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Initiated stem cells in murine intestinal carcinogenesis: Prolonged survival, control by nk cells, and progression
Author(s) -
Altmann G. G.,
Lala P. K.
Publication year - 1994
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910590422
Subject(s) - crypt , azoxymethane , hyperplasia , stem cell , aberrant crypt foci , biology , carcinogenesis , basophilic , carcinogen , cancer research , pathology , immunology , medicine , endocrinology , colorectal cancer , cancer , microbiology and biotechnology , biochemistry , colonic disease
Weekly injections of dimethylhydrazine (DMH) (25 mg/kg), or azoxymethane (AOM) (8 mg/kg) to young adult male CDI mice for 1–2 months produced generalized intestinal crypt hyperplasia, which we measured in duodenum in terms of number of interphase and mitotic cells present in crypts. As shown earlier, the crypts expanded because of the presence of a hyperproliferative “initiated” crypt subpopulation which was also sensitive to natural killer (NK) cells. Hyperplasia was thus present as long as NK activity was suppressed by the carcinogen treatment. After interruption of the treatment for periods of 1, 2, 3, 6 and 10 months in the various groups, hyperplasia soon regressed as a result of elimination of the subpopulation by the recovering NK cells. When NK activity was once again eliminated during the terminal days of these “interruption periods” (by injections of anti‐asialo GM‐l antibody, αAGM‐l), the original hyperplasia was fully reconstituted, apparently from stem cells of the subpopulation which survived up to 10 months in their crypt base location. These “initiated stem cells” represented, then, the original carcinogenic insult during the pre‐cancerous period. They also appeared to be the source of the eventual neoplasia, as treating the animals with mutagens during the interruption periods produced specific changes in crypt base histology: new “crypt base basophilic” (CBB) cells appeared which produced large accumulations as well as microscopic tumors when NK activity was suppressed (by αAGM‐l). Some of the initiated stem cells were apparently transformed into neoplastic ones which remained under NK control, the NK cells preventing the establishment of their progeny. Further experiments indicated that, although the initiated stem cells are not eliminated by normal NK activity, activated NK cells can kill them, thereby eliminating the potential source of neoplasia. © 1994 Wiley‐Liss, Inc.