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

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.

[1]  P. M. O'Connor,et al.  Mechanisms by which inflammation may increase intestinal cancer risk in inflammatory bowel disease , 2010, Inflammatory bowel diseases.

[2]  J. Campisi,et al.  Inflammatory networks during cellular senescence: causes and consequences. , 2010, Trends in molecular medicine.

[3]  M. Hande,et al.  Tumor cell redox state and mitochondria at the center of the non-canonical activity of telomerase reverse transcriptase. , 2010, Molecular aspects of medicine.

[4]  J. Campisi,et al.  The senescence-associated secretory phenotype: the dark side of tumor suppression. , 2010, Annual review of pathology.

[5]  Robert E. Brown,et al.  Field effect in cancer-an update. , 2009, Annals of clinical and laboratory science.

[6]  F. D. D. Fagagna,et al.  SASPense and DDRama in cancer and ageing , 2009, Nature Cell Biology.

[7]  G. Saretzki.  Telomerase, mitochondria and oxidative stress , 2009, Experimental Gerontology.

[8]  Jasmine L. Gallaher,et al.  Ulcerative colitis is a disease of accelerated colon aging: evidence from telomere attrition and DNA damage. , 2008, Gastroenterology.

[9]  P. Malfertheiner,et al.  Oxidative stress in ulcerative colitis-associated carcinogenesis. , 2008, Pathology, research and practice.

[10]  P. Allavena,et al.  Pathways connecting inflammation and cancer. , 2008, Current opinion in genetics & development.

[11]  Xinbin Chen,et al.  DEC1, a Basic Helix-Loop-Helix Transcription Factor and a Novel Target Gene of the p53 Family, Mediates p53-dependent Premature Senescence* , 2008, Journal of Biological Chemistry.

[12]  Tsutomu Yoshida,et al.  Epithelial and stromal genetic instability linked to tumor suppressor genes in ulcerative colitis-associated tumorigenesis , 2008, Scandinavian journal of gastroenterology.

[13]  Jasmine L. Gallaher,et al.  Leukocyte Telomere Length Predicts Cancer Risk in Barrett's Esophagus , 2007, Cancer Epidemiology Biomarkers & Prevention.

[14]  P. Rabinovitch,et al.  Cancer surveillance in inflammatory bowel disease: new molecular approaches , 2006, Current opinion in gastroenterology.

[15]  M. Serrano,et al.  The power and the promise of oncogene-induced senescence markers , 2006, Nature Reviews Cancer.

[16]  J. Potter,et al.  Telomere Length in the Colon Declines with Age: a Relation to Colorectal Cancer? , 2006, Cancer Epidemiology Biomarkers & Prevention.

[17]  S. Artandi,et al.  Pathways connecting telomeres and p53 in senescence, apoptosis, and cancer. , 2005, Biochemical and biophysical research communications.

[18]  R. Weinberg,et al.  The signals and pathways activating cellular senescence. , 2005, The international journal of biochemistry & cell biology.

[19]  Kenoki Ohuchida,et al.  Quantitative Assessment of Telomerase Activity and Human Telomerase Reverse Transcriptase Messenger RNA Levels in Pancreatic Juice Samples for the Diagnosis of Pancreatic Cancer , 2005, Clinical Cancer Research.

[20]  P. Desreumaux,et al.  5-aminosalicylic acid is an attractive candidate agent for chemoprevention of colon cancer in patients with inflammatory bowel disease. , 2005, World journal of gastroenterology.

[21]  I. Okayasu,et al.  Upregulation of p16INK4A and Bax in p53 wild/p53-overexpressing crypts in ulcerative colitis-associated tumours , 2004, British Journal of Cancer.

[22]  S. Itzkowitz,et al.  Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. , 2004, American journal of physiology. Gastrointestinal and liver physiology.

[23]  John M Sedivy,et al.  Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). , 2004, Molecular cell.

[24]  C. Harley,et al.  Telomere length assessment in tissue sections by quantitative FISH: Image analysis algorithms , 2004, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[25]  Alastair Forbes,et al.  Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. , 2004, Gastroenterology.

[26]  N. Carter,et al.  A DNA damage checkpoint response in telomere-initiated senescence , 2003, Nature.

[27]  Tsutomu Yoshida,et al.  High epithelial and stromal genetic instability of chromosome 17 in ulcerative colitis-associated carcinogenesis. , 2003, Cancer research.

[28]  Jie Liao,et al.  Oxidative stress and ulcerative colitis-associated carcinogenesis: studies in humans and animal models. , 2003, Carcinogenesis.

[29]  J. Potter,et al.  Chromosomal instability in ulcerative colitis is related to telomere shortening , 2002, Nature Genetics.

[30]  A. Smogorzewska,et al.  Different telomere damage signaling pathways in human and mouse cells , 2002, The EMBO journal.

[31]  T. Zglinicki.  Oxidative stress shortens telomeres , 2002 .

[32]  N. Ahuja,et al.  Accelerated age-related CpG island methylation in ulcerative colitis. , 2001, Cancer research.

[33]  S. Mackell,et al.  Immunohistochemical assessment of Ki67 and p53 expression assists the diagnosis and grading of ulcerative colitis‐related dysplasia , 2000, Histopathology.

[34]  K Raja,et al.  Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease. , 2000, Cancer research.

[35]  M. Bronner,et al.  Pancolonic chromosomal instability precedes dysplasia and cancer in ulcerative colitis. , 1999, Cancer research.

[36]  F. Waldman,et al.  Genomic instability is an early event during the progression pathway of ulcerative-colitis-related neoplasia. , 1999, The American journal of pathology.

[37]  P. Rabinovitch,et al.  Mutations in the p53 gene: an early marker of neoplastic progression in ulcerative colitis. , 1994, Gastroenterology.

[38]  P. Rabinovitch,et al.  Neoplastic progression in ulcerative colitis: histology, DNA content, and loss of a p53 allele. , 1992, Gastroenterology.

[39]  T. Brentnall.  Molecular underpinnings of cancer in ulcerative colitis. , 2003, Current opinion in gastroenterology.