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. 2022 Nov 27;12(12):1769.
doi: 10.3390/biom12121769.

Galanin Receptors (GALR1, GALR2, and GALR3) Immunoexpression in Enteric Plexuses of Colorectal Cancer Patients: Correlation with the Clinico-Pathological Parameters

Jacek Kiezun  1 , Marta Kiezun  2 , Bartlomiej Emil Krazinski  1 , Lukasz Paukszto  3 , Anna Koprowicz-Wielguszewska  1 , Zbigniew Kmiec  4 , Janusz Godlewski  1
Affiliations

Galanin Receptors (GALR1, GALR2, and GALR3) Immunoexpression in Enteric Plexuses of Colorectal Cancer Patients: Correlation with the Clinico-Pathological Parameters

Jacek Kiezun et al. Biomolecules. .

Abstract

Galanin (GAL) is an important neurotransmitter released by the enteric nervous system (ENS) neurons located in the muscularis externa and submucosa enteric plexuses that acts by binding to GAL receptors 1, 2 and 3 (GALR1, 2 and 3). In our previous studies, the GAL immunoexpression was compared in colorectal cancer (CRC) tissue and the adjacent parts of the large intestine wall including myenteric and submucosal plexuses. Recently we have also found that expression levels of GALR1 and GALR3 proteins are elevated in CRC tissue as compared with their expression in epithelial cells of unchanged mucosa. Moreover, higher GALR3 immunoreactivity in CRC cells correlated with better prognosis of CRC patients. To understand the distribution of GALRs in enteric plexuses distal and close to CRC invasion, in the present study we decided to evaluate GALRs expression within the myenteric and submucosal plexuses located proximally and distally to the cancer invasion and correlated the GALRs expression levels with the clinico-pathological data of CRC patients. The immunohistochemical and immunofluorescent methods showed only slightly decreased immunoexpression of GALR1 and GALR3 in myenteric plexuses close to cancer but did not reveal any correlation in the immunoexpression of all three GAL receptors in myenteric plexuses and tumour progression. No significant changes were found between the expression levels of GALRs in submucosal plexuses distal and close to the tumour. However, elevated GALR1 expression in submucosal plexuses in vicinity of CRC correlated with poor prognosis, higher tumour grading and shorter overall survival. When myenteric plexuses undergo morphological and functional alterations characteristic for atrophy, GALRs maintain or only slightly decrease their expression status. In contrast, the correlation between high expression of GALR1 in the submucosal plexuses and overall survival of CRC patients suggest that GAL and GALRs can act as a components of local neuro-paracrine pro-proliferative pathways accelerating the invasion and metastasis of cancer cell. The obtained results suggest an important role of GALR1 in submucosal plexuses function during the progression of CRC and imply that GALR1 expression in submucosal plexuses of ENS could be an important predictive factor for CRC progression.

Keywords: colorectal cancer; enteric plexuses; galanin receptors; immunohistochemistry; prognosis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Immunohistochemical expression of galanin receptors (GALR1, GALR2, and GALR3) in myenteric plexuses (MP) distantly located from the colorectal cancer (CRC) tissue compared with their expression in the myenteric plexuses in the vicinity of cancer invasion of the same, representative CRC patients (n = 31). Neurons expressing respective GALRs are marked by arrows. Total magnification: 400× g.
Figure 2
Figure 2
Immunoreactivity (IR) of galanin receptors (GALR1—(A), GALR2—(C), and GALR3—(E)) in myenteric plexuses (MP) distantly and proximity located to cancer invasion in individual colorectal (CRC) patients. The average immunoreactivities of GALRs (GALR1—(B), GALR2—(D), and GALR3—(F)) in myenteric plexuses (MP) located distantly from CRCcells were compared with those in plexuses in the vicinity of cancer cells of colorectal (CRC) patients (n = 31).
Figure 3
Figure 3
Immunolocalization of galanin receptors (GALR1, GALR2, and GALR3) in myenteric plexuses (MP) close and distant to tumour tissue of CRCpatients (n = 5). Neurons expressing respective GALRs are marked by arrows. Total magnification: 400× g.
Figure 4
Figure 4
Kaplan–Meier diagrams that show the relative immunoexpression of galanin receptors (GALR1—(A), GALR2—(B), and GALR3—(C)) in myenteric plexuses (MP) regarding the overall survival of colorectal cancer (CRC) patients (n = 31).
Figure 5
Figure 5
Immunohistochemical expression of galanin receptors (GALR1, GALR2, and GALR3) in submucosal plexuses (SP) distantly located from the colorectal cancer (CRC) tissue compared with their expression in the submucosal plexuses in the vicinity of cancer invasion of the same, representative CRC patients (n = 32). Neurons expressing respective GALRs are marked by arrows. Total magnification: 400× g.
Figure 6
Figure 6
Immunoreactivity (IR) of galanin receptors (GALR1—(A), GALR2—(C), and GALR3—(E)) in submucosal plexuses (SP) distantly and in proximally located to cancer invasion in individual colorectal (CRC) patients. The average immunoreactivities of GALRs (GALR1—(B), GALR2—(D), and GALR3—(F)) in submucosal plexuses (SP) located distantly from CRC tissue were compared with those in plexuses in the vicinity of cancer cells of colorectal (CRC) patients (n = 31).
Figure 7
Figure 7
Immunolocalization of galanin receptors (GALR1, GALR2, and GALR3) in submucosal plexuses (SP) close and distant to tumour tissue of colorectal cancer patients (n = 5). Neurons expressing respective GALRs are marked by arrows. Total magnification: 400× g.
Figure 8
Figure 8
Kaplan–Meier diagrams that show the relative immunoexpression of galanin receptors (GALR1—(A), GALR2—(B), and GALR3—(C)) in submucosal plexuses (SP) regarding the overall survival of colorectal cancer (CRC) patients (n = 32).
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