Angiogenesis is continuous with two peaks during azaserine-induced rat pancreatic adenocarcinoma progression: an electron microscopic morphometrical study.

Although the indispensable role of neoangiogenesis in tumour growth became generally accepted, quantitative microvascular changes associated to tumour progression have been followed only in a few experimental models. In our study a further experimental system, the azaserine-induced rat pancreatic adenocarcinoma was applied for this purpose. The 15-20 month long progression of this tumour provides us a special opportunity to dissect multistage carcinogenesis in different respects. Tumour samples were taken at months 6, 8 (early lesions), 10, 13, 15 (adenomas), and 20 (differentiated and anaplastic adenocarcinomas) and identified by semithin section histology. We applied reliable and reproducible electron microscopic morphometry for quantification of capillary volume and surface densities in unit tissue volume. Correlation of microvessel volume (MVVD) and surface (MVSD) density data indicated that their changes were the consequence of the changing balance between tumour growth and neoangiogenesis. The significantly decreased but persistent size of the tumour microvasculature during the early slow premalignant growth (months 6-10) is indicative for a slow, but continuous balanced angiogenesis. A dramatic MVVD and MVSD increase at month 13 and the consecutive decrease measured in month 15 adenomas depicted a hitherto unprecedented angiogenic wave within the month 10-15 premalignant growth period. The size of the tumour microvasculature became again stabilized below the control level for the next 5 months of slow growth during which, however, several differentiated adenocarcinomas were transformed to fastly growing angiogenic anaplastic carcinomas, some of which gave rise to invasive tumours. These findings once again verify the angiogenic switch theory.