title: Alterations in cell proliferation and apoptosis in colon cancers with microsatellite instability.
abstract: Colon cancers with microsatellite instability (MSI) demonstrate a host immune response characterized by tumor infiltrating lymphocytes (TILs) that may exert effects upon tumor cell apoptosis and cell proliferation. Accordingly, we compared rates of apoptosis and cell proliferation in colon cancers with defective DNA mismatch repair and their association with phenotypic features and clinical outcome. Primary Astler-Coller stage B2 and C colon carcinomas (n = 329) were analyzed for MSI and for hMLH1 and hMSH2 protein expression. Apoptosis (TUNEL assay) and p53 expression were also analyzed by immunohistochemistry, and TILs were quantified by morphology. DNA ploidy and proliferation (PI: S phase + G(2)M) were evaluated using flow cytometry. MSI-H (n = 58) colon cancers showed increased TILs that were significantly associated with increased apoptosis, higher apoptosis to proliferation (AI/PI) ratios, reduced proliferative indices (PI) and diploid DNA content. Increased TILs (p = 0.036) and reduced PI (p = 0.042), but not AI or AI/PI, were associated with improved disease-free survival. Tumors with MSI-H (p = 0.032) or loss of hMLH1 or hMSH2 proteins (p = 0.040), or diploidy (p = 0.0015), had better adjusted overall survival rates. Interestingly, similar rates of cell turnover and overlapping survival rates were found in diploid MSS/MSI-L tumors and in MSI-H cases. In conclusion, higher apoptosis/proliferation ratios and reduced cell proliferation are phenotypic features of MSI-H tumors that are associated with increased TILs, indicating an activated immune response that may contribute to their favorable survival rates.
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. sinicrope.frank@mayo.edu
authors.forename: Frank A
authors.initials: FA
authors.lastname: Sinicrope
authors.forename: Rafaela L
authors.initials: RL
authors.lastname: Rego
authors.forename: Megan M
authors.initials: MM
authors.lastname: Garrity-Park
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Foster
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sargent
authors.forename: Richard M
authors.initials: RM
authors.lastname: Goldberg
authors.forename: Myron
authors.initials: M
authors.lastname: Wiesenfeld
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Witzig
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Burgart
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D053843:DNA Mismatch Repair; D005260:Female; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D053842:Microsatellite Instability; D018895:Microsatellite Repeats; D008875:Middle Aged; D011003:Ploidies; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53