Involvement of adrenomedullin induced by hypoxia in angiogenesis in human renal cell carcinoma.
BACKGROUND
Adrenomedullin (AM) has pluripotent activities and is involved in the regulation of vasomotor tone, cell differentiation and embryogenesis. However, the expression and pathophysiological role of AM has not been determined in human renal cell carcinoma (RCC).


METHODS
Twenty-six RCC specimens and three cultured human RCC cell lines (A498, SN12C and KPK-13) were analyzed. Expression of AM was determined by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) analysis. The correlation between AM expression and microvessel count (MVC) in RCC specimens was examined to determine if AM plays a role in tumor angiogenesis. The correlation between the expression of AM and vascular endothelial growth factor (VEGF) was also investigated. Lastly, the effect of hypoxia upon the mRNA expression of AM, VEGF and hypoxia inducible factor-1 (HIF-1) by RCC cell lines was determined.


RESULTS
Immunohistochemistry indicated that AM and VEGF were primarily localized in the cytosol of RCC cells. AM and VEGF mRNA were detected in all RCC specimens and cultured RCC cell lines analyzed by RT-PCR. There was a positive correlation between AM mRNA expression and MVC (r = 0.516, P = 0.0062), and between VEGF mRNA expression and MVC (r = 0.485, P = 0.0111). We also observed a positive correlation between AM mRNA expression and VEGF mRNA expression (r = 0.552, P = 0.0029). Hypoxia significantly induced AM and VEGF mRNA expression, although the increase of the AM mRNA level (10.6-26.7 fold) was markedly greater than that of the VEGF mRNA level (1.5-1.9 fold).


CONCLUSIONS
These results suggest that hypoxia-induced AM plays a part in tumor angiogenesis in conjunction with VEGF and facilitates human RCC growth under hypoxic conditions.
Department of Urology, Oita Medical University, Japan. SPOTS@oita-med.ac.jp
Yoshitsugu
Y
Fujita
Hiromitsu
H
Mimata
Nobuyoshi
N
Nasu
Takeo
T
Nomura
Yoshio
Y
Nomura
Masayuki
M
Nakagawa
D053607:Adrenomedullin; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000473:pathology / Q000503:physiopathology*; D066298:In Vitro Techniques; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects / Q000503:physiopathology*; D007680:Kidney Neoplasms / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D010455:Peptides / Q000032:analysis / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D014665:Vasodilator Agents / Q000032:analysis / Q000494:pharmacology*
D010455:Peptides; D014665:Vasodilator Agents; D053607:Adrenomedullin