Ulcerative colitis-associated colorectal cancer arises in a field of short telomeres, senescence, and inflammation

Abstract

Inflammation plays a role in the progression to cancer and it is linked to the presence of senescent cells. Ulcerative colitis (UC) is a chronic inflammatory disease that predisposes to colorectal cancer. Tumorigenesis in this setting is associated with telomere shortening that can be observed in the nondysplastic epithelium of UC patients with high-grade dysplasia (HGD) or cancer (UC progressors). We hypothesized that a preneoplastic field of inflammation, telomere shortening, and senescence underlies tumor progression in UC progressors. Multiple biopsies of varying histologic grade were collected along the colon of nine UC progressors and analyzed for telomere length, DNA damage, senescence, p53, p16, and chronic and acute inflammation. Twenty biopsies from four UC nonprogressors and twenty-one biopsies from control individuals without UC were also analyzed. Short telomeres and increased DNA damage, senescence, and infiltrating leukocytes were observed in biopsies located less than 10 cm from HGD or cancer. Low-grade dysplasia (LGD) had the shortest telomeres along with the highest levels of senescence and infiltrating leukocytes, whereas HGD biopsies showed the opposite pattern. The expression of p16 and p53 was low in nondysplastic biopsies but progressively increased in LGD and HGD. In addition, high levels of infiltrating leukocytes were associated with telomere shortening, senescence, and reduced p53 expression. These results suggest that dysplasia arises in a preneoplastic field of chronic inflammation, which leads to telomere shortening, DNA damage, and senescence. Our findings argue that senescence acts as a tumor suppressor mechanism that is abrogated during the transition from LGD to HGD in UC.

Figure 1

Comparison of means by histological grade. Error bars indicate standard errors of the mean (sem). A: epithelial telomere length; B: stromal telomere length; C: epithelial telomerase activity; D: stromal telomerase activity; E: γ-H2AX; F: Dec1, G: p16; and H: p53. * p<0.05, ** p<0.005, based on Mann-Whitney tests.

Figure 2

Correlation between the percentage of dysplasia and the frequency of alterations in histologically negative biopsies for each UC progressor. A: epithelial telomere length; B: telomerase activity; C: γ-H2AX; D: Dec1; E: p16; and F: p53. p-values correspond to the Spearman's correlation coefficient.

Figure 3

A-F: Scoring system used for infiltrating leukocytes based on H&E staining. A: non UC colon, 1+; B: non progressor, 2+; C: negative ≥10cm from HGD/cancer, 2+; D: negative <10cm from HGD/cancer, 3+; E: LGD, 3+; F: HGD, 2+. G-L: IHC staining from colon of a UC non progressor (G-I) and a LGD biopsy from a UC progressor (J-L). G,J: T-cells (CD3); H,K: B-cells (CD20); I-L: macrophages (CD68). 400×.

Figure 4

Association between lamina propria infiltrating leukocytes and A: epithelial telomere length, B: stromal telomere length, C: epithelial telomerase, D: stromal telomerase, E: γ-H2AX, F: Dec1, G: p16, and I: p53. p-values correspond to Mann-Whitney tests.