APOPTOSIS IN HUMAN COLORECTAL TUMORS - ULTRASTRUCTURE AND QUANTITATIVE STUDIES ON TISSUE LOCALIZATION AND ASSOCIATION WITH BAK EXPRESSION

Apoptotic cell death in human tumours has been demonstrated by electro n and light microscopy. In adenomas, fragmented and apoptotic nuclei a nd signs of phagocytosis have been observed close to the basement memb rane. In carcinomas the characteristic structures were apoptotic bodie s with small fragments of chromatin. DNA fragmentation was shown by in situ end-labelling. Quantitative assessment of apoptosis and prolifer ation revealed a high apoptotic index (AI) in all types of adenoma (tu bular: 1.77+/-0.35%, tubulovillous: 2.38+/-0.41%; villous: 3.3+/-0.39% ) as well as loss of compartmentalization of proliferating and dying c ells. In carcinomas a shift towards proliferation was evident, as show n by lower AIs than in adenomas (0.9+/-0.68% and 1.1+/-0.12% for moder ately and poorly differentiated tumours), higher Ki67 indices (38.32+/ -2.23% and 57+/-3.89% respectively) and higher mitosis (0.9+/-0.56% an d 1.21+/-0.17%, respectively). However, apoptosis was observed in all tumours and is available as a target for therapeutic intervention. Exp ression of the apoptosis related proteins bcl-2 and bak also reflected loss of compartmentalization. While bcl-2 did not show a consistent r elationship to AI in tumour specimens, bak was positively correlated w ith apoptosis in 4 of 8 adenomas and 4 of 7 carcinomas, suggesting a r ole for this protein in the induction of apoptosis in a subset of tumo urs.