Lymphangiogenesis and angiogenesis in bladder cancer: prognostic implications and regulation by vascular endothelial growth factors-A, -C, and -D.
OBJECTIVE
Lymph vessel density (LVD) and microvessel density (MVD) correlate with the malignant potential of tumors and patient survival. Vascular endothelial growth factors (VEGF)-A, VEGF-C, and VEGF-D could modulate LVD and MVD. We investigated the clinical and prognostic significance of LVD and MVD on lymphangiogenic and angiogenic function of VEGF-A, VEGF-C, and VEGF-D in human bladder cancer.


METHODS
We reviewed tissue samples from patients with nonmetastatic bladder cancer who had undergone transurethral resections (n = 126). The densities of D2-40-positive vessels (LVD) and CD34-positive vessels (MVD) were measured by a computer-aided image analysis system. Expression of VEGF-A, VEGF-C, and VEGF-D was examined by immunohistochemistry; survival analyses and their independent roles were investigated using multivariate analysis models.


RESULTS
LVD was associated with tumor grade but not with pT stage. LVD was associated with metastasis-free survival (log rank P = 0.039), but was not an independent prognostic factor. Although MVD affected survival, the combination of high LVD and high MVD in tumors was an independent predictor of metastasis-free survival. Although VEGF-C expression was positively associated with both LVD and MVD, VEGF-D was associated only with LVD. VEGF-A expression was associated with MVD in univariate analysis, however, it was not an independent factor.


CONCLUSIONS
Lymphangiogenesis and angiogenesis influence metastasis-free survival, and are regulated by VEGF-C and/or VEGF-D. Our results suggest that LVD and MVD are useful tools for the selection of postoperative management and treatment strategies in patients with bladder cancer.
Miyata
Yasuyoshi
Y
Department of Urology, Nagasaki University School of Medicine, Sakamoto, Nagasaki, Japan. int.doc.miya@m3.dion.ne.jp
Kanda
Shigeru
S
Ohba
Kojiro
K
Nomata
Koichiro
K
Hayashida
Yasushi
Y
Eguchi
Jiro
J
Hayashi
Tomayoshi
T
Kanetake
Hiroshi
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000032:analysis; D058846:Antibodies, Monoclonal, Murine-Derived; D018952:Antigens, CD34 / Q000032:analysis; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D042583:Lymphangiogenesis; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D011379:Prognosis; D016019:Survival Analysis; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics* / Q000378:metabolism; D042643:Vascular Endothelial Growth Factor D / Q000235:genetics* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018952:Antigens, CD34; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; C500987:monoclonal antibody D2-40