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Regulator of G-protein signaling 5 (RGS5) protein: a novel marker of cancer vasculature elicited and sustained by the tumor's proangiogenic microenvironment.

Silini A, Ghilardi C, Figini S, Sangalli F, Fruscio R, Dahse R, Pedley RB, Giavazzi R, Bani M - Cell. Mol. Life Sci. (2011)

Bottom Line: Supporting these findings, we show elevated levels of Rgs5 mRNA in the stroma from strongly (as opposed to weakly) angiogenic ovarian carcinoma xenografts and accordingly, we also show more of the protein associated to the abnormal vasculature.RGS5 protein predominantly colocalizes with the endothelium expressing platelet/endothelial cell adhesion molecule-1 (PECAM-1/CD31) and to a much lesser extent with perivascular/mural cells expressing platelet-derived growth factor receptor-beta (PDGFR-β) or alpha smooth muscle actin (αSMA).To toughen the relevance of the findings, we demonstrate RGS5 in the blood vessels of other cancer models endowed with a proangiogenic environment, such as human melanoma and renal carcinoma xenografts; to the contrary, it was undetectable in the vasculature of normal mouse tissues.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Laboratory of Biology and Treatment of Metastases, MarioNegri Institute for Pharmacological Research, Milan, Italy.

ABSTRACT
We previously identified regulator of G-protein signaling 5 (RGS5) among several genes expressed by tumor-derived endothelial cells (EC). In this study, we provide the first in vivo/ex vivo evidence of RGS5 protein in the vasculature of ovarian carcinoma clinical specimens and its absence in human ovaries. Consistent with this, we show higher amounts of Rgs5 transcript in EC isolated from human cancers (as opposed to normal tissues) and demonstrate that expression is sustained by a milieu of factors typical of the proangiogenic tumor environment, including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2). Supporting these findings, we show elevated levels of Rgs5 mRNA in the stroma from strongly (as opposed to weakly) angiogenic ovarian carcinoma xenografts and accordingly, we also show more of the protein associated to the abnormal vasculature. RGS5 protein predominantly colocalizes with the endothelium expressing platelet/endothelial cell adhesion molecule-1 (PECAM-1/CD31) and to a much lesser extent with perivascular/mural cells expressing platelet-derived growth factor receptor-beta (PDGFR-β) or alpha smooth muscle actin (αSMA). To toughen the relevance of the findings, we demonstrate RGS5 in the blood vessels of other cancer models endowed with a proangiogenic environment, such as human melanoma and renal carcinoma xenografts; to the contrary, it was undetectable in the vasculature of normal mouse tissues. RGS5 expression by the cancer vasculature triggered and retained by the proangiogenic microenvironment supports its exploitation as a novel biomarker and opens the path to explore new possibilities of therapeutic intervention aimed at targeting tumor blood vessels.

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RGS5 protein is expressed by vascular endothelium of human melanoma and renal carcinoma xenografts. Representative images illustrating WM1552/5p and RXF393 tissue sections co-stained with RGS5 (green), CD31 (blue) and/or αSMA (red). a–f (scale bars 100 μm), RGS5-CD31 overlap (light blue) is shown for both tumors in the merge images (c and f). g–l (scale bars 20 μm), note the great overlapping of RGS5 to CD31 (i, white arrows) mostly excluding the αSMA positive stain (l, yellow arrows) in the triple stained section
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Fig5: RGS5 protein is expressed by vascular endothelium of human melanoma and renal carcinoma xenografts. Representative images illustrating WM1552/5p and RXF393 tissue sections co-stained with RGS5 (green), CD31 (blue) and/or αSMA (red). a–f (scale bars 100 μm), RGS5-CD31 overlap (light blue) is shown for both tumors in the merge images (c and f). g–l (scale bars 20 μm), note the great overlapping of RGS5 to CD31 (i, white arrows) mostly excluding the αSMA positive stain (l, yellow arrows) in the triple stained section

Mentions: We demonstrate the expression of RGS5 protein and its association with the endothelium in both these xenografts. The vascular network is different between the two tumors (Fig. 5b, e), and RGS5 recapitulate the same staining patterns (Fig. 5a, d); indeed the merge images show a great degree of RGS5-CD31 overlap in both RXF393 and WM1552/5p (Fig. 5c, f). Moreover, triple-stained sections confirm that RGS5 overlaps with CD31 (Fig. 5i) rather than with αSMA (Fig. 5l). Altogether, these results provide strong evidence that the endothelium lining the blood vessels of cancer expresses RGS5. Conversely, no clear signal of RGS5 staining in association with the vasculature of normal mouse organs is visible (supplementary material 1).Fig. 5


Regulator of G-protein signaling 5 (RGS5) protein: a novel marker of cancer vasculature elicited and sustained by the tumor's proangiogenic microenvironment.

