Tracing Cell Fates in Human Colorectal Tumors from Somatic Microsatellite Mutations

Abstract

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.

Inhibition of the Na+/H+ antiporter induces cell death in TF-1 erythroleukemia cells stimulated by the stem cell factor

“…Mutations accumulate differently when cell fates are determined intrinsically before or extrinsically after division. Proliferation of stem cells (based on asymmetrical division, as in intestinal crypts) and random proliferation (based on asymmetrical and symmetrical division) represent cell fates determined before and after division, respectively [27]. In the event that malignant stem cells divide asymmetrically, it is possible that they evolved from normal stem cells.…”

Lineage tracing reveals multipotent stem cells maintain human adenomas and the pattern of clonal expansion in tumor evolution

“…Indeed, the diversity of adenomatous crypts was comparable to that observed in normal crypts, implying that the dynamics of stem cell turnover in the normal and adenomatous crypt are comparable. Furthermore, analysis of the variance in the microsatellite pattern in mismatch repair-deficient adenomas (49) and in the methylation patterns in colorectal cancers (24) suggests that cell hierarchies may persist throughout carcinogenesis, albeit with altered numbers of stem cells.…”

Hypermutable DNA chronicles the evolution of human colon cancer

“…Due to replication slippage (16), mutations are introduced frequently but presumably have no effect on fitness. In patients with DNA mismatch repair (MMR) defects and resulting microsatellite instability (MSI), variation in dinucleotide repeats has been used to study several aspects of tumor progression (17)(18)(19), but mutation rates in tumors with intact MMR are too low to make this approach widely applicable (20).…”