Semaphorin 4F as a Critical Regulator of Neuroepithelial Interactions and a Biomarker of Aggressive Prostate Cancer

Ding, Yi; He, Dandan; Florentin, Diego; Frolov, Anna; Hilsenbeck, Susan G.; Ittmann, Michael; Kadmon, Dov; Miles, Brian J.; Rowley, David R.; Ayala, Gustavo

doi:10.1158/1078-0432.ccr-12-3669

Cited by 45 publications

(45 citation statements)

References 11 publications

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“…249 However, there is also evidence suggesting that it promotes the progression of prostate cancer 250,251 and it was reported to contribute the progression of neurofibromatosis type 1 (NF1). 249 Class-5 semaphorins: Sema5A was recently found to promote tumor metastasis in gastric cancer 252 and in pancreatic cancer 107 but inhibited the motility of glioma cells.…”

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confidence: 99%

The role of the semaphorins in cancer

Neufeld

Mumblat

Smolkin

et al. 2016

Cell Adhesion & Migration

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The semaphorins were initially characterized as axon guidance factors, but have subsequently been implicated also in the regulation of immune responses, angiogenesis, organ formation, and a variety of additional physiological and developmental functions. The semaphorin family contains more then 20 genes divided into 7 subfamilies, all of which contain the signature sema domain. The semaphorins transduce signals by binding to receptors belonging to the neuropilin or plexin families. Additional receptors which form complexes with these primary semaphorin receptors are also frequently involved in semaphorin signaling. Recent evidence suggests that semaphorins also fulfill important roles in the etiology of multiple forms of cancer. Some semaphorins have been found to function as bona-fide tumor suppressors and to inhibit tumor progression by various mechanisms while other semaphorins function as inducers and promoters of tumor progression. The semaphorin familyThe semaphorin family members are divided into 8 subclasses of which subclasses 1 and 2 contain invertebrate semaphorins while subclasses 3-7 contain the 22 vertebrate semaphorins. The 8th subclass contains viral semaphorins. In early publications, semaphorins were assigned confusing names. This situation was rectified by the adoption of a unified nomenclature in which sema is followed by the subclass number and by alphabetic designation within the subclass.1 Semaphorins are characterized by the presence of a »500 amino-acids long sema domain located close to their N-termini which is also present in semaphorin receptors of the plexin family, and by a plexin-semaphorin-integrin (PSI) domain located downstream to the sema domain. The sema domain is essential for semaphorin activity and plays a role in the determination of the receptor binding specificity.2 The sema domains of several different semaphorins were characterized by X-ray crystallography revealing a b propeller topology.3-5 Different semaphorin subclasses are characterized by class specific structural motifs. Thus, the vertebrate semaphorins belonging to classes 3, 4 and 7 contain immunoglobulin like domains, class-5 semaphorins contain thrombospondin repeats and class-3 semaphorins contain a basic domain. Class-3 semaphorins are the only vertebrate semaphorins produced as secreted proteins while other vertebrate semaphorins are membrane anchored or trans-membrane proteins that can be further processed into soluble forms by proteolytic cleavage (Fig.

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confidence: 99%

The role of the semaphorins in cancer

Neufeld

Mumblat

Smolkin

et al. 2016

Cell Adhesion & Migration

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“…85 Another member of this subclass, Sema4F, is a critical regulator of neuroepithelial interactions and considered as a biomarker in prostate cancer, as its cytoplasmic expression also correlates with nerve density and perineural invasion. 86 Also Sema5A-receptor PlexinB3 was found to interact with MET and promote tumor cell invasiveness. 29 Sema5A regulates cell motility and morphology of human glioma cells via RhoGDIalpha-mediated inactivation of Rac1 GTPase and the functional regulation of fascin-1 actin-binding protein.…”

Section: Transmembrane Semaphorins In Embryo Developmentmentioning

confidence: 99%

“…Biomarker of aggressive prostate cancer and critical regulator of neuroepithelial interactions 86,170 Sema4G…”

Section: Sema4fmentioning

confidence: 99%

Transmembrane semaphorins: Multimodal signaling cues in development and cancer

Gurrapu

Tamagnone

2016

Cell Adhesion & Migration

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Semaphorins constitute a large family of membrane-bound and secreted proteins that provide guidance cues for axon pathfinding and cell migration. Although initially discovered as repelling cues for axons in nervous system, they have been found to regulate cell adhesion and motility, angiogenesis, immune function and tumor progression. Notably, semaphorins are bifunctional cues and for instance can mediate both repulsive and attractive functions in different contexts. While many studies focused so far on the function of secreted family members, class 1 semaphorins in invertebrates and class 4, 5 and 6 in vertebrate species comprise around 14 transmembrane semaphorin molecules with emerging functional relevance. These can signal in juxtacrine, paracrine and autocrine fashion, hence mediating long and short range repulsive and attractive guidance cues which have a profound impact on cellular morphology and functions. Importantly, transmembrane semaphorins are capable of bidirectional signaling, acting both in "forward" mode via plexins (sometimes in association with receptor tyrosine kinases), and in "reverse" manner through their cytoplasmic domains. In this review, we will survey known molecular mechanisms underlying the functions of transmembrane semaphorins in development and cancer.

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“…17,22 PCa-induced neurogenesis is regulated, at least partly, by semaphorin 4F. 23 Furthermore, nerve-cancer interactions during perineural invasion (PNI) results in a survival advantage for cancer cells. 18,19,24,25 These phenomena have been demonstrated in many other cancer types, [26][27][28][29] demonstrating that nerves have a fundamental role in cancer progression.…”

Section: Introductionmentioning

confidence: 99%