title: 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.
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington 98195-7705, USA. rrisques@u.washington.edu
authors.forename: Rosa Ana
authors.initials: RA
authors.lastname: Risques
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Lai
authors.forename: Cigdem
authors.initials: C
authors.lastname: Himmetoglu
authors.forename: Anoosheh
authors.initials: A
authors.lastname: Ebaee
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Ziding
authors.initials: Z
authors.lastname: Feng
authors.forename: Mary P
authors.initials: MP
authors.lastname: Bronner
authors.forename: Bassel
authors.initials: B
authors.lastname: Al-Lahham
authors.forename: Kris V
authors.initials: KV
authors.lastname: Kowdley
authors.forename: Keith D
authors.initials: KD
authors.lastname: Lindor
authors.forename: Peter S
authors.initials: PS
authors.lastname: Rabinovitch
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Brentnall
mesh_terms: D000328:Adult; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence / Q000502:physiology*; D003093:Colitis, Ulcerative / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018450:Disease Progression; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016615:Telomere / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D055815:Young Adult
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53