CXCR4: From Signaling to Clinical Applications in Neuroendocrine Neoplasms

Simple Summary Neuroendocrine neoplasms are a heterogeneous group of malignant tumors that originate from the diffuse endocrine system. They generally have a slow course and somatostatin receptor-targeted based management is the first line of treatment. However, high-grade tumors and neuroendocrine carcinomas have a poor prognosis and somatostatin receptor-targeted therapy is not effective. The membrane receptor CXCR4 has been studied in several neoplasms and it is known to be overexpressed in aggressive tumors and associated with a worse prognosis. However, there is a lack of evidence of its use in neuroendocrine neoplasms. For that reason, this review describes the significance of CXCR4 and its possible clinical applications in the diagnostic and therapeutic management of neuroendocrine neoplasms.Abstract There are several well-described molecular mechanisms that influence cell growth and are related to the development of cancer. Chemokines constitute a fundamental element that is not only involved in local growth but also affects angiogenesis, tumor spread, and metastatic disease. Among them, the C-X-C motif chemokine ligand 12 (CXCL12) and its specific receptor the chemokine C-X-C motif receptor 4 (CXCR4) have been widely studied. The overexpression in cell membranes of CXCR4 has been shown to be associated with the development of different kinds of histological malignancies, such as adenocarcinomas, epidermoid carcinomas, mesenchymal tumors, or neuroendocrine neoplasms (NENs). The molecular synapsis between CXCL12 and CXCR4 leads to the interaction of G proteins and the activation of different intracellular signaling pathways in both gastroenteropancreatic (GEP) and bronchopulmonary (BP) NENs, conferring greater capacity for locoregional aggressiveness, the epithelial-mesenchymal transition (EMT), and the appearance of metastases. Therefore, it has been hypothesized as to how to design tools that target this receptor. The aim of this review is to focus on current knowledge of the relationship between CXCR4 and NENs, with a special emphasis on diagnostic and therapeutic molecular targets.