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 language | English (US) |
|---|---|
| Pages (from-to) | 1232-1238 |
| Number of pages | 7 |
| Journal | International Journal of Cancer |
| Volume | 120 |
| Issue number | 6 |
| DOIs | |
| State | Published - Mar 15 2007 |
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Keywords
- Apoptosis
- Colon cancer
- Microsatellite instability
- Prognosis
- Proliferation
- Tumor infiltrating lymphocytes
ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
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 journal › Article
}
TY - JOUR
T1 - Alterations in cell proliferation and apoptosis in colon cancers with microsatellite instability
AU - Sinicrope, Frank A
AU - Rego, Rafaela L.
AU - Garrity-Park, Megan M.
AU - Foster, Nathan R.
AU - Sargent, Daniel J.
AU - Goldberg, Richard M.
AU - Wiesenfeld, Myron
AU - Witzig, Thomas Elmer
AU - Thibodeau, Stephen N
AU - Burgart, Lawrence J.
PY - 2007/3/15
Y1 - 2007/3/15
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Colon cancer
KW - Microsatellite instability
KW - Prognosis
KW - Proliferation
KW - Tumor infiltrating lymphocytes
UR - http://www.scopus.com/inward/record.url?scp=33846990102&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33846990102&partnerID=8YFLogxK
U2 - 10.1002/ijc.22429
DO - 10.1002/ijc.22429
M3 - Article
C2 - 17187355
AN - SCOPUS:33846990102
VL - 120
SP - 1232
EP - 1238
JO - International Journal of Cancer
JF - International Journal of Cancer
SN - 0020-7136
IS - 6
ER -