The Impact of Ulcerative Colitis on Colorectal Cancer Prognosis: The Jury is Still Out

Introduction: Given the lack of data we aimed to assess the impact of the length of diagnostic delay on natural history of ulcerative colitis in pediatric (diagnosed <18 years) and adult patients (diagnosed ≥18 years). Methods: Data from the Swiss Inflammatory Bowel Disease cohort study were analyzed. Diagnostic delay was defined as interval between the first appearance of UC-related symptoms until diagnosis. Logistic regression modeling evaluated the appearance of the following complications in the long term according to the length of diagnostic delay: colonic dysplasia, colorectal cancer, UC-related hospitalization, colectomy, and extra-intestinal manifestations (EIM). Results: A total of 184 pediatric and 846 adult patients were included. Median diagnostic delay was 4 [IQR 2-7.5] months for the pediatric-onset group and 3 [IQR 2-10] months for the adult-onset group (P=0.873). In both, pediatric and adult-onset groups, length of diagnostic delay at UC diagnosis was not associated with colectomy, UC-related hospitalization, colon dysplasia, and colorectal cancer. EIM were significantly more prevalent at UC diagnosis in the adult-onset group with long diagnostic delay compared to the adult-onset group with short diagnostic delay (p = 0.022). In the long term, length of diagnostic delay was associated in the adult onset group with colorectal dysplasia (p=0.023), EIMs (p<0.001) and more specifically arthritis/arthralgias (p<0.001) and ankylosing spondylitis/sacroiliitis (p<0.001). In the pediatric-onset UC group, length of diagnostic delay in the long term was associated with arthritis/arthralgias (p=0.017); however, it was not predictive for colectomy and UC-related hospitalization. Conclusions: As colorectal cancer and EIMs are associated with considerable morbidity and costs, every effort should be made to reduce diagnostic delay in UC patients.

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Colorectal Cancer Prognosis: The Impact of Signet Ring Cell

Gastrointestinal Tumors ◽

10.1159/000501454 ◽

2019 ◽

Vol 6 (3-4) ◽

pp. 57-63

Author(s):

Refik Bademci ◽

Jesus Bollo ◽

M. Carmen Martinez ◽

Maria Pilar Hernadez ◽

Eduardo Maria Targarona

Keyword(s):

Colorectal Cancer ◽

Signet Ring Cell ◽

Cancer Prognosis ◽

Signet Ring ◽

Ring Cell ◽

The Impact

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Implications for Ulcerative Colitis and Colorectal Cancer: Role of Pyruvate Kinase M2 in Regulating the Oxidation of Fiber-derived Butyrate in the Diseased Colonocyte (OR04-04-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz030.or04-04-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Dallas Donohoe ◽

Bohye Park ◽

Ji Yeon Kim ◽

Emily Simon ◽

Haley Porter ◽

...

Keyword(s):

Colorectal Cancer ◽

Ulcerative Colitis ◽

Cancer Cells ◽

Pyruvate Kinase ◽

Mitochondrial Function ◽

Apoptotic Cell ◽

Conditional Knockout ◽

Colorectal Cancer Cells ◽

The Impact

Abstract Objectives Dietary fiber has been proposed to protect against colorectal cancer. Butyrate, a fiber metabolite that is produced by bacteria in the colon, is known to inhibit cell proliferation and promote cell differentiation, while also inducing apoptotic cell death in colorectal cancer cells at physiologically relevant concentrations. Unlike the majority of cells in the human body that prefer utilizing glucose, non-cancerous colonocytes use butyrate as their primary energy source. However, colorectal cancer cells shift away from utilizing butyrate towards glucose (the Warburg effect). A decrease in butyrate utilization by the colonocyte has been reported in ulcerative colitis (UC) and colorectal cancer (CRC). In both of these diseases, the protein called Pyruvate Kinase Isoform M2 (PKM2) is a factor that has been found to be elevated in colonocytes and is known to catalyze a key step in glycolysis. We hypothesize that upregulation of PKM2 in ulcerative colitis and colorectal cancer results in diminished butyrate oxidation, and increased glucose utilization in colonocytes. Methods Mitochondrial function, substrate utilization will be analyzed in several colorectal cell lines, isolated colonocytes, or colonocytes grown in 3-D culture where PKM2 is knocked down, knocked-out, or overexpressed. An in vivo mouse model of colitis will be used to study the impact of PKM2 in the injury and repair process. Results Knockdown of PKM2 in cancerous colonocytes was associated with reduced proliferation and increased apoptosis. Butyrate oxidation was also increased in PKM2 knockdown cells. PKM2 regulated mitochondrial function and impacted the expression of uncoupling proteins (UCPs). Elevated PKM2 in primary colonocytes was associated with diminished butyrate utilization. Finally, conditional knockout of PKM2 in the colon resulted inhibited DSS-induced colitis. Conclusions These results show an important role for PKM2 in promoting ulcerative colitis and colorectal cancer through shifting colonocyte metabolism away from butyrate utilization. Funding Sources University of Tennessee - Start-up Funds.

