title: Temozolomide increases the number of mismatch repair-deficient intestinal crypts and accelerates tumorigenesis in a mouse model of Lynch syndrome.
abstract: OBJECTIVE
  Lynch syndrome, a nonpolyposis form of hereditary colorectal cancer, is caused by inherited defects in DNA mismatch repair (MMR) genes. Most patients carry a germline mutation in 1 allele of the MMR genes MSH2 or MLH1. With spontaneous loss of the wild-type allele, cells with defects in MMR exist among MMR-proficient cells, as observed in healthy intestinal tissues from patients with Lynch syndrome. We aimed to create a mouse model of this situation to aid in identification of environmental factors that affect MMR-defective cells and their propensity for oncogenic transformation.
  
  
  METHODS
  We created mice in which the MMR gene Msh2 can be inactivated in a defined fraction of crypt base columnar stem cells to generate MSH2-deficient intestinal crypts among an excess of wild-type crypts (Lgr5-CreERT2;Msh2(flox/-) mice). Intestinal tissues were collected; immunohistochemical analyses were performed for MSH2, along with allele-specific PCR assays. We traced the fate of MSH2-deficient crypts under the influence of different external factors.
  
  
  RESULTS
  Lgr5-CreERT2;Msh2(flox/-) mice developed more adenomas and adenocarcinomas than control mice; all tumors were MSH2 deficient. Exposure of Lgr5-CreERT2;Msh2(flox/-) mice to the methylating agent temozolomide caused MSH2-deficient intestinal stem cells to proliferate more rapidly than wild-type stem cells. The MSH2-deficient intestinal stem cells were able to colonize the intestinal epithelium and many underwent oncogenic transformation, forming intestinal neoplasias.
  
  
  CONCLUSIONS
  We developed a mouse model of Lynch syndrome (Lgr5-CreERT2;Msh2(flox/-) mice) and found that environmental factors can modify the number and mutability of the MMR-deficient stem cells. These findings provide evidence that environmental factors can promote development of neoplasias and tumors in patients with Lynch syndrome.
authors.affiliation: The Netherlands Cancer Institute, Division of Biological Stress Response, Amsterdam, The Netherlands.
authors.forename: Kamila
authors.initials: K
authors.lastname: Wojciechowicz
authors.affiliation: The Netherlands Cancer Institute, Division of Biological Stress Response, Amsterdam, The Netherlands.
authors.forename: Erika
authors.initials: E
authors.lastname: Cantelli
authors.affiliation: The Netherlands Cancer Institute, Division of Biological Stress Response, Amsterdam, The Netherlands.
authors.forename: Bastiaan
authors.initials: B
authors.lastname: Van Gerwen
authors.affiliation: The Netherlands Cancer Institute, Division of Biological Stress Response, Amsterdam, The Netherlands.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Plug
authors.affiliation: The Netherlands Cancer Institute, Division of Biological Stress Response, Amsterdam, The Netherlands.
authors.forename: Anja
authors.initials: A
authors.lastname: Van Der Wal
authors.affiliation: The Netherlands Cancer Institute, Division of Biological Stress Response, Amsterdam, The Netherlands.
authors.forename: Elly
authors.initials: E
authors.lastname: Delzenne-Goette
authors.affiliation: Department of Animal Pathology, Amsterdam, The Netherlands.
authors.forename: Ji-Ying
authors.initials: JY
authors.lastname: Song
authors.affiliation: The Netherlands Cancer Institute, Division of Biological Stress Response, Amsterdam, The Netherlands.
authors.forename: Sandra
authors.initials: S
authors.lastname: De Vries
authors.affiliation: The Netherlands Cancer Institute, Division of Biological Stress Response, Amsterdam, The Netherlands.
authors.forename: Marleen
authors.initials: M
authors.lastname: Dekker
authors.affiliation: The Netherlands Cancer Institute, Division of Biological Stress Response, Amsterdam, The Netherlands. Electronic address: h.t.riele@nki.nl.
authors.forename: Hein
authors.initials: H
authors.lastname: Te Riele
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000236:Adenoma / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053843:DNA Mismatch Repair / Q000187:drug effects*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000473:pathology; D008297:Male; D018345:Mice, Knockout; D051718:MutS Homolog 2 Protein / Q000172:deficiency / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012307:Risk Factors; D000077204:Temozolomide; D013997:Time Factors
chemical_list: D003606:Dacarbazine; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein; D000077204:Temozolomide
keywords: Cancer Risk; Carcinogen; Defective Mismatch Repair; Dietary Factors