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Powerful anti-tumor and anti-angiogenic activity of a new anti-vascular endothelial growth factor receptor 1 peptide in colorectal cancer models.

Cicatiello V, Apicella I, Tudisco L, Tarallo V, Formisano L, Sandomenico A, Kim Y, Bastos-Carvalho A, Orlandi A, Ambati J, Ruvo M, Bianco R, De Falco S - Oncotarget (2015)

Bottom Line: Such treatment induced a significant prolongation of survival similar to that observed with bevacizumab and irinotecan combination. iVR1 also fully prevented lung invasion by HCT-116 cells injected in mouse tail vein.Also, iVR1 impressively inhibited choroid neovascularization after a single intravitreal injection.Collectively, data showed the strong potential of iVR1 peptide as a new anti-tumor and anti-metastatic agent and demonstrate the high flexibility of VEGFR1 antagonists as therapeutic anti-angiogenic agents in different pathological contexts.

View Article: PubMed Central - PubMed

Affiliation: Angiogenesis Lab, Institute of Genetics and Biophysics "Adriano Buzzati-Traverso" - CNR, Naples, Italy.

ABSTRACT
To assess the therapeutic outcome of selective block of VEGFR1, we have evaluated the activity of a new specific antagonist of VEGFR1, named iVR1 (inhibitor of VEGFR1), in syngenic and xenograft colorectal cancer models, in an artificial model of metastatization, and in laser-induced choroid neovascularization. iVR1 inhibited tumor growth and neoangiogenesis in both models of colorectal cancer, with an extent similar to that of bevacizumab, a monoclonal antibody anti-VEGF-A. It potently inhibited VEGFR1 phosphorylation in vivo, determining a strong inhibition of the recruitment of monocyte-macrophages and of mural cells as confirmed, in vitro, by the ability to inhibit macrophages migration. iVR1 was able to synergize with irinotecan determining a shrinkage of tumors that became undetectable after three weeks of combined treatment. Such treatment induced a significant prolongation of survival similar to that observed with bevacizumab and irinotecan combination. iVR1 also fully prevented lung invasion by HCT-116 cells injected in mouse tail vein. Also, iVR1 impressively inhibited choroid neovascularization after a single intravitreal injection. Collectively, data showed the strong potential of iVR1 peptide as a new anti-tumor and anti-metastatic agent and demonstrate the high flexibility of VEGFR1 antagonists as therapeutic anti-angiogenic agents in different pathological contexts.

No MeSH data available.


Related in: MedlinePlus

iVR1 inhibited the recruitment of monocyte-macrophages in syngenic and xenograft colorectal tumorsThe area of monocyte-macrophage infiltrate in syngenic (A) and xenograft (B) tumors was determined by immunostaining with anti-F4/80 antibody and calculated on five optical fields for each tumor. Data are represented as the mean ± SEM (N = 7). A, *p < 0.0005 and §p < 0.01 versus vehicle and CP; #p < 0.002 versus 5D11D4. B, *p < 0.0005, §p < 0.005 and #p < 0.05, versus vehicle and CP; #p < 0.05 versus bevacizumab (bevaciz); §p < 0.005 versus 16D3 (anti human PlGF mAb). (C) Representative pictures of F4/80 staining (brown) of HCT-116 tumors. Scale bar, 100 μm.
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Figure 3: iVR1 inhibited the recruitment of monocyte-macrophages in syngenic and xenograft colorectal tumorsThe area of monocyte-macrophage infiltrate in syngenic (A) and xenograft (B) tumors was determined by immunostaining with anti-F4/80 antibody and calculated on five optical fields for each tumor. Data are represented as the mean ± SEM (N = 7). A, *p < 0.0005 and §p < 0.01 versus vehicle and CP; #p < 0.002 versus 5D11D4. B, *p < 0.0005, §p < 0.005 and #p < 0.05, versus vehicle and CP; #p < 0.05 versus bevacizumab (bevaciz); §p < 0.005 versus 16D3 (anti human PlGF mAb). (C) Representative pictures of F4/80 staining (brown) of HCT-116 tumors. Scale bar, 100 μm.

Mentions: Monocytes-macrophages play a well-established role in tumor angiogenesis [30, 31], and VEGFR1 has an active role for their recruitment at neo-angiogenic sites. We thereby determined the extent of monocytes-macrophages infiltration in tumors by F4/80 immunohistochemical analysis. In syngenic tumors, mAb 5D11D4 determined a significant reduction of F4/80 positive area compared to vehicle and CP (−52.7% on average), as expected by blocking one of theVEGFR1 specific ligands. The block of all the VEGFR1 ligands by iVR1 determined a greater reduction of F4/80 positive area compared to vehicle and CP (−78.0% on average). Such reduction was also significantly higher compared to 5D11D4 (−53.6%) (Figure 3A). In tumor xenografts, iVR1 treatment induced an impressive suppression of monocyte-macrophages recruitment compared to vehicle and CP (−81.3% on average). The inhibition resulted considerably higher compared to that produced by bevacizumab or 16D3 treatments, which, however, also induced a substantial inhibition with respect to vehicle and CP (−67.6% and −49.4%, on average) (Figure 3B, 3C).


