Stages of intestinal carcinogenesis and their control by host NK cells. Implications to prevention and therapy.

Abstract

DMH-induced (25mg/kg/wk) rodent intestinal carcinogenesis was re-examined using histometry under various conditions including modulation of host natural killer (NK) cell activity and mutagen administration. Early lesion was enterocyte hyperplasia all along the intestinal tract. Cell kinetic analysis showed that it was caused by a slightly altered but still functional "initiated" enterocyte population added to the normal population which remained unchanged. Primarily, initiated stem (IS) cells were added which then produced their initiated progeny which still renewed normally. NK cells countered the initiated cells selectively, either inhibiting IS cell proliferation or killing them when activated by lymphokines. Evidence was obtained that the IS cells could further transform into preneoplastic stem (PS) and then neoplastic stem (NS) cells under the influence of promoters and mutagens, respectively. Subsequent transformation of normal stem cells into IS, PS, and NS cells apparently is the basis of carcinogenesis. These produce lesions, hyperplastic, preneoplastic, and neoplastic, respectively, only when and where NK activity is inhibited. Under the influence of normal NK cells, they remain dormant (nonproliferative), compatible with normal life.