Expression pattern and clinicopathological relevance of neurotensin and its receptors in colorectal cancer

Abstract

Introduction Colorectal cancer (CRC) is the third commonest cancer diagnosed in the world with more than 1.9 million new cases and 935,000 deaths. Neurotensin and its receptors have been implicated in carcinogenesis. There is evidence in the literature to support the presence of tissue NT, NTSR1 and NTSR3 in colorectal cancers with a potential diagnostic and prognostic role in the disease.

Aims 1. To assess NT, NTSR1 and NTSR3 expression in polyps and colorectal cancer in a prospectively collected cohort of patients and to establish whether there is correlation between NT and its receptors to stage of disease and histopathological factors. 2. Assess plasma NT and correlation to tissue expression of NT, NTSR1 and NTSR3 3. Assess the diagnostic accuracy of plasma NT in distinguishing polyps and colorectal cancer from normal or benign colonic disease.

Methods To assess aims 1 and 2, patients were prospectively recruited from 2 centres. In total, 106 patients were recruited in the study and both, blood samples and tissue were collected for analysis for plasma NT, tissue NT, NTSR1 and NTSR3 expression. Patients included in the study were either referred for a 2ww colonoscopy or had a new diagnosis of CRC. Immunohistochemical staining of NT, NTSR1 and NTSR3 was performed on all patients and the intensity of expression was measured using the histascore system (H-score). H-score was then correlated between stage of disease, clinical and histological features.

To assess aim 3, two further prospective cohorts were included in the study to evaluate the diagnostic value of NT in detecting polyps and cancers in patients with high -risk symptoms.

Results In the first study 106 patients were recruited but 2 excluded due to non-colorectal adenocarcinoma diagnosis. From the remaining 104, 78 had colorectal adenocarcinoma, 5 had normal colonoscopies, 17 had polyps and 4 had recurrent disease. There was increasing expression of NT from polyps to stage IV disease but no difference in the NTSR 1 and 3 receptors. Several prognostic factors (mucin presence and LVI) were associated with higher NT expression in tissue (p= 0.01, p<0.01 respectively, Kruskal Wallis test). There was significantly reduced NTSR1 expression in cancers post chemoradiotherapy (p<0.01, Kruskal Wallis) and borderline difference between rectal and colon cancers (p= 0.05, Kruskal Walllis test). There was no correlation between plasma NT and tissue NT and its receptors. For assessing the diagnostic ability of NT, a total of 364 patients were included (135 normal, 108 cancers, 75 polyps, 4 recurrences, 27 diverticular disease and 15 colitis). ROC curve analysis and optimal cut-off values of >637.9 pg/mL gave 80.6% sensitivity and 76% specificity in distinguishing normal colons from cancers. With a cut-off of >460.8, plasma NT showed sensitivity of 69.3% in detecting polyps from normal and specificity of 62%.

Conclusion NT expression in colorectal cancer is associated with worsening stage of disease and presence of mucin and possibly lymphatic invasion. Furthermore, plasma NT is a promising diagnostic marker for detecting polyps and colorectal cancer. Future work is required to investigate the pathway through which neurotensin drives carcinogenesis which can lead to identification of therapeutic targets.