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Mechanisms and Barriers in Cancer Nanomedicine: Addressing Challenges, Looking for Solutions *
Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Thomas J. Anchordoquy, Yechezkel Barenholz, Diana Boraschi, Michael Chorny, Paolo Decuzzi, Marina A. Dobrovolskaia, Z. Shadi Farhangrazi, Dorothy Farrell, Alberto Gabizon, Hamidreza Ghandehari, Biana Godin, Ninh M. La-Beck, Julia Ljubimova, S. Moein Moghimi, Len Pagliaro, Ji-Ho Park, Dan Peer, Erkki Ruoslahti, Natalie J. Serkova, Dmitri Simberg
Several strategies to improve tumor penetration of compounds have been discussed. An approach to boost tumor permeability by tumor-penetrating peptides was presented. These peptides bind to a primary receptor specific for tumor blood vessels, tumor cells, and stroma, then undergo proteolytic cleavage and shift their affinity from the primary receptor to neuropilin-1. Binding to neuropilin