Abstract
Expression of neuropeptides and their corresponding receptors has been demonstrated in different cancer types, where they can play a role in tumor cell growth, invasion, and migration. Human galanin (GAL) is a 30-amino-acid regulatory neuropeptide which acts through three G protein-coupled receptors, GAL1-R, GAL2-R, and GAL3-R that differ in their signal transduction pathways. GAL and galanin receptors (GALRs) are expressed by different tumors, and direct involvement of GAL in tumorigenesis has been shown. Despite its strong expression in the central nervous system (CNS), the role of GAL in CNS tumors has not been extensively studied. To date, GAL peptide expression, GAL receptor binding and mRNA expression have been reported in glioma, meningioma, and pituitary adenoma. However, data on the cellular distribution of GALRs are sparse. The aim of the present study was to examine the expression of GAL and GALRs in different brain tumors by immunohistochemistry. Anterior pituitary gland (n = 7), pituitary adenoma (n = 9) and glioma of different WHO grades I–IV (n = 55) were analyzed for the expression of GAL and the three GALRs with antibodies recently extensively validated for specificity. While high focal GAL immunoreactivity was detected in up to 40% of cells in the anterior pituitary gland samples, only one pituitary adenoma showed focal GAL expression, at a low level. In the anterior pituitary, GAL1-R and GAL3-R protein expression was observed in up to 15% of cells, whereas receptor expression was not detected in pituitary adenoma. In glioma, diffuse and focal GAL staining was noticed in the majority of cases. GAL1-R was observed in eight out of nine glioma subtypes. GAL2-R immunoreactivity was not detected in glioma and pituitary adenoma, while GAL3-R expression was significantly associated to high-grade glioma (WHO grade IV). Most interestingly, expression of GAL and GALRs was observed in tumor-infiltrating immune cells, including neutrophils and glioma-associated macrophages/microglia. The presence of GALRs on tumor-associated immune cells, especially macrophages, indicates that GAL signaling contributes to homeostasis of the tumor microenvironment. Thus, our data indicate that GAL signaling in tumor-supportive myeloid cells could be a novel therapeutic target.
Highlights
Malignant brain tumors are the most common cause of cancerrelated deaths in adolescents and young adults aged 15–39 and the most common cancer occurring among 15–19 year olds [1]
We show for the first time the cellular distribution of galanin receptors (GALRs) proteins in human glioma, pituitary adenoma, and anterior pituitary gland
Our findings correlate with our previous study, where GAL staining in glial cell bodies was found in 18 out of 20 (90%) human brain tumors, including glioblastoma multiforme (WHO grade IV), meningioma (WHO grade I-II), and gliosarcoma (WHO grade IV) [21]
Summary
Malignant brain tumors are the most common cause of cancerrelated deaths in adolescents and young adults aged 15–39 and the most common cancer occurring among 15–19 year olds [1]. There is an urgent need to understand tumor biology and subsequently identify new drug targets for the treatment of brain tumors. Possible new drug candidates might be found in the group of neuropeptides. Neuropeptide expression has been shown in many different cancer types, and neuropeptide expression levels correlate with tumor differentiation or aggressive behavior. Neuropeptides are involved in tumor cell growth, invasion, and migration [3,4,5], supporting their potential in developing novel anti-tumor treatment strategies
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