title: Chemokine receptor CXCR4: role in gastrointestinal cancer.
abstract: Chemokines (CK)s, small proinflammatory chemoattractant cytokines that bind to specific G-protein coupled seven-span transmembrane receptors, are major regulators of cell trafficking and adhesion. The CXCL12 [stromal cell-derived factor-1 (SDF-1)] binds primarily to CXC receptor 4 (CXCR4; CD184). The binding of CXCL12 to CXCR4 induces intracellular signaling through several divergent pathways initiating signals related to chemotaxis, cell survival and/or proliferation, increase in intracellular calcium, and gene transcription. CXCR4 is expressed on multiple cell types including lymphocytes, hematopoietic stem cells, endothelial and epithelial cells, and cancer cells. One of the most intriguing and perhaps important roles that CKs and the CK receptors have is in regulating metastasis. Here, CK receptors may potentially facilitate tumor dissemination at each of the key steps of metastasis, including adherence of tumor cells to endothelium, extravasation from blood vessels, metastatic colonization, angiogenesis, proliferation, and protection from the host response via activation of key survival pathways such as ERK/MAPK, PI-3K/Akt/mTOR, or Jak/STAT, etc. In addition, it is increasingly recognized that CKs play an important role in facilitating communication between cancer cells and non-neoplatic cells in the tumor microenvironment (TME), including endothelial cells and fibroblasts, promoting the infiltration, activation of neutrophils, and tumor-associated macrophages within the TME. In this review, we mainly focus on the roles of chemokines CXCL12 and its cognate receptors CXCR4 as they pertain to cancer progression. In particular, we summarizes our current understanding regarding the contribution of CXCR4 and SDF-1 to gastrointestinal tumor behavior and its role in local progression, dissemination, and immune evasion of tumor cells. Also, describes recent therapeutic approaches that target these receptors or their ligands.
authors.affiliation: Department of Oncology, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy. Electronic address: lombardilucia@hotmail.com.
authors.forename: Lucia
authors.initials: L
authors.lastname: Lombardi
authors.forename: Francesca
authors.initials: F
authors.lastname: Tavano
authors.forename: Franco
authors.initials: F
authors.lastname: Morelli
authors.forename: Tiziana Pia
authors.initials: TP
authors.lastname: Latiano
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Di Sebastiano
authors.forename: Evaristo
authors.initials: E
authors.lastname: Maiello
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D006801:Humans; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology
chemical_list: D054377:Chemokine CXCL12; D019718:Receptors, CXCR4
keywords: CXCR4/SDF-1; Chemokine; Gastrointestinal cancer; Immunology; Therapy; Tumor microenvironment