Growth regulation is a crucial event in tumour progression. Surprisingly, relatively few papers have dealt with the catabolic side of regulation, and there are practically no data regarding the autophagic process during tumour development. We approach this problem by morphometrical investigation into the possible changes of autophagic activity during the progression of rat pancreatic adenocarcinoma induced by azaserine. In the present study, autophagic capacity of the azaserine-induced premalignant and malignant cells were characterised and compared to the respective host tissue cells of the rat pancreas and to the acinar cells in other stages of tumour development. Using vinblastine (VBL) as an enhancer, and cycloheximide (CHI) as an inhibitor of autophagic segregation we observed that autophagic capacity of premalignant cells (month 6 and 10 after initiation) is much higher than in the host tissue cells. We found a sharp decrease in self-digesting capacity in adenocarcinoma cells (month 20) where VBL induced a minimal accumulation of autophagic vacuoles which was, surprisingly, not inhibited by CHI, i.e. the CHI-sensitive regulatory step was lost. The changes in autophagic capacity are probably associated to specific steps of tumour progression in our system.
Ahlberg, J., Yucel, T., Eriksson, L., Glaumann, H. (1987) Characterization of the proteolytic compartment in rat hepatocyte nodules. Virchows Arch. B. Cell Path. 53, 79–88.
Baccino, F. M., Tessitore, L., Bonelli, G. (1984) Control of protein degradation and growth phase in normal and neoplastic cells. Toxicol. Pathol. 12, 281–287.
Boyer, M. J., Tannock, I. F. (1993) Lysosomes, lysosomal enzymes and cancer. Adv. Canc. Res. 60, 269–291.
Bursch, W., Ellinger, A., Kienzl, H., Török, L., Pandey, S., Sikorska, M. Walker, R., Hermann, R. S. (1996) Active cell death induced by the anti-estrogens tamoxifen and ICI 164 384 in human mammary carcinoma cells (MCF-7) in culture: the role of autophagy. Carcinogenesis 17, 1595–1607.
Farguhar, M. G. (1969) Lysosome function in regulating secretion: disposal of secretory granules in cells of the anterior pituitary gland. In: Dingle, J. T., Fell, H. B. (eds) Lysosomes in biology and pathology. North-Holland Publ. Co., Amsterdam-London, Vol. 2, pp. 462–482.
Gunn, J. M., Clank, M. G., Knowles, S. E., Hopgood, M. F., Ballard, F. J. (1977) Reduced rates of proteolysis in transformed cells. Nature 266, 58–60.
Kovács, J. (1983) Regression of autophagic vacuoles in seminal vesicle cells following cycloheximide treatment. Exp. Cell Res. 144, 231–234.
Kisen, G. X., Tessitore, L., Costelli, P., Gordon, P. B., Schwarze, P. E., Baccino, F. M., Seglen, P. O. (1993) Reduced autophagic activity in primary rat hepatocellular carcinoma and ascites hepatoma cells. Carcinogenesis 14(2), 2501–2505.
Longnecker, D. S., Roebuck, B. D., Yager, J. D., Lilja, H. S., Sigmund, B. (1981) Pancreatic carcinoma in azaserine-treated rats (induction, classification and dietary modulation of incidence). Cancer 47, 1562–1572.
Longnecker, D. S. (1986) Experimental models of exocrine pancreatic tumors. In: Go, V. L. W., Gardner, J. D., Brooks, F. P., Lebenthal, E., Di Magno, E. P., Scheele, G. A. (eds) The exocrine pancreas biology, pathobiology and diseases. Raven Press, New York. pp. 443–458.
Oliva, O., László, L., Pálfia, Z., Réz, G. (1991) Translational inhibitors cycloheximide, emetin and puromycin inhibit cellular autophagy in mouse liver parenchymal and pancreatic acinar cells in vivo. Acta Morphologica Hung. 39(2), 79–85.
Oliva, O., Réz, G., Pálfia, Z., Fellinger, E. (1992) Dynamics of vinblastine-induced autophagocytosis in murine pancreatic acinar cells: influence of cycloheximide post-treatments. Exp. Molec. Pathol. 56, 76–86.
Papadopoulos, T., Pfeifer, U. (1986) Regression of rat liver autophagic vacuoles by locally applied cycloheximide. Lab. Invest. 54, 100–107.
Pfeifer, U. (1987) Functional morphology of the lysosomal apparatus. In: Glaumann, H., Ballard, F. J. (eds) Lysosomes, their role in protein breakdown. Academic Press, London, UK, pp. 3–59.
Pfeifer, U., Tessitore, L., Bonelli, G., Baccino, F. M. (1988) Regulation of protein turnover versus growth state III. Growth cessation is associated with activation of autophagy in Yoshida ascites hepatoma AH-130. Virchows Arch. B Cell Pathol. 55, 3763–3769.
Punnonen, E. L., Reunanen, H. (1990) Effects of vinblastine, leucine, and histidine, and 3-methyladenine on autophagy in Ehrlich ascites cells. Exp. Mol. Pathol. 52, 87–97.
Réz, G., Tóth, S., Pálfia, Z. (1999) Cellular autophagic capacity is highly increased in azaserineinduced premalignant atypical acinar nodule cells. Carcinogenesis 20, 1893–1898.
Réz, G., Csák, J., Fellinger, E., László, L., Kovács, A. L., Oliva, O., Kovács, J. (1996) Time course of vinblastine-induced autophagocytosis and changes in the endoplasmic reticulum in murine pancreatic acinar cells: a morphometrical and biochemical study. Eur. J. Cell Biol. 71, 341–350.
Schulte-Hermann, R., Bursch, W., Grasl-Kraupp, B., Torok, L., Ellinger, A., Mullauer, L. (1995) Role of active cell death (apoptosis) in multi-stage carcinogenesis. Toxicol. Lett. 82-83, 143–148.
Schwarze, P. E., Seglen, P. O. (1985) Reduced autophagic activity, improved protein balance and enhanced in vitro survival of hepatocytes isolated from carcinogen-treated rats. Exp. Cell Res. 157, 15–28.
Seglen, P. O., Schwarze, P. E., Saeter, G. (1986) Changes in cellular ploidy and autophagic responsiveness during rat liver carcinogenesis. Toxicol. Pathol. 14, 342–348.
Seglen, P. O. (1997) DNA ploidy and autophagic protein degradation as determinants of hepatocellular growth and survival. Cell Biol. Toxicol. 13, 301–315.
Tessitore, L., Bonelli, G., Cecchini, G., Amenta, J. S., Baccino, F. M. (1987) Regulation of protein turnover versus growth state: ascites hepatoma as a model for studies both in the animal and in vitro. Arch. Biochem. Biophys. 255, 372–384.
Weibel, E. R. (1969) Stereological principles for morphometry in electron microscopic cytology. Int. Rev. Cytol. 26, 235–302.
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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Tóth, S., Nagy, K., Pálfia, Z. et al. Changes in Cellular Autophagic Capacity During Azaserine-Initiated Pancreatic Carcinogenesis. BIOLOGIA FUTURA 52, 393–401 (2001). https://doi.org/10.1556/ABiol.52.2001.4.4
- tumour progression