Immunolocalization of neurokinin 1 receptor in WHO grade 4 astrocytomas, oral squamous cell and urothelial carcinoma

Abstract

Introduction:Neurokinin-1 receptor (NK-1R) induces inflammatory reactions in peripheral tissues but its regulatory effects in target tissues is dependent on receptor signalling. Substance P (SP) has a high affinity for the NK-1R, to which it binds preferentially. We aimed to investigate the expression of NK-1R in World Health Organization (WHO) grade 4 astrocytomas as well as in oral squamous cell carcinoma (OSCC) and urothelial carcinoma, and its association with disease progression. Material and methods: The study included tissue samples from 19 brain astrocytomas, 40 OSCCs and 10 urothelial carcinomas. NK-1R expression was quantitatively assessed in the tumour cells using immunohistochemistry. The relationship between NK-1R expression in astrocytomas and recurrence-free interval has been explored. Results: The results showed that the NK-1R was intensely expressed in patients with WHO grade 4 astrocytoma, OSCC and urothelial carcinoma. However, cases clinically diagnosed as a low-grade cancer showed reduced NK-1R expression. Conclusions: NK-1R is overexpressed in all cases of WHO grade 4 astrocytoma, OSCC and urothelial carcinoma. The ubiquitous presence of SP/NK-1R complex during tumour development and progression suggests a possible therapeutic key strategy to use NK-1R antagonist as an adjuvant therapy in the future.

The Neurokinin-1 Receptor: A Promising Antitumor Target

“…(9) the undecapeptide acts through endocrine (from tumor mass), paracrine and autocrine mechanisms; (10) SP comes from multiple sources: cancer cells, immune cells placed in the tumor microenvironment, nerve terminals, and bloodstream; (11) SP increases the expression of NK-1R but not that of other tachykinin receptors (NK-2R and NK-3R); ( 12) SP exerts an anti-apoptotic effect (activating the basal kinase activity of the anti-apoptotic molecule protein kinase B (Akt)) and increases the glycolytic rate (Warburg effect) of tumor cells (which augment their metabolism due to the glucose obtained); (13) SP promotes the growth of blood vessels (angiogenesis, favoring the development of tumors by increasing the supply of blood; endothelial cells express NK-1R and SP), and ( 14) a higher serum SP level and a higher number of NK-1Rs have been observed in patients with cancer than in healthy individuals [1,9,15,25,[73][74][75][76][77][78][79][80][81][82][83][84][85][86]. Moreover, the TAC and TACR1 genes are expressed in primary stem cells derived from human placental cord blood and human stem cell lines.…”

The Repurposing of Non-Peptide Neurokinin-1 Receptor Antagonists as Antitumor Drugs: An Urgent Challenge for Aprepitant

“…In recent years, the knowledge of the involvement of the substance P (SP)/neurokinin-1 receptor (NK-1R) system in cancer progression has notably increased [6][7][8][9][10]. It is currently known that tumor cells express receptors for peptides, explicitly emphasizing the overexpression of NK-1R reported in these cells [11]. This finding opens the door to new cancer research avenues, cancer diagnosis, and antitumor therapeutic strategies using NK-1R agonists/antagonists-based cancer therapy, cytotoxic peptide conjugate-based cancer therapy, or peptide-receptor radionuclide therapy [12][13][14][15][16][17][18][19][20].…”

“…6 Cancer cells express/overexpress NK-1R [11,[56][57][58][59][60][61][62][63][64], which is involved in the viability of these cells. It has been suggested that the higher the number of NK-1R, the higher the tumor malignancy, and NK-1R mRNA expression is lower in benign compared to malignant tissues.…”

The in vitro anti‐cancer synergy of neurokinin‐1 receptor antagonist, aprepitant, and 5‐aminolevulinic acid in glioblastoma

“…6 Overexpression of NK1R and its preferred ligand, substance P (SP), has been observed in several human glioma cell lines and tissues and is associated with the degree of tumor malignancy. [7][8][9][10][11][12] SP/NK1R complex initiates several oncogenic processes including cell proliferation, metastasis, angiogenesis, inflammation, and oxidative stress. 6,7,[13][14][15] Considering the tumorigenic function of the SP/NK1R complex, numerous NK1R antagonists have been developed and many of them are currently under study in different tumor types.…”

“…Neurokinin‐1 receptor (NK1R), a member of the G protein‐coupled receptor family, is widely expressed on tumor cells and tissues and has recently been validated as a critical target for the treatment of different tumors, including GBM 6 . Overexpression of NK1R and its preferred ligand, substance P (SP), has been observed in several human glioma cell lines and tissues and is associated with the degree of tumor malignancy 7–12 . SP/NK1R complex initiates several oncogenic processes including cell proliferation, metastasis, angiogenesis, inflammation, and oxidative stress 6,7,13–15 .…”