Brain-Derived Neurotrophic Factor, Neutrophils and Cysteinyl Leukotriene Receptor 1 as Potential Prognostic Biomarkers for Patients with Colon Cancer.

Anita Sjölander,Lubna M. Mehdawi,Souvik Ghatak,Shakti Ranjan Satapathy,Geriolda Topi,Syrina F. Mehrabi

doi:10.3390/cancers13215520

Anita Sjölander, Lubna M. Mehdawi + Show 4 more

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https://doi.org/10.3390/cancers13215520

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Journal: Cancers	Publication Date: Nov 3, 2021
Citations: 2	License type: CC BY 4.0

Affiliation: Lund University

Abstract

Simple SummaryColorectal cancer (CRC) is one of the most common type of cancer and the third leading cause of cancer-related death. CRC is associated with inflammatory bowel disease. We have earlier shown that high levels of the inflammatory receptor CysLT1 goes with poor prognosis for CRC patients. In this study, we found that high levels of neutrophils (CD66b) and brain-derived neurotropic factor (BDNF) goes with poor prognosis for colon cancer patient. We discovered a strong positive correlation between CysLT1, CD66b and BDNF. Our data support that these three proteins can be used as a combined biomarker for CC patients.The tumor microenvironment has been recognized as a complex network in which immune cells play an important role in cancer progression. We found significantly higher CD66b neutrophil expression in tumor tissue than in matched normal mucosa in the Malmö colon cancer (CC) cohort and poorer survival of stage I-III patients with high CD66b expression. Additionally, mice lacking CysLT1R expression (cysltr1−/−) produce less brain-derived neurotrophic factor (BDNF) compared to WT mice and Montelukast (a CysLT1R antagonist)-treated mice also reduced BDNF expression in a mouse xenograft model with human SW480 CC cells. CD66b and BDNF expression was significantly higher in patient tumor tissues than in the matched normal mucosa. The univariate Cox PH analysis yielded CD66b and BDNF as an independent predictor of overall survival, which was also found in the public TCGA-COAD dataset. We also discovered a strong positive correlation between CD66b, BDNF and CysLT1R expression in the Malmö CC cohort and in the TCGA-COAD dataset. Our data suggest that CD66b/BDNF/CysLT1R expression as a prognostic combined biomarker signature for CC patients.

Highlights

There is growing evidence suggesting that chronic inflammation contribute significantly to the development of various types of cancers, including colorectal cancer (CRC) [1].Colitis-associated cancer (CAC) is a type of colon cancer (CC) that is preceded by clinically detectable inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis
Neutrophil infiltration varied widely in the tumor tissues, and we found a significant difference between normal mucosa with a mean of 8/core and tumor tissue with a mean of 225/core, p < 0.001 (Figure 1d)
We investigated the distribution of neutrophils in the tumor tissues and in the normal matched pair area

Summary

Introduction

Colitis-associated cancer (CAC) is a type of colon cancer (CC) that is preceded by clinically detectable inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis. It has been shown that inflammatory bowel disease ranks as the third-highest risk factor for CC, behind familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer syndrome [2]. There are various similar features among CAC and sporadic CC, e.g., chromosome instability, microsatellite instability, KRAS and BRAF mutations, oncogene activation, which in turn initiates the allele removal of p53, and mutation of the tumor suppressor gene adenomatous polyposis coli (APC) [3]. In sporadic CC, following mutation of the APC gene, the WNT/β-catenin signaling pathway is activated, and a number of potential oncogenic target genes lead to progression from adenoma to carcinoma [4]. CRC is a heterogeneous disease and it is closely associated with genetic and environmental factors [5]

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