Semaphorins and their Receptors in Stem and Cancer Cells

C.      Micucci; S.      Orciari; A.      Catalano

Abstract

There is a growing body of evidence that links cancer with genes and pathways that are required for normal embryonic development, increasing the possibility that cancer cells with stem cell properties, particularly self-renewal and multipotentiality, are primarily involved in tumor formation and progression. One novel pathway that is important in regulating the morphogenesis, proliferation, survival and growth in a variety of adult and embryonic tissues is the semaphorin signaling pathway. Semaphorins are a large family of secreted, transmembrane and GPI-linked proteins with a broad spectrum of functions. Semaphorin signaling is transduced by plexins which, in the case of most class 3 semaphorins, require high affinity neuropilin receptors. The neuropilins also function as receptors for VEGF and other growth factors, and their expression is abnormal in tumors. Various semaphorins can either promote or inhibit tumor progression through the promotion or inhibition of processes such as tumor angiogenesis, metastasis and tumor cell survival. In normal tissues, semaphorin signaling is mainly active in precursor cells. This increases the possibility of tumors being derived from such cells, possibly even stem cells, which are unable to differentiate and/or to stop proliferating. In this review, we summarize the molecular mechanisms of semaphorin signal transduction involved in the stem cell compartment, and describe the evidence that links semaphorins to the control of tumor progression.

Keywords: Semaphorins, plexins, cancer cells, tumor progression, stem cells, Receptors, stem cell, morphogenesis, proliferation, neuropilin receptors, neuropilins, tumor angiogenesis, metastasis, cancer stem cells, tumorigenic, Darwinian model, neuropilin (NRP), Plexin, vasculogenesis, misexpression, eukaryotes, procaryotes, Met oncoprotein, cysteine residues, intrasubunit disulfide bonds, C-termini, Proteolytic processing, dorsal root ganglion (DRG), Xenopus spinal neurons, guanosine 3??,5??-monophosphate, plexins type B, Receptor tyrosine kinases (RTKs), pro-migratory, anti-migratory, FAK tyrosine kinases, vascular endothelial growth factor (VEGF), plexin cytoplasmic domain, receptor-type kinases, chemotaxis, embryogenesis, cell proliferation, lung epithelial cells, neuroendocrine cells, mesenchymal, endothelial cells, Sema3A, endodermal cells, autonomously, non-autonomously, multiple semaphorin-plexin, marrow-derived cells, cardiovascular system, olfactory sensory axons, olfactory bulb, ventricular hypertrophy, organogenesis, intramuscular motoneuron network, hepatocyte growth factor (HGF), HGF, collagen membrane, semaphorin proteins, anti-CD3, anti-CD28, dendritic cells (DCs), immune cell migration, tumor metastasis, breast cancer, anchorage-independent growth, plexin-D1, anti-migratory effects, Rho-initiated signaling, leukemic cells, glioblastoma cell migration, angiogenesis, hematopoiesis, cancerogenesis