tumor tissues. Representative pictures for the expression of Cleaved-Caspase 3 in tumor tissue sections determined using the immunohistochemical staining. #p<0.05 and **p<0.01 compared with the control vector group. Results shown in (C), (E), (G) and (I) are mean ± SD from 5 mice per group.
Mentions: These in vitro studies provided us important information regarding the importance of VASH1 in controlling colon cancer tumor cell growth and metastasis. We next performed complementary in vivo studies, using human colon cancer cells in humanized nude and Rag1−/− immunodeficient mouse models, and explored whether VASH1 is critical for the tumorigenesis and metastasis of colon cancer in vivo [36, 37]. We first performed xenograft models to investigate whether overexpression of VASH1 in colon cancer cells can inhibit tumor growth and tumorigenesis. Human colon cancer HT29 cells transfected with VASH1-A, VASH1-B or control vector, were subcutaneously injected into nude mice. Tumor growth was evaluated. At the end of experiments, tumors were isolated from different groups of the sacrificed mice and weighted. HT29 tumor cells transfected with control vector grew progressively in nude mice. However, transfection of VASH1-A or VASH1-B in HT29 cells dramatically inhibited tumor growth (Figure 6A). Furthermore, tumor sizes collected from the VASH1-A or VASH1-B transfected HT29 groups on day 24 post inoculation were much smaller than those in the control vector-transfected group (Figure 6B). In addition, the average tumor weights obtained from the VASH1-A- and VASH1-B-transfected groups also showed much lower than that of control vector group (Figure 6C). Besides the tumor growth, we also verified the effects of VASH1 overexpression on tumor cell proliferation, apoptosis, senescence, and angiogenesis in tumor tissues. A large numbers of Ki-67+ cells were observed in HT29 tumor cells transfected with control vector. In contrast, transfection of VASH1-A or VASH1-B in HT29 cells significantly decreased Ki-67+ cell populations in the tumor tissues (Figure 6D and 6E). In addition, consistent to our in vitro observations (Figure 4), transfection of VASH1-A significantly induced tumor cell senescence evidencing by the increased SA-β-Gal positive cell populations (Figure 6F and 6G); and transfection of VASH1-B markedly increased the apoptotic cells (cleaved caspase 3+ cells) in the tumor tissues (Figure 6H and 6I). However, we did not find significantly inhibitory effects on tumor angiogenesis mediated by VASH1-A & B overexpression in tumor cells based on CD34+ blood vessel analyses in vessels in tumor tissues (Supplemental Figure 5). These results clearly suggest that VASH1 overexpression in colon cancer cells directly suppresses tumor growth and tumorigenesis, resulting from the induction of tumor cell apoptosis and senescence.

Bottom Line: Here we showed that stromal VASH1 levels were negatively correlated with tumor size, advanced clinical stage and distant metastases in colon cancer patients.Overexpression of VASH1 in colon cancer cells induced apoptosis and senescence, inhibiting cancer cell growth and colony formation in vitro and tumor growth in vivo.In addition, knockdown of VASH1 in cancer cells promoted cell growth, adhesion and migration in vitro, and enhanced tumorigenesis and metastasis in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Jinan Central Hospital, Affiliated to Shandong University, Jinan, P. R. China.

ABSTRACT
Vasohibin-1 (VASH1) is an endogenous angiogenesis inhibitor.However, the clinical relevance of VASH1 in colon cancer and its regulations on cancer angiogenesis and cancer cell biological characteristics are still unknown. Here we showed that stromal VASH1 levels were negatively correlated with tumor size, advanced clinical stage and distant metastases in colon cancer patients. Overexpression of VASH1 in colon cancer cells induced apoptosis and senescence, inhibiting cancer cell growth and colony formation in vitro and tumor growth in vivo. In addition, knockdown of VASH1 in cancer cells promoted cell growth, adhesion and migration in vitro, and enhanced tumorigenesis and metastasis in vivo.

No MeSH data available.


Related in: MedlinePlus