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.

Differences in telomerase activity between colon and rectal cancer

“…55 In a recent report, patients with ulcerative colitis demonstrated low p53 expression and short telomeres in low-grade dysplasia, while p53 and telomere length were progressively increased in high-grade dysplasia, indicating an inverse association between the 2 in these preneoplastic conditions. 56 These findings are in agreement with our finding of an inverse association between p53 and hTERT in patients with colon cancer.…”

Transcriptional Analysis of Left-sided Colitis, Pancolitis, and Ulcerative Colitis-associated Dysplasia

“…3 UC and colonic CD are associated with a higher risk of colorectal cancer (CRC), 4 and the typical pathological changes progress from quiescent disease to active chronic inflammation without dysplasia to dysplasia, and ultimately cancer. 5 It is assumed that this neoplastic process is inflammation driven, 6 which is supported by recent studies 7-9 identifying a continuous inflammatory state in the colonic mucosa of patients with UC, but not in CD, revealing a plausible explanation as to why the risk of CRC is higher in UC than CD. Hence, the chronic inflammatory load seems to be the central element for an increased risk of UC-associated CRC.…”

The role of innate immune-stimulated epithelial apoptosis during gastrointestinal inflammatory diseases

“…Another key contributor to the development of cancer within the intestine is chronic inflammation, and this field of focus has expanded significantly in recent years with the observation that anti-inflammatory strategies that may reduce the risk of malignant change [116][117][118]. In particular, inflammatory mediators such as IL-1, TNF-a, IL-8, nitric oxide, or prostaglandin-2 derivatives may each act as mediators connecting inflammation and cancer development [119].…”