Abstract
The recent years have witnessed an exponential increase in cancer research, leading to a considerable investment in the field. However, with few exceptions, this effort has not yet translated into a better overall prognosis for patients with cancer, and the search for new drug targets continues. After binding to the specific neurokinin-1 (NK-1) receptor, the peptide substance P (SP), which is widely distributed in both the central and peripheral nervous systems, triggers a wide variety of functions. Antagonists against the NK-1 receptor are safe clinical drugs that are known to have anti-inflammatory, analgesic, anxiolytic, antidepressant, and antiemetic effects. Recently, it has become apparent that SP can induce tumor cell proliferation, angiogenesis, and migration via the NK-1 receptor, and that the SP/NK-1 receptor complex is an integral part of the microenvironment of inflammation and cancer. Therefore, the use of NK-1 receptor antagonists as a novel and promising approach for treating patients with cancer is currently under intense investigation. In this paper, we evaluate the recent scientific developments regarding this receptor system, its role in the microenvironment of inflammation and cancer, and its potentials and pitfalls for the usage as part of modern anticancer strategies.
Highlights
Cancer research in general has seen an endorsed and exponential increase in the recent years and extensive financial venture and manpower have been invested in the field
substance P (SP) stimulates mitogenesis and exerts an antiapoptotic effect by activating NK-1 receptors in tumor cells mainly via four mechanisms: (1) through an autocrine mechanism, by which SP is secreted from primary tumors, (2) through a paracrine mechanism, by which SP is released from tumor cells acting on endothelial cells and on other surrounding cells in the tumor microenvironment, (3) through means of the peripheral nervous system, since SP is released from peripheral nerve terminals, and possibly, (4) through an endocrine mechanism, related to emotional behaviour, by which SP reaches the peripheral tumors through the blood stream [66]
According to the data obtained from animal experiments, cell cultures, and clinical studies, it seems that NK-1 receptor antagonists should be effective in the treatment of affective and anxiety disorders, pain syndromes, intestinal motility disorders, and cancer
Summary
Cancer research in general has seen an endorsed and exponential increase in the recent years and extensive financial venture and manpower have been invested in the field. GPCRs comprise a large family of membrane receptors involved in signal transduction These receptors are linked to a variety of physiological and biological processes such as regulation of neurotransmission, pain, inflammation, cell growth and differentiation, and oncogenesis, among others. SP and NK-1 receptor interaction strongly influence the tumor microenvironment In this respect, it has been demonstrated that SP acts through the NK-1 receptor as a mitogen in several human cancer cell lines, including astrocytoma, melanoma, neuroblastoma, glioma, retinoblastoma as well as pancreatic, larynx, colon, and gastric carcinoma, leukemia, and breast cancer [17,18,19,20,21,22,23,24,25]. We review the recent scientific developments regarding the NK-1 receptor and its biological influence in tumor microenvironment and inflammation. The SP/NK-1 signaling cascade has great potential for pharmaceutical tumor targeting, and understanding of the role of NK-1 and its ligand SP might help to design modern, specific anticancer tumor strategies
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