Powerful anti-tumor and anti-angiogenic activity of a new anti-vascular endothelial growth factor receptor 1 peptide in colorectal cancer models.

Cicatiello V, Apicella I, Tudisco L, Tarallo V, Formisano L, Sandomenico A, Kim Y, Bastos-Carvalho A, Orlandi A, Ambati J, Ruvo M, Bianco R, De Falco S - Oncotarget (2015)

iVR1 inhibited the recruitment of monocyte-macrophages in syngenic and xenograft colorectal tumorsThe area of monocyte-macrophage infiltrate in syngenic (A) and xenograft (B) tumors was determined by immunostaining with anti-F4/80 antibody and calculated on five optical fields for each tumor. Data are represented as the mean ± SEM (N = 7). A, *p < 0.0005 and §p < 0.01 versus vehicle and CP; #p < 0.002 versus 5D11D4. B, *p < 0.0005, §p < 0.005 and #p < 0.05, versus vehicle and CP; #p < 0.05 versus bevacizumab (bevaciz); §p < 0.005 versus 16D3 (anti human PlGF mAb). (C) Representative pictures of F4/80 staining (brown) of HCT-116 tumors. Scale bar, 100 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496375&req=5

Figure 3: iVR1 inhibited the recruitment of monocyte-macrophages in syngenic and xenograft colorectal tumorsThe area of monocyte-macrophage infiltrate in syngenic (A) and xenograft (B) tumors was determined by immunostaining with anti-F4/80 antibody and calculated on five optical fields for each tumor. Data are represented as the mean ± SEM (N = 7). A, *p < 0.0005 and §p < 0.01 versus vehicle and CP; #p < 0.002 versus 5D11D4. B, *p < 0.0005, §p < 0.005 and #p < 0.05, versus vehicle and CP; #p < 0.05 versus bevacizumab (bevaciz); §p < 0.005 versus 16D3 (anti human PlGF mAb). (C) Representative pictures of F4/80 staining (brown) of HCT-116 tumors. Scale bar, 100 μm.
Mentions: Monocytes-macrophages play a well-established role in tumor angiogenesis [30, 31], and VEGFR1 has an active role for their recruitment at neo-angiogenic sites. We thereby determined the extent of monocytes-macrophages infiltration in tumors by F4/80 immunohistochemical analysis. In syngenic tumors, mAb 5D11D4 determined a significant reduction of F4/80 positive area compared to vehicle and CP (−52.7% on average), as expected by blocking one of theVEGFR1 specific ligands. The block of all the VEGFR1 ligands by iVR1 determined a greater reduction of F4/80 positive area compared to vehicle and CP (−78.0% on average). Such reduction was also significantly higher compared to 5D11D4 (−53.6%) (Figure 3A). In tumor xenografts, iVR1 treatment induced an impressive suppression of monocyte-macrophages recruitment compared to vehicle and CP (−81.3% on average). The inhibition resulted considerably higher compared to that produced by bevacizumab or 16D3 treatments, which, however, also induced a substantial inhibition with respect to vehicle and CP (−67.6% and −49.4%, on average) (Figure 3B, 3C).

Bottom Line: Such treatment induced a significant prolongation of survival similar to that observed with bevacizumab and irinotecan combination. iVR1 also fully prevented lung invasion by HCT-116 cells injected in mouse tail vein.Also, iVR1 impressively inhibited choroid neovascularization after a single intravitreal injection.Collectively, data showed the strong potential of iVR1 peptide as a new anti-tumor and anti-metastatic agent and demonstrate the high flexibility of VEGFR1 antagonists as therapeutic anti-angiogenic agents in different pathological contexts.

View Article: PubMed Central - PubMed

Affiliation: Angiogenesis Lab, Institute of Genetics and Biophysics "Adriano Buzzati-Traverso" - CNR, Naples, Italy.

ABSTRACT
To assess the therapeutic outcome of selective block of VEGFR1, we have evaluated the activity of a new specific antagonist of VEGFR1, named iVR1 (inhibitor of VEGFR1), in syngenic and xenograft colorectal cancer models, in an artificial model of metastatization, and in laser-induced choroid neovascularization. iVR1 inhibited tumor growth and neoangiogenesis in both models of colorectal cancer, with an extent similar to that of bevacizumab, a monoclonal antibody anti-VEGF-A. It potently inhibited VEGFR1 phosphorylation in vivo, determining a strong inhibition of the recruitment of monocyte-macrophages and of mural cells as confirmed, in vitro, by the ability to inhibit macrophages migration. iVR1 was able to synergize with irinotecan determining a shrinkage of tumors that became undetectable after three weeks of combined treatment. Such treatment induced a significant prolongation of survival similar to that observed with bevacizumab and irinotecan combination. iVR1 also fully prevented lung invasion by HCT-116 cells injected in mouse tail vein. Also, iVR1 impressively inhibited choroid neovascularization after a single intravitreal injection. Collectively, data showed the strong potential of iVR1 peptide as a new anti-tumor and anti-metastatic agent and demonstrate the high flexibility of VEGFR1 antagonists as therapeutic anti-angiogenic agents in different pathological contexts.

No MeSH data available.


Related in: MedlinePlus