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

Rosa Ana Risques, Lisa A. Lai, Cigdem Himmetoglu, Anoosheh Ebaee, Lin Li, Ziding Feng, Mary P. Bronner, Bassel Al-Lahham, Kris V. Kowdley, Keith Lindor, Peter S. Rabinovitch, Teresa A. Brentnall

Research output: Contribution to journalArticle

71 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1669-1679
Number of pages11
JournalCancer Research
Volume71
Issue number5
DOIs
StatePublished - Mar 1 2011
Externally publishedYes

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Telomere
Ulcerative Colitis
Colorectal Neoplasms
Inflammation
Telomere Shortening
Biopsy
DNA Damage
Leukocytes
Neoplasms
Colon
Carcinogenesis
Chronic Disease
Epithelium

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Risques, R. A., Lai, L. A., Himmetoglu, C., Ebaee, A., Li, L., Feng, Z., ... Brentnall, T. A. (2011). Ulcerative colitis-associated colorectal cancer arises in a field of short telomeres, senescence, and inflammation. Cancer Research, 71(5), 1669-1679. https://doi.org/10.1158/0008-5472.CAN-10-1966

Ulcerative colitis-associated colorectal cancer arises in a field of short telomeres, senescence, and inflammation. / Risques, Rosa Ana; Lai, Lisa A.; Himmetoglu, Cigdem; Ebaee, Anoosheh; Li, Lin; Feng, Ziding; Bronner, Mary P.; Al-Lahham, Bassel; Kowdley, Kris V.; Lindor, Keith; Rabinovitch, Peter S.; Brentnall, Teresa A.

In: Cancer Research, Vol. 71, No. 5, 01.03.2011, p. 1669-1679.

Research output: Contribution to journalArticle

Risques, RA, Lai, LA, Himmetoglu, C, Ebaee, A, Li, L, Feng, Z, Bronner, MP, Al-Lahham, B, Kowdley, KV, Lindor, K, Rabinovitch, PS & Brentnall, TA 2011, 'Ulcerative colitis-associated colorectal cancer arises in a field of short telomeres, senescence, and inflammation', Cancer Research, vol. 71, no. 5, pp. 1669-1679. https://doi.org/10.1158/0008-5472.CAN-10-1966
Risques, Rosa Ana ; Lai, Lisa A. ; Himmetoglu, Cigdem ; Ebaee, Anoosheh ; Li, Lin ; Feng, Ziding ; Bronner, Mary P. ; Al-Lahham, Bassel ; Kowdley, Kris V. ; Lindor, Keith ; Rabinovitch, Peter S. ; Brentnall, Teresa A. / Ulcerative colitis-associated colorectal cancer arises in a field of short telomeres, senescence, and inflammation. In: Cancer Research. 2011 ; Vol. 71, No. 5. pp. 1669-1679.
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AU - Bronner, Mary P.

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