Silini A, Ghilardi C, Figini S, Sangalli F, Fruscio R, Dahse R, Pedley RB, Giavazzi R, Bani M - Cell. Mol. Life Sci. (2011)

RGS5 protein is expressed by vascular endothelium of human melanoma and renal carcinoma xenografts. Representative images illustrating WM1552/5p and RXF393 tissue sections co-stained with RGS5 (green), CD31 (blue) and/or αSMA (red). a–f (scale bars 100 μm), RGS5-CD31 overlap (light blue) is shown for both tumors in the merge images (c and f). g–l (scale bars 20 μm), note the great overlapping of RGS5 to CD31 (i, white arrows) mostly excluding the αSMA positive stain (l, yellow arrows) in the triple stained section
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3299962&req=5

Fig5: RGS5 protein is expressed by vascular endothelium of human melanoma and renal carcinoma xenografts. Representative images illustrating WM1552/5p and RXF393 tissue sections co-stained with RGS5 (green), CD31 (blue) and/or αSMA (red). a–f (scale bars 100 μm), RGS5-CD31 overlap (light blue) is shown for both tumors in the merge images (c and f). g–l (scale bars 20 μm), note the great overlapping of RGS5 to CD31 (i, white arrows) mostly excluding the αSMA positive stain (l, yellow arrows) in the triple stained section
Mentions: We demonstrate the expression of RGS5 protein and its association with the endothelium in both these xenografts. The vascular network is different between the two tumors (Fig. 5b, e), and RGS5 recapitulate the same staining patterns (Fig. 5a, d); indeed the merge images show a great degree of RGS5-CD31 overlap in both RXF393 and WM1552/5p (Fig. 5c, f). Moreover, triple-stained sections confirm that RGS5 overlaps with CD31 (Fig. 5i) rather than with αSMA (Fig. 5l). Altogether, these results provide strong evidence that the endothelium lining the blood vessels of cancer expresses RGS5. Conversely, no clear signal of RGS5 staining in association with the vasculature of normal mouse organs is visible (supplementary material 1).Fig. 5

Bottom Line: Supporting these findings, we show elevated levels of Rgs5 mRNA in the stroma from strongly (as opposed to weakly) angiogenic ovarian carcinoma xenografts and accordingly, we also show more of the protein associated to the abnormal vasculature.RGS5 protein predominantly colocalizes with the endothelium expressing platelet/endothelial cell adhesion molecule-1 (PECAM-1/CD31) and to a much lesser extent with perivascular/mural cells expressing platelet-derived growth factor receptor-beta (PDGFR-β) or alpha smooth muscle actin (αSMA).To toughen the relevance of the findings, we demonstrate RGS5 in the blood vessels of other cancer models endowed with a proangiogenic environment, such as human melanoma and renal carcinoma xenografts; to the contrary, it was undetectable in the vasculature of normal mouse tissues.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Laboratory of Biology and Treatment of Metastases, MarioNegri Institute for Pharmacological Research, Milan, Italy.

ABSTRACT
We previously identified regulator of G-protein signaling 5 (RGS5) among several genes expressed by tumor-derived endothelial cells (EC). In this study, we provide the first in vivo/ex vivo evidence of RGS5 protein in the vasculature of ovarian carcinoma clinical specimens and its absence in human ovaries. Consistent with this, we show higher amounts of Rgs5 transcript in EC isolated from human cancers (as opposed to normal tissues) and demonstrate that expression is sustained by a milieu of factors typical of the proangiogenic tumor environment, including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2). Supporting these findings, we show elevated levels of Rgs5 mRNA in the stroma from strongly (as opposed to weakly) angiogenic ovarian carcinoma xenografts and accordingly, we also show more of the protein associated to the abnormal vasculature. RGS5 protein predominantly colocalizes with the endothelium expressing platelet/endothelial cell adhesion molecule-1 (PECAM-1/CD31) and to a much lesser extent with perivascular/mural cells expressing platelet-derived growth factor receptor-beta (PDGFR-β) or alpha smooth muscle actin (αSMA). To toughen the relevance of the findings, we demonstrate RGS5 in the blood vessels of other cancer models endowed with a proangiogenic environment, such as human melanoma and renal carcinoma xenografts; to the contrary, it was undetectable in the vasculature of normal mouse tissues. RGS5 expression by the cancer vasculature triggered and retained by the proangiogenic microenvironment supports its exploitation as a novel biomarker and opens the path to explore new possibilities of therapeutic intervention aimed at targeting tumor blood vessels.

Show MeSH
Related in: MedlinePlus