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The Ron receptor tyrosine kinase positively regulates angiogenic chemokine production in prostate cancer cells.

Thobe MN, Gurusamy D, Pathrose P, Waltz SE - Oncogene (2009)

Bottom Line: The knockdown of Ron in PC-3 or DU145 cells results in a significant decrease in angiogenic chemokine production and is associated with a decreased activation of the transcription factor nuclear factor-kappaB (NF-kappaB).Moreover, exogenous overexpression of Ron in LNCaP cells is sufficient to induce a significant increase in angiogenic chemokines that can be abrogated by inhibition of NF-kappaB signaling.Our data show that knockdown of Ron in prostate cancer cells results in significantly less endothelial cell chemotaxis when compared with Ron-expressing cells in vitro as well as in reduced tumor growth and decreased microvessel density after orthotopic transplantation into the prostate in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

ABSTRACT
Overexpression of the Ron receptor tyrosine kinase has recently been shown in a wide variety of human cancers. However, no studies have examined Ron receptor expression or function during prostate tumorigenesis. In this study we report that Ron is highly expressed in human prostate adenocarcinoma and metastatic lymph nodes when compared with normal prostate or benign prostate hyperplasia. Furthermore, we show that Ron is overexpressed in PC-3 and DU145 prostate cancer cell lines, and that the levels of angiogenic chemokines produced by prostate cancer cells positively correlate with Ron expression. The knockdown of Ron in PC-3 or DU145 cells results in a significant decrease in angiogenic chemokine production and is associated with a decreased activation of the transcription factor nuclear factor-kappaB (NF-kappaB). Moreover, exogenous overexpression of Ron in LNCaP cells is sufficient to induce a significant increase in angiogenic chemokines that can be abrogated by inhibition of NF-kappaB signaling. Given that the function of angiogenic chemokines is important in the development of new blood vessels, we also examined the ability of Ron to modulate endothelial cell migration. Our data show that knockdown of Ron in prostate cancer cells results in significantly less endothelial cell chemotaxis when compared with Ron-expressing cells in vitro as well as in reduced tumor growth and decreased microvessel density after orthotopic transplantation into the prostate in vivo. In total, our data suggest that the Ron receptor is important in modulating prostate tumor growth by modulating angiogenic chemokine production and subsequent endothelial cell recruitment.

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Ron expression promotes prostate tumor cell growth and microvessel density in vivoA, PC-3 cells were stably infected with Ron shRNA and analyzed for Ron expression by Western analysis. B, Seven weeks post orthotopic injection into the prostate, PC-3 Ron knockdown cells form significantly smaller tumors compared to control PC-3 cells. C and D, Tissue sections from tumors were stained for CD31 to examine microvessel density. C, Ron knockdown PC-3 tumors have decreased tumor vasculature as determined by CD31 staining. D, Representative pictures of CD31 staining (arrows depict positive areas) are depicted from both control PC-3 tumors and PC-3-Ron knockdown tumors (original magnification 200×). Data are expressed as means ± SE. *p<0.05 compared to PC-3 Control group.
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Figure 7: Ron expression promotes prostate tumor cell growth and microvessel density in vivoA, PC-3 cells were stably infected with Ron shRNA and analyzed for Ron expression by Western analysis. B, Seven weeks post orthotopic injection into the prostate, PC-3 Ron knockdown cells form significantly smaller tumors compared to control PC-3 cells. C and D, Tissue sections from tumors were stained for CD31 to examine microvessel density. C, Ron knockdown PC-3 tumors have decreased tumor vasculature as determined by CD31 staining. D, Representative pictures of CD31 staining (arrows depict positive areas) are depicted from both control PC-3 tumors and PC-3-Ron knockdown tumors (original magnification 200×). Data are expressed as means ± SE. *p<0.05 compared to PC-3 Control group.

Mentions: To examine a role for Ron in tumor vascularization in vivo, PC-3 cells with a stable knockdown of Ron (Figure 7A) or control cells were orthotopically injected into the prostates of nude mice. Seven weeks after injection, the prostates were harvested and prostate tumor mass (Figure 7B) and microvessel density was determined (Figure 7C and D). Compared to control cells, Ron knockdown cells not only formed smaller tumors but the overall microvessel density per equal area of tumor was significantly less.


The Ron receptor tyrosine kinase positively regulates angiogenic chemokine production in prostate cancer cells.

Thobe MN, Gurusamy D, Pathrose P, Waltz SE - Oncogene (2009)

Ron expression promotes prostate tumor cell growth and microvessel density in vivoA, PC-3 cells were stably infected with Ron shRNA and analyzed for Ron expression by Western analysis. B, Seven weeks post orthotopic injection into the prostate, PC-3 Ron knockdown cells form significantly smaller tumors compared to control PC-3 cells. C and D, Tissue sections from tumors were stained for CD31 to examine microvessel density. C, Ron knockdown PC-3 tumors have decreased tumor vasculature as determined by CD31 staining. D, Representative pictures of CD31 staining (arrows depict positive areas) are depicted from both control PC-3 tumors and PC-3-Ron knockdown tumors (original magnification 200×). Data are expressed as means ± SE. *p<0.05 compared to PC-3 Control group.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2806938&req=5

Figure 7: Ron expression promotes prostate tumor cell growth and microvessel density in vivoA, PC-3 cells were stably infected with Ron shRNA and analyzed for Ron expression by Western analysis. B, Seven weeks post orthotopic injection into the prostate, PC-3 Ron knockdown cells form significantly smaller tumors compared to control PC-3 cells. C and D, Tissue sections from tumors were stained for CD31 to examine microvessel density. C, Ron knockdown PC-3 tumors have decreased tumor vasculature as determined by CD31 staining. D, Representative pictures of CD31 staining (arrows depict positive areas) are depicted from both control PC-3 tumors and PC-3-Ron knockdown tumors (original magnification 200×). Data are expressed as means ± SE. *p<0.05 compared to PC-3 Control group.
Mentions: To examine a role for Ron in tumor vascularization in vivo, PC-3 cells with a stable knockdown of Ron (Figure 7A) or control cells were orthotopically injected into the prostates of nude mice. Seven weeks after injection, the prostates were harvested and prostate tumor mass (Figure 7B) and microvessel density was determined (Figure 7C and D). Compared to control cells, Ron knockdown cells not only formed smaller tumors but the overall microvessel density per equal area of tumor was significantly less.

Bottom Line: The knockdown of Ron in PC-3 or DU145 cells results in a significant decrease in angiogenic chemokine production and is associated with a decreased activation of the transcription factor nuclear factor-kappaB (NF-kappaB).Moreover, exogenous overexpression of Ron in LNCaP cells is sufficient to induce a significant increase in angiogenic chemokines that can be abrogated by inhibition of NF-kappaB signaling.Our data show that knockdown of Ron in prostate cancer cells results in significantly less endothelial cell chemotaxis when compared with Ron-expressing cells in vitro as well as in reduced tumor growth and decreased microvessel density after orthotopic transplantation into the prostate in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

ABSTRACT
Overexpression of the Ron receptor tyrosine kinase has recently been shown in a wide variety of human cancers. However, no studies have examined Ron receptor expression or function during prostate tumorigenesis. In this study we report that Ron is highly expressed in human prostate adenocarcinoma and metastatic lymph nodes when compared with normal prostate or benign prostate hyperplasia. Furthermore, we show that Ron is overexpressed in PC-3 and DU145 prostate cancer cell lines, and that the levels of angiogenic chemokines produced by prostate cancer cells positively correlate with Ron expression. The knockdown of Ron in PC-3 or DU145 cells results in a significant decrease in angiogenic chemokine production and is associated with a decreased activation of the transcription factor nuclear factor-kappaB (NF-kappaB). Moreover, exogenous overexpression of Ron in LNCaP cells is sufficient to induce a significant increase in angiogenic chemokines that can be abrogated by inhibition of NF-kappaB signaling. Given that the function of angiogenic chemokines is important in the development of new blood vessels, we also examined the ability of Ron to modulate endothelial cell migration. Our data show that knockdown of Ron in prostate cancer cells results in significantly less endothelial cell chemotaxis when compared with Ron-expressing cells in vitro as well as in reduced tumor growth and decreased microvessel density after orthotopic transplantation into the prostate in vivo. In total, our data suggest that the Ron receptor is important in modulating prostate tumor growth by modulating angiogenic chemokine production and subsequent endothelial cell recruitment.

Show MeSH
Related in: MedlinePlus