title: Plexin-B1 and semaphorin 4D cooperate to promote perineural invasion in a RhoA/ROK-dependent manner.
abstract: Perineural invasion (PNI) is a tropism of tumor cells for nerve bundles located in the surrounding stroma. It is a pathological feature observed in certain tumors, referred to as neurotropic malignancies, that severely limits the ability to establish local control of disease and results in pain, recurrent growth, and distant metastases. Despite the importance of PNI as a prognostic indicator, its biological mechanisms are poorly understood. The semaphorins and their receptors, the plexins, compose a family of proteins originally shown to be important in nerve cell adhesion, axon migration, and proper central nervous system development. Emerging evidence has demonstrated that these factors are expressed in tissues outside of the nervous system and represent a widespread signal transduction system that is involved in the regulation of motility and adhesion in different cell types. We believe that the plexins and semaphorins, which are strongly expressed in both axons and many carcinomas, play a role in PNI. In this study, we show that plexin-B1 is overexpressed in tissues and cell lines from neurotropic malignancies and is attracted to nerves that express its ligand, semaphorin 4D, in a Rho/Rho kinase-dependent manner. We also demonstrate that nerves are attracted to tumors through this same system of proteins, suggesting that both plexin-B1 and semaphorin 4D are important in the promotion of PNI.
authors.affiliation: Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland; Department of Oral, Basic, and Clinical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Nada O
authors.initials: NO
authors.lastname: Binmadi
authors.affiliation: Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland.
authors.forename: Ying-Hua
authors.initials: YH
authors.lastname: Yang
authors.affiliation: Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland; Department of Sports Science, University of Palermo, Palermo, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Proia
authors.affiliation: Department of Diagnostic and Surgical Sciences, University of California at Los Angeles, School of Dentistry, Los Angeles, California.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Lin
authors.affiliation: Health Science Program, Department of Dentistry, State University of Montes Claros, Minas Gerais, Brazil.
authors.forename: Alfredo M
authors.initials: AM
authors.lastname: Batista De Paula
authors.affiliation: Health Science Program, Department of Dentistry, State University of Montes Claros, Minas Gerais, Brazil.
authors.forename: André L
authors.initials: AL
authors.lastname: Sena Guimarães
authors.affiliation: Health Science Program, Department of Medicine, State University of Montes Claros, Minas Gerais, Brazil.
authors.forename: Fabiano O
authors.initials: FO
authors.lastname: Poswar
authors.affiliation: Department of Oral and Maxillofacial Pathology, Boston University Goldman School of Dental Medicine, Boston, Massachusetts.
authors.forename: Devaki
authors.initials: D
authors.lastname: Sundararajan
authors.affiliation: Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, Baltimore, Maryland; Marlene and Stuart Greenebaum Cancer Center, Baltimore, Maryland. Electronic address: jbasile@umaryland.edu.
authors.forename: John R
authors.initials: JR
authors.lastname: Basile
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism / Q000502:physiology*; D001369:Axons / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D009423:Nervous System Neoplasms / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism / Q000502:physiology*; D039961:Semaphorins / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C093224:CD100 antigen; D009419:Nerve Tissue Proteins; C492119:PLXNB1 protein, human; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D039961:Semaphorins; D020742:rhoA GTP-Binding Protein