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Silencing PSME3 induces colorectal cancer radiosensitivity by downregulating the expression of cyclin B1 and CKD1

Experimental Biology and Medicine ◽

10.1177/1535370219883408 ◽

2019 ◽

Vol 244 (16) ◽

pp. 1409-1418

Author(s):

Wen Song ◽

Cuiping Guo ◽

Jianxiong Chen ◽

Shiyu Duan ◽

Yukun Hu ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Cycle ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Locally Advanced ◽

Cyclin B1 ◽

Cancer Prognosis ◽

Cycle Arrest ◽

Colorectal Cancer Cells ◽

The Impact

Resistance to radiotherapy remains a severe obstacle in the treatment of high-risk colorectal cancer patients. Recent studies have indicated that proteasome activator complex subunit 3 (PSME3) participates in the development and progression of various human malignancies and is proposed to play a role in tumor radioresistance. However, the impact of PSME3 on radioresistance of colorectal cancer has been largely unknown. In the present study, the enhanced expression of PSME3 was observed in colorectal cancer cells and tissue. Upregulation of PSME3 was significantly implicated in lymph node state, lymphovascular invasion, and Dukes' stage. Furthermore, high PSME3 expression was closely linked to poorer overall and progression-free survival in patients with colorectal cancer. The study further demonstrated that the proliferative, invasive and migratory potential of colorectal cancer cells was effectively inhibited in vitro after silencing PSME3. Our results verified that knockdown of PSME3 probably triggered cell cycle arrest at the G2/M phase by downregulation of cyclinB1 and CDK1, thereby enhancing the radiosensitivity of colorectal cancer cells. These data illustrated that PSME3 is a promising biomarker predictive of colorectal cancer prognosis and silencing of PSME3 may provide with a new approach for sensitizing the radiotherapy in colorectal cancer. Impact statement It is reported that colorectal cancer (CRC) is the third most common cancer worldwide and the fourth leading cause of cancer-related death. At present, the main treatment method of colorectal cancer is surgery, supplemented by radiotherapy and chemotherapy. Among them, radiotherapy plays an important role in the treatment of locally advanced colorectal cancer, surgery, and chemotherapy. Our study found that down-regulation of PSME3 may enhance the radiosensitivity of CRC cells by triggering cell cycle arrest, which suggests that silence PSME3 may provide a new method for improving the radiosensitivity of CRC. What’more, our research also demonstrated that PSME3 may promote proliferation, invasive and migratory potential of CRC cells, which implies that PSME3 might be a biomarker of CRC for early diagnosis and treatment.

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Magnitude of the Age-Advancement Effect of Comorbidities in Colorectal Cancer Prognosis

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2019.7346 ◽

2020 ◽

Vol 18 (1) ◽

pp. 59-68 ◽

Cited By ~ 1

Author(s):

Daniel Boakye ◽

Viola Walter ◽

Lina Jansen ◽

Uwe M. Martens ◽

Jenny Chang-Claude ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Disease Free Survival ◽

Cox Proportional Hazards ◽

Cancer Prognosis ◽

Free Survival ◽

Hazard Ratios ◽

The Impact ◽

Disease Free ◽

Worse Prognosis

Background: Comorbidities and old age independently compromise prognosis of patients with colorectal cancer (CRC). The impact of comorbidities could thus be considered as conveying worse prognosis already at younger ages, but evidence is lacking on how much worsening of prognosis with age is advanced to younger ages in comorbid versus noncomorbid patients. We aimed to quantify, for the first time, the impact of comorbidities on CRC prognosis in “age advancement” of worse prognosis. Methods: A total of 4,602 patients aged ≥30 years who were diagnosed with CRC in 2003 through 2014 were recruited into a population-based study in the Rhine-Neckar region of Germany and observed over a median period of 5.1 years. Overall comorbidity was quantified using the Charlson comorbidity index (CCI). Hazard ratios and age advancement periods (AAPs) for comorbidities were calculated from multivariable Cox proportional hazards models for relevant survival outcomes. Results: Hazard ratios for CCI scores 1, 2, and ≥3 compared with CCI 0 were 1.25, 1.53, and 2.30 (P<.001) for overall survival and 1.20, 1.48, and 2.03 (P<.001) for disease-free survival, respectively. Corresponding AAP estimates for CCI scores 1, 2, and ≥3 were 5.0 (95% CI, 1.9–8.1), 9.7 (95% CI, 6.1–13.3), and 18.9 years (95% CI, 14.4–23.3) for overall survival and 5.5 (95% CI, 1.5–9.5), 11.7 (95% CI, 7.0–16.4), and 21.0 years (95% CI, 15.1–26.9) for disease-free survival. Particularly pronounced effects of comorbidity on CRC prognosis were observed in patients with stage I–III CRC. Conclusions: Comorbidities advance the commonly observed deterioration of prognosis with age by many years, meaning that at substantially younger ages, comorbid patients with CRC experience survival rates comparable to those of older patients without comorbidity. This first derivation of AAPs may enhance the empirical basis for treatment decisions in patients with comorbidities and highlight the need to incorporate comorbidities into prognostic nomograms for CRC.

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