癌細胞の発生とプログレッション

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Long-term studies of in vivo kinetics of growth and proliferation of human cancers in vivo have revealed that carcinomas become manifest in patients some 25 years after carcinogenetic process has begun (Fujita '78). During this long period of cancer growth, do cancer cells remain unchanged, in morphology and function? So far, few pathologists have attempted to answer the question. At late stages of cancer growth, human carcinoma cells show high degree of atypism so that correct diagnoses can always be established by microscopic examination of the atypism. By DNA quantification or karyotype analyses of individual cancer cells, however, we found that incipient cancers show much less DNA abnormalities than the advanced ones. It is now clear, from molecular studies (Fialkow '76) that, in principle, a human cancer starts from one mutated host cell. Histochemical studies revealed that the newborn cancer cell and their direct progeny, at least during the earliest stage of carcinogenesis, are diploid in DNA content and seem to show very little abnormalities. Obviously during the progression of cancer growth from the single cell to the final stage, gross changes are accumulated in the cancer cell genome so that highly atypical cells are constant final outcome of the human cancer growth in vivo. We analyzed abnormalities of chromosomal morphology together with DNA contents in advanced human cancer cells and found that, commonly, 10〜20 chromosomal changes accumulate in individual cancer cells, thereby marked atypisms are produced in morphology and DNA contents in the cancer cells. Gross mutations in the cancer cell DNA occurr very frequently and accumulate in the genome 1 per 2〜4 doubling times. This is extremely high rate of mutation that cannot be explained by any theories and observations of genomic mutation in human cells so far known. To explain this high rate of mutation in cancer cells, we adopt the "cross linkage hypothesis" (Nakanishi and Fujita '80). This is to assume presence of cross linkage between 2 strands in the double helix of DNA. In quiescent state, it does nothing, but when the cell enters into DNA synthesis and mitosis, the 2 daughter chromatids cannot be separated from each other by the presence of the cross linkage, and the aborted mitosis may sometimes produce polyploid cells. If, however, the mitosis is accomplished, forced separation in mitosis may pruduce breakage, partial loss, translocaton, monosomy, trisomy, tetrasomy, and other abnormalities of chromosomes. This "instability of chromosome" should recur every time the cell with the cross linkage enters into DNA synthesis and division, since the abnormality of DNA is replicated and inherited to the daughter cells, From this cross linkage theory, following conclusions were drawn : 1) At an earlier phase of carcinogenesis, there should be a stage in which cancer cells are not fully developed in atypical morphology and malignant function, though they are destined to produce full-blown cancer cells at high probability later in its natural history. They are thought to be high risk cell population and rightly called "pre-cancerous", but cannot be classified either benign or malignant in any deterministic way, because their risk depends on the future phenomena that will be produced by DNA cross linkage and repeated mitoses. Thus the meaning of the pre-cancerous or dysplastic lesions could only be understood by a concept of probability. 2) The pre-cancerous lesions mentioned above are characterized with chromosomal instability so that they can show some degree of cellular atypism. Such state of chromosomal instability tends to produce polyploid cells and show anisomorphosis of nuclei. So far, this kind of change in cell population should have been called "dysplasia". 3) For correct diagnosis of earliest lesions of human cancers, we pathologists should develop new concepts and criteria, because simple projection of those established with full-blown cancer cells shou
社団法人日本産科婦人科学会の論文
1991-08-01

癌細胞の発生とプログレッション

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