The Galaninergic System: A Target for Cancer Treatment

Abstract

The aim of this review is to show the involvement of the galaninergic system in neuroendocrine (phaeochromocytomas, insulinomas, neuroblastic tumors, pituitary tumors, small-cell lung cancer) and non-neuroendocrine (gastric cancer, colorectal cancer, head and neck squamous cell carcinoma, glioma) tumors. The galaninergic system is involved in tumorigenesis, invasion/migration of tumor cells and angiogenesis, and this system has been correlated with tumor size/stage/subtypes, metastasis and recurrence rate. In the galaninergic system, epigenetic mechanisms have been related with carcinogenesis and recurrence rate. Galanin (GAL) exerts both proliferative and antiproliferative actions in tumor cells. GAL receptors (GALRs) mediate different signal transduction pathways and actions, depending on the particular G protein involved and the tumor cell type. In general, the activation of GAL1R promoted an antiproliferative effect, whereas the activation of GAL2R induced antiproliferative or proliferative actions. GALRs could be used in certain tumors as therapeutic targets and diagnostic markers for treatment, prognosis and surgical outcome. The current data show the importance of the galaninergic system in the development of certain tumors and suggest future potential clinical antitumor applications using GAL agonists or antagonists.

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

“…Although the myenteric plexuses in the vicinity of the CRC tissue were much smaller than far from the tumour, the concentration of GAL protein in homogenates of muscularis externa (containing myenteric plexuses) in the vicinity of the CRC tissue was higher than in the samples distant to cancer cells [ 16 ]. These studies seemed to be consistent with data describing that neurons of atrophic myenteric plexuses located close to cancer cells express the elevated presence of GAL compared to those located distantly in 15 CRC patients [ 13 ], suggesting that smooth muscle cells of muscularis externa may be the target of GAL in the large intestine wall. However, not only cells of muscularis externa but also cells present in the mucosa and submucosa of the large intestine (epithelial cells, stromal/immune cells, immune cells, or neurons) may produce GAL [ 13 ].…”

“…These studies seemed to be consistent with data describing that neurons of atrophic myenteric plexuses located close to cancer cells express the elevated presence of GAL compared to those located distantly in 15 CRC patients [ 13 ], suggesting that smooth muscle cells of muscularis externa may be the target of GAL in the large intestine wall. However, not only cells of muscularis externa but also cells present in the mucosa and submucosa of the large intestine (epithelial cells, stromal/immune cells, immune cells, or neurons) may produce GAL [ 13 ]. We decided to analyse the immunoexpression of three types of GAL receptors in the plexuses of large intestine submucosa and muscularis externa of CRC patients in two locations: close and distant from the tumour invasion tissue.…”

“…Galanin and its specific receptors form the galaninergic system, which is expressed in normal tissue, as well as in cancer cells and it seems to be an important molecular factor involved in cancerogenesis, metastasis, and invasion [ 13 ]. Our group was the first to report a higher level of GAL in the blood serum of 68 CRC patients, than in healthy volunteers [ 16 ].…”

“…Enteric neurons also interact with the extensive intrinsic immune system of the gastrointestinal tract [ 26 ]. GALRs show a high expression in human glioma and pituitary adenoma tumour-infiltrating immune cells [ 12 ], and GAL was found to regulate the expression of chemokines (CCL2, CCL3, CCL5) [ 13 , 37 ]. The neurons of submucosa plexuses expressing GALR1 may activate the release of factors related to the activation of cancer cell proliferation and metastasis by tumour-infiltrating immune cells.…”

“…In neurons, GAL exerts a neuroprotective action [ 9 ] and it has been suggested that this neuropeptide plays an emerging role in inflammatory bowel diseases [ 10 ] and cancerogenesis [ 11 ]. In human glioma and pituitary adenoma, GAL acts on tumour-infiltrating immune cells and regulates the tumour microenvironment [ 12 , 13 ]. In previous studies, the GAL protein expression was determined in serum and tissue of colorectal cancer (CRC) patients [ 12 , 14 , 15 , 16 ] as well as the parts of the colon wall including myenteric and submucosal plexuses [ 16 ].…”