Colorectal Cancer Prognosis Following Obesity Surgery in a Population-Based Cohort Study

Background: Obesity surgery involves mechanical and physiological changes of the gastrointestinal tract that might promote colorectal cancer progression. Thus, we hypothesised that obesity surgery is associated with poorer prognosis in patients with colorectal cancer. Methods: This nationwide population-based cohort study included all patients with an obesity diagnosis who subsequently developed colorectal cancer in Sweden from 1980 to 2012. The exposure was obesity surgery, and the main and secondary outcomes were disease-specific mortality and all-cause mortality, respectively. Cox proportional hazard survival models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs), adjusted for sex, age, calendar year and education level. Results: The exposed and unexposed cohort included 131 obesity surgery and 1332 non-obesity surgery patients with colorectal cancer. There was a statistically significant increased rate of colorectal cancer deaths following obesity surgery (disease-specific HR 1.50, 95% CI 1.00–2.19). When analysed separately, the mortality rate was more than threefold increased in rectal cancer patients with prior obesity surgery (disease-specific HR 3.70, 95% CI 2.00–6.90), while no increased mortality rate was found in colon cancer patients (disease-specific HR 1.10, 85% CI 0.67–1.70). Conclusion: This population-based study among obese individuals found a poorer prognosis in colorectal cancer following obesity surgery, which was primarily driven by the higher mortality rate in rectal cancer

Expression of prostasin and its inhibitors during colorectal cancer carcinogenesis

<p>Abstract</p> <p>Background</p> <p>Clinical trials where cancer patients were treated with protease inhibitors have suggested that the serine protease, prostasin, may act as a tumour suppressor. Prostasin is proteolytically activated by the serine protease, matriptase, which has a very high oncogenic potential. Prostasin is inhibited by protease nexin-1 (PN-1) and the two isoforms encoded by the mRNA splice variants of <it>hepatocyte growth factor activator inhibitor-1 </it>(<it>HAI-1</it>), <it>HAI-1A</it>, and <it>HAI-1B</it>.</p> <p>Methods</p> <p>Using quantitative RT-PCR, we have determined the mRNA levels for <it>prostasin </it>and <it>PN-1 </it>in colorectal cancer tissue (n = 116), severe dysplasia (n = 13), mild/moderate dysplasia (n = 93), and in normal tissue from the same individuals. In addition, corresponding tissues were examined from healthy volunteers (n = 23). A part of the cohort was further analysed for the mRNA levels of the two variants of HAI-1, here denoted <it>HAI-1A </it>and <it>HAI-1B</it>. mRNA levels were normalised to <it>β-actin</it>. Immunohistochemical analysis of prostasin and HAI-1 was performed on normal and cancer tissue.</p> <p>Results</p> <p>The mRNA level of prostasin was slightly but significantly decreased in both mild/moderate dysplasia (p < 0.001) and severe dysplasia (p < 0.01) and in carcinomas (p < 0.05) compared to normal tissue from the same individual. The mRNA level of <it>PN-1 </it>was more that two-fold elevated in colorectal cancer tissue as compared to healthy individuals (p < 0.001) and elevated in both mild/moderate dysplasia (p < 0.01), severe dysplasia (p < 0.05) and in colorectal cancer tissue (p < 0.001) as compared to normal tissue from the same individual. The mRNA levels of <it>HAI-1A </it>and <it>HAI-1B </it>mRNAs showed the same patterns of expression. Immunohistochemistry showed that prostasin is located mainly on the apical plasma membrane in normal colorectal tissue. A large variation was found in the degree of polarization of prostasin in colorectal cancer tissue.</p> <p>Conclusion</p> <p>These results show that the mRNA level of <it>PN-1 </it>is significantly elevated in colorectal cancer tissue. Future studies are required to clarify whether down-regulation of prostasin activity via up regulation of PN-1 is causing the malignant progression or if it is a consequence of it.</p

Initiation of human colon cancer cell proliferation by trypsin acting at protease-activated receptor-2

The protease-activated receptor-2 (PAR-2) is a G protein-coupled receptor that is cleaved and activated by trypsin. We investigated the expression of PAR-2 and the role of trypsin in cell proliferation in human colon cancer cell lines. A total of 10 cell lines were tested for expression of PAR-2 mRNA by Northern blot and RT-PCR. PAR-2 protein was detected by immunofluorescence. Trypsin and the peptide agonist SLIGKV (AP2) were tested for their ability to induce calcium mobilization and to promote cell proliferation on serum-deprived cells. PAR-2 mRNA was detected by Northern blot analysis in 6 out of 10 cell lines [HT-29, Cl.19A, Caco-2, SW480, HCT-8 and T84]. Other cell lines expressed low levels of transcripts, which were detected only by RT-PCR. Further results were obtained with HT-29 cells: (1) PAR-2 protein is expressed at the cell surface; (2) an increase in intracellular calcium concentration was observed upon trypsin (1–100 nM) or AP2 (10–100 μM) challenges; (3) cells grown in serum-deprived media supplemented with trypsin (0.1–1 nM) or AP2 (1–300 μM) exhibited important mitogenic responses (3-fold increase of cell number). Proliferative effects of trypsin or AP2 were also observed in other cell lines expressing PAR-2. These data show that subnanomolar concentrations of trypsin, acting at PAR-2, promoted the proliferation of human colon cancer cells. The results of this study indicate that trypsin could be considered as a growth factor and unravel a new mechanism whereby serine proteases control colon tumours. © 2001 Cancer Research Campaign http://www.bjcancer.co