Expression of gastrin releasing Peptide receptor in renal cell carcinomas: a potential function for the regulation of neoangiogenesis and microvascular perfusion.
OBJECTIVE
Gastrin releasing peptide (GRP) is a growth factor for renal cell carcinoma (RCC) and it has vasoactive properties. Blockade of GRP receptor inhibits the growth of GRP receptor positive and negative tumors in nude mice, suggesting GRP effects other than those related to tumor epithelium. Therefore, in this study we analyzed the effects of GRP receptor blockade on neoangiogenesis in RCC.


METHODS
GRP receptor expression was determined in human RCC and corresponding normal tissue by real-time reverse transcriptase-polymerase chain reaction, immunohistochemistry and confocal laser scanning microscopy. Multicellular spheroids of the A498 RCC line were implanted into dorsal skin fold chambers of athymic nude mice. Neoangiogenesis was measured by intravital microscopy after blockade of GRP receptors by the GRP antagonist RC-3095. The influence of GRP on vascular endothelial growth factor secretion in A498 cells was studied in vitro.


RESULTS
GRP receptor expression was immunolocalized in tumor cells and microvessels. Implanted tumor cell spheroids and spheroid microvessels of the chamber also expressed GRP receptors. Spheroid neoangiogenesis was significantly inhibited by RC-3095 when given immediately after spheroid implantation. Vascular endothelial growth factor secretion of A498 cells was not affected by GRP.


CONCLUSIONS
RCC angiogenesis is sensitive to GRP receptor blockade. Therefore, GRP receptors may not only stimulate tumor cell proliferation, but also affect tumor microcirculation.
Heuser
M
M
Department of Urology, Georg-August-University, Goettingen, Germany, and Veterans Affairs Medical Center, New Orleans, Louisiana, USA. mheuser@gwdg.de
Schlott
T
T
Schally
A V
AV
Kahler
E
E
Schliephake
R
R
Laabs
S O
SO
Hemmerlein
B
B
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000098:blood supply* / Q000473:pathology; D002455:Cell Division / Q000235:genetics; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D007680:Kidney Neoplasms / Q000098:blood supply* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation / Q000473:pathology; D018613:Microscopy, Confocal; D009367:Neoplasm Staging; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics*; D016133:Polymerase Chain Reaction; D018004:Receptors, Bombesin / Q000235:genetics*
D018004:Receptors, Bombesin