Alterations in cell proliferation and apoptosis in colon cancers with microsatellite instability

Frank A Sinicrope, Rafaela L. Rego, Megan M. Garrity-Park, Nathan R. Foster, Daniel J. Sargent, Richard M. Goldberg, Myron Wiesenfeld, Thomas Elmer Witzig, Stephen N Thibodeau, Lawrence J. Burgart

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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 + G2M) 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.

Original languageEnglish (US)
Pages (from-to)1232-1238
Number of pages7
JournalInternational Journal of Cancer
Volume120
Issue number6
DOIs
StatePublished - Mar 15 2007

Fingerprint

Microsatellite Instability
Tumor-Infiltrating Lymphocytes
Colonic Neoplasms
Cell Proliferation
Apoptosis
Diploidy
Neoplasms
DNA Mismatch Repair
Ploidies
DNA
In Situ Nick-End Labeling
S Phase
Disease-Free Survival
Flow Cytometry
Colon
Proteins
Immunohistochemistry
Carcinoma

Keywords

  • Apoptosis
  • Colon cancer
  • Microsatellite instability
  • Prognosis
  • Proliferation
  • Tumor infiltrating lymphocytes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Sinicrope, F. A., Rego, R. L., Garrity-Park, M. M., Foster, N. R., Sargent, D. J., Goldberg, R. M., ... Burgart, L. J. (2007). Alterations in cell proliferation and apoptosis in colon cancers with microsatellite instability. International Journal of Cancer, 120(6), 1232-1238. https://doi.org/10.1002/ijc.22429

Alterations in cell proliferation and apoptosis in colon cancers with microsatellite instability. / Sinicrope, Frank A; Rego, Rafaela L.; Garrity-Park, Megan M.; Foster, Nathan R.; Sargent, Daniel J.; Goldberg, Richard M.; Wiesenfeld, Myron; Witzig, Thomas Elmer; Thibodeau, Stephen N; Burgart, Lawrence J.

In: International Journal of Cancer, Vol. 120, No. 6, 15.03.2007, p. 1232-1238.

Research output: Contribution to journalArticle

Sinicrope, FA, Rego, RL, Garrity-Park, MM, Foster, NR, Sargent, DJ, Goldberg, RM, Wiesenfeld, M, Witzig, TE, Thibodeau, SN & Burgart, LJ 2007, 'Alterations in cell proliferation and apoptosis in colon cancers with microsatellite instability', International Journal of Cancer, vol. 120, no. 6, pp. 1232-1238. https://doi.org/10.1002/ijc.22429
Sinicrope, Frank A ; Rego, Rafaela L. ; Garrity-Park, Megan M. ; Foster, Nathan R. ; Sargent, Daniel J. ; Goldberg, Richard M. ; Wiesenfeld, Myron ; Witzig, Thomas Elmer ; Thibodeau, Stephen N ; Burgart, Lawrence J. / Alterations in cell proliferation and apoptosis in colon cancers with microsatellite instability. In: International Journal of Cancer. 2007 ; Vol. 120, No. 6. pp. 1232-1238.
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