Neoangiogenesis is assumed to play an important role in the progression,
metastasis and prognosis of a wide variety of
tumors. To get insights into the molecular-genetic pathways and the
biological role of angiogenesis in urothelial
carcinogenesis, we analyzed comparatively the expression of the
mRNA of the
vascular endothelial growth factor (
VEGF) and of the angiopoietins-1 and -2 (Ang-1 and Ang-2) in 71
transitional cell carcinomas (TCC) of the urinary bladder in relation to the
tumor grades and stages, and referring to epidemiological risk factors. Using real-time quantitative reverse transcription-polymerase chain reaction, low-stage superficial TCC expressed
VEGF and Ang-2
mRNA at a significantly higher level than high-stage muscle invasive
carcinomas, and low-grade TCC at an insignificantly higher level than high-grade
tumors. The activity of both angiogenic factors was found to be significantly correlated. Conversely, Ang-1
mRNA was expressed at a 3-fold significantly lower level in low-grade, low-stage compared to high-grade, high-stage TCC. A significantly 3- and 2-fold respectively, drop of the
VEGF and Ang-2
mRNA expression in conjunction with a 2-fold significantly higher expression of Ang-1
mRNA in the group of grade 2 TCC when infiltrating the muscle layer may represent a crucial event during urothelial
carcinogenesis, and possibly indicates an important step in promoting the conversion of
bladder cancer from a low to a high
malignancy in this subset of
carcinomas. By immunhistochemistry, high-grade, high-stage
carcinomas less frequently displayed areas with a strong reactivity for the
VEGF protein ('hot spots") than low-grade, low-stage TCC, paralleling the expression of the
mRNA. The expression patterns observed are compatible with a reduced vascular destabilization and decreased formation of new blood vessels in advanced TCC, suggesting a balance between vessel regression and vascular growth, with a less pronounced
vascular remodeling during late phases of urothelial
carcinogenesis. Analyzing the effect of life-style
bladder cancer risk factors, habitual smoking and
coffee consumption was not observed to substantially alter the expression of the angiogenic mediators, except for weakly elevated levels of
VEGF and Ang-2
mRNA in TCC of strong smokers and a borderline significantly decreased
VEGF mRNA expression associated with heavy
coffee consumption. Certain hazardous occupational exposures (
polycyclic hydrocarbons, paints and lacquer, stone dust) may play a role in modulating
tumor angiogenesis. The current data indicate that the signaling molecular-genetic pathways underlying
vascular remodeling are involved in the progression of
urinary bladder cancer to a more malignant and aggressive behaviour.