Although angiogenesis is considered to be indispensable for continuous tumour growth, only very few studies have been published performing microvessel quantification during tumour progression. We measured the tumour vascularity in different stages of rat pancreatic carcinogenesis induced by azaserine and promoted by raw soya flour-containing pancreatotrophic diet. Besides the tumour samples taken at 6 (atypical acinar cell nodules), 15 (adenomas) and 20 (localised adenocarcinomas) months after carcinogen initiation, we also investigated 3 control groups: tumour-bearing host tissue of azaserine-treated rats and normal tissue of untreated rats kept on standard or pancreatotrophic diet. In contrast with the usual microvessel counting on hot spots, we determined microvascular surface density (SV) and volume density (VV) by electron microscopic morphometry. There was no significant difference in these respect between the control groups. At month 6 after the azaserine induction SV and VV showed slight, nonsignificant decrease as compared to the host control. Both values remained unchanged until the 15th month and increased significantly by the 20th month. These results may indicate comparable growth rate of tumour and new microvessels in the premalignant stages of carcinogenesis while a more intense angiogenesis than tumour growth afterwards.
American Institute of Nutrition (1977) Report of the American Institute of Nutrition ad hoc committee on standards for nutritional studies. J. Nutr. 107, 1340–1348.
Barth, P. J., Weingärtner, K., Köhler, H. H., Bittinger, A. (1996) Assessment of the vascularization in prostatic carcinoma: A morphometric investigation. Hum. Pathol. 27, 1306–1310.
Beliën, J. A., Somi, S., de Jong, J. S., van Diest, P. J., Baak, J. P. (1999) Fully automated microvessel counting and hot spot selection by image processing of whole tumour sections in invasive breast cancer. J. Clin. Pathol. 52:3, 184–192.
Bochner, B. H., Cote, R. J., Weidner, N., Groshen, S., Chen, S. C, Skinner, D. G., Nichols, P. W. (1995) Angiogenesis in bladder cancer: relationship between microvessel density and tumour prognosis. J. Natl. Cancer Inst. 87:21, 1603–1612.
De Jaeger, K., Merlo, F. M., Kavanagh, M. C., Fyles, A. W., Hedley, D., Hill, R. P. (1998) Heterogeneity of tumour oxygenation: relationship to tumour necrosis, tumour size, and metastasis. Int. J. Radiat. Oncol. Biol. Phys. 42:4, 717–721.
Folkman, J. (1985) Tumor angiogenesis. Adv. Cancer Res. 43, 175–203.
Fontanini, G., Lucchi, M., Vignati, S., Mussi, A., Ciardiello, F., De Laurentiis, M., De Placido, S., Basolo, F., Angeletti, C. A., Bevilacqua, G. (1997) Angiogenesis as a prognostic indicator of survival in non-small-cell lung carcinoma: a prospective study. J. Natl. Cancer Inst. 89:12, 881–886.
Gasparini, G., Weidner, N., Maluta, S., Pozza, F., Boracchi, P., Mezzetti, M., Testolin, A., Bevilacqua, P. (1993) Intratumoral microvessel density and p53 protein: correlation with metastasis in head and neck squamous-cell carcinoma. Int. J. Cancer 55:5, 739–744.
Hanahan, D., Folkman, J. (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353–364.
Köhler, H. H., Barth, P. J., Siebel, A., Gerharz, E. W., Bittinger, A. (1996) Quantitative assessment of vascular surface density in renal cell carcinomas. Br. J. Urol. 42:4, 717–721.
Longnecker, D. S. (1987) The azaserine-induced model of pancreatic carcinogenesis in rats. In: Scarpelli, D. G., Reddy, J. K. and Longnecker, D. S. (eds): Experimental pancreatic carcinogenesis. CRC Press, Boca Raton. pp. 117–132.
McGuinness, E. E., Hopwood, D., Wormsley, K. G. (1982) Further studies of the effects of raw soya flour on the rat pancreas. Scand. J. Gastroenterol. 17, 273–277.
Milgross, C. G., Tucker, S. L., Mason, K. A., Hunter, N. R., Peters, L. J., Milas, L. (1997) The effect of tumor size on necrosis and polarographically measured pO2. Acta Oncol. 36:2, 183–189.
Porschen, R., Classen, S., Piontek, M., Borchard, F. (1994) Vascularization of carcinomas of the esophagus and its correlation with tumor proliferation. Cancer Res. 54:2, 587–591.
Réz, G., Tóth, S., Pálfia, Z. (1999) Cellular autophagic capacity is highly increased in azaserine-induced premalignant atypical acinar nodule cells. Carcinogenesis 20, 1893–1898.
Rockwell, S., Knisley, J. P. S. (1997) Hypoxia and angiogenesis in experimental tumor models: Therapeutic implications. In Goldberg, I. D. and Rosen, E. M. (eds): Regulation of angiogenesis. Birkhäuser Verlag, Basel. pp. 335–360.
Tanigawa, N., Lu, C., Mitsui, T., Miura, S. (1997) Quantitation of sinusoid-like vessels in hepatocellular carcinoma: its clinical and prognostic significance. Hepathology 26:5, 1216–1223.
Toth, S., Nagy, K., Pálfia, Z., Réz, G. Regulation of cellular autophagic capacity: data from the azaserine-induced pancreatic tumor progression (in preparation)
Vermeulen, P. B., Libura, M., Libura, J., O’Neill, P. J., van Dam, P., van Marck, E., van Oosterom, A. T., Dirix, L. Y. (1997) Influence of investigator experience and microscopic field size on microvessel density in node-negative breast carcinoma. Breast Cancer Res. Treat. 42:2, 165–172.
Weibel, E. R. (1969) Stereological principles for morphometry in electron microscopic cytology. Int. Rev. Cytol. 26, 235–302.
Weidner, N., Folkman, J., Pozza, F., Bevilacqua, P., Allred, E. N, Moore, D. H., Meli, S., Gasparini, G. (1992) Tumour angiogenesis: a new significant and independent prognostic indicator in earlystage breast carcinoma. J. Natl. Cancer Inst. 84:24, 1875–1887.
Yager, J. D., Roebuck, B. D., Zurlo, J., Longnecker, D. S., Weselcouch, E. O., Wilpone, S. A. (1981) A single-dose protocol for azaserine initiation of pancreatic carcinogenesis in the rat. Int. J. Cancer 28, 601–606.
Dedicated to Professor János Kovács on the occasion of his 70th birthday
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Nagy, K., Pálfia, Z. & Réz, G. Quantitative Microvascular Changes During Azaserine-Initiated Pancreatic Carcinogenesis. BIOLOGIA FUTURA 52, 403–409 (2001). https://doi.org/10.1556/ABiol.52.2001.4.5
- tumour progression