The role of galanin in the progression and prognosis of colorectal cancer: the unfinished story

Abstract

The paper presents a summary of immunohistochemical (IHC) and biochemical investigations on the presence of galanin (Gal), one of the neuropeptides abundant in the enteric nervous systems, and three types of its receptors (GalR1-3) in colorectal cancer (CRC) tissue and non-involved colon wall and their associations with clinical-pathological data of the CRC patients. We were the first to morphologically demonstrate the presence of endogenous Gal in CRC sections and measure its content in homogenates of tumor tissue and dissected compartments of unchanged colon wall. The prominent atrophy of myenteric plexuses displaying Gal immunoreactivity (Gal-Ir) located close to the tumor invasion was found to be accompanied by higher Gal content in the tumor-adjacent muscularis externa than in tumor-distant tissue. In further studies for the first time, we demonstrated by the IHC technique the presence of the GalR1-3 receptors in the CRC tumors and the colon mucosa and found that higher GalR3-Ir in the tumor tissue correlated with longer overall survival of CRC patients. Furthermore, we discovered that lower GalR1 expression in submucosal plexuses located near the tumor correlated with a better prognosis in patients with CRC. These findings suggest that GalR1 could be considered as a novel therapeutic target in CRC. In conclusion, our morphological investigations provided novel data documenting the involvement of Gal and its receptors in the progression of CRC and showed the usefulness of the IHC technique for the prognosis of CRC patients.

Figure 1.

The design of the study. Two major compartments of large intestine wall, the mucosa with submucosa (2 and 4) and muscularis externa (3 and 5) that were localized closely to (2 and 3) or distantly from (4 and 5) colorectal cancer (CRC) tissue (1) were separated (central blue line) immediately after tumor resection within the morphologically unchanged margins of the ‘healthy’ tissue by an experienced surgeon (JG). The tissue samples were frozen in liquid nitrogen for biochemical measurements and fixed in 4% formaldehyde for morphological investigations. IMSP, intermediate submucosal plexus; ISP, inner submucosal plexus; MP, myenteric plexus; OSP, outer submucosal plexus.

Figure 2.

The design and major findings of the study of serum galanin (Gal) concentration in CRC patients and healthy volunteers, and Gal content in the tissue homogenates of CRC tissue and two separate compartments of large intestine wall located closely or distantly from tumor mass. Gal serum and tissue contents were determined by ELISA. Histograms were modified based on Kwiatkowski et al. Oncol Lett 2016;12:3323-9 (with permission). Data represent mean ± SEM; *p<0.05; ***p<0.001.

Figure 3.

The immunohistochemical expression of galanin receptors (GalR1, GalR2 and GalR3) in colorectal cancer cells compared with their immunoreactivity in the epithelial cells of the unchanged mucosa (based on).

Figure 4.

The immunoreactivity of three types of galanin receptors (GalRs) in the submucosal (SP) and myenteric (MP) plexuses located closely to and distantly from the colon cancer tissue and their association with the prognosis of the CRC patients. Arrows indicate localization of GalR3-Ir within neurons of the submucosal plexuses (based on). T and M refer to the TNM tumor grading: T, tumor size; N, lymph node involvement; M, metastasis.