Tracing Cell Fates in Human Colorectal Tumors from Somatic Microsatellite Mutations: Evidence of Adenomas with Stem Cell Architecture

Occult aspects of tumor proliferation are likely recorded genetically as their microsatellite (MS) loci become polymorphic. However, MS mutations generated by division may also be eliminated with death as noncoding MS loci lack selective value. Therefore, highly polymorphic MS loci cannot exist unless mutation rates are high, or unless mutation losses are inherently minimized. Mutations accumulate differently when cell fates are determined intrinsically before or extrinsically after division. Stem cell (asymmetrical division as in intestinal crypts) and random (asymmetrical and symmetrical division) proliferation, respectively, represent simulated cell fates determined before or after division. Whereas mutations regardless of selection systematically persist once inherited with stem cell proliferation, mutations are eliminated by the symmetrical losses of both daughter cells with random proliferation. Therefore, greater genetic diversity or MS variance accumulate with stem cell compared with random proliferation. MS loci in normal murine intestinal mucosa and xenografts of cancer cell lines accumulated mutations, respectively, consistent with stem cell and random proliferation. Tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC) demonstrated polymorphic MS loci. Overall, three of five adenomas and one of six cancers exhibited high MS variances. Assuming mutation rates are not significantly greater in adenomas than in cancers, these studies suggest the stem cell proliferation and hierarchy of normal intestines persists in many HNPCC adenomas and some cancers. An adenoma stem cell architecture can explain the complex polymorphic MS loci observed in HNPCC adenomas and account for many adenoma features. in contrast, cancers may lose intrinsic control of cell fate. These studies illustrate a feasible phylogenetic approach to unravel and describe occult aspects of human tumor proliferation. The switch from predominantly stem cell to random proliferation may be a critical and defining characteristic of malignancy.