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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 expression by the vasculature of human clinical specimens. In human clinical specimens, RGS5 protein is expressed in ovarian carcinomas but absent in non-neoplastic ovaries. a Representative images (scale bars 100 μm) illustrating tissue sections immunostained for RGS5 (green) and counterstained with DAPI (blue) from human ovarian cancer specimens and non-neoplastic ovaries. [Note that the latter is negative for RGS5, but positive for CD31 and αSMA]. Demonstrative H&E images are shown. b Quantification of protein *p < 0.05. Representative images (scale bars 20 μm) illustrating the positive RGS5 staining of clinical specimens. c RGS5 protein immunofluorescence resembles vessel-like structures. Representative images (scale bars 100 μm) of serial sections (top vs. bottom) from ovarian carcinoma specimens stained for RGS5, CD31, αSMA
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Fig2: RGS5 protein expression by the vasculature of human clinical specimens. In human clinical specimens, RGS5 protein is expressed in ovarian carcinomas but absent in non-neoplastic ovaries. a Representative images (scale bars 100 μm) illustrating tissue sections immunostained for RGS5 (green) and counterstained with DAPI (blue) from human ovarian cancer specimens and non-neoplastic ovaries. [Note that the latter is negative for RGS5, but positive for CD31 and αSMA]. Demonstrative H&E images are shown. b Quantification of protein *p < 0.05. Representative images (scale bars 20 μm) illustrating the positive RGS5 staining of clinical specimens. c RGS5 protein immunofluorescence resembles vessel-like structures. Representative images (scale bars 100 μm) of serial sections (top vs. bottom) from ovarian carcinoma specimens stained for RGS5, CD31, αSMA

Mentions: Sections from ovarian carcinomas and non-neoplastic ovaries (patients’ biopsies) were investigated to assess RGS5 protein by immunofluorescence. All the cancer specimens stain positive for RGS5 (Fig. 2a, b), whereas no clearly visible signal is detectable in any of the ovaries (Fig. 2a). Imaging analyses reveal that RGS5 fluorescence covers 7.3% of the area in ovarian carcinoma specimens and less than 1% in healthy ovaries (Fig. 2b).Fig. 2


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 expression by the vasculature of human clinical specimens. In human clinical specimens, RGS5 protein is expressed in ovarian carcinomas but absent in non-neoplastic ovaries. a Representative images (scale bars 100 μm) illustrating tissue sections immunostained for RGS5 (green) and counterstained with DAPI (blue) from human ovarian cancer specimens and non-neoplastic ovaries. [Note that the latter is negative for RGS5, but positive for CD31 and αSMA]. Demonstrative H&E images are shown. b Quantification of protein *p < 0.05. Representative images (scale bars 20 μm) illustrating the positive RGS5 staining of clinical specimens. c RGS5 protein immunofluorescence resembles vessel-like structures. Representative images (scale bars 100 μm) of serial sections (top vs. bottom) from ovarian carcinoma specimens stained for RGS5, CD31, αSMA
© Copyright Policy
Related In: Results  -  Collection

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

Fig2: RGS5 protein expression by the vasculature of human clinical specimens. In human clinical specimens, RGS5 protein is expressed in ovarian carcinomas but absent in non-neoplastic ovaries. a Representative images (scale bars 100 μm) illustrating tissue sections immunostained for RGS5 (green) and counterstained with DAPI (blue) from human ovarian cancer specimens and non-neoplastic ovaries. [Note that the latter is negative for RGS5, but positive for CD31 and αSMA]. Demonstrative H&E images are shown. b Quantification of protein *p < 0.05. Representative images (scale bars 20 μm) illustrating the positive RGS5 staining of clinical specimens. c RGS5 protein immunofluorescence resembles vessel-like structures. Representative images (scale bars 100 μm) of serial sections (top vs. bottom) from ovarian carcinoma specimens stained for RGS5, CD31, αSMA
Mentions: Sections from ovarian carcinomas and non-neoplastic ovaries (patients’ biopsies) were investigated to assess RGS5 protein by immunofluorescence. All the cancer specimens stain positive for RGS5 (Fig. 2a, b), whereas no clearly visible signal is detectable in any of the ovaries (Fig. 2a). Imaging analyses reveal that RGS5 fluorescence covers 7.3% of the area in ovarian carcinoma specimens and less than 1% in healthy ovaries (Fig. 2b).Fig. 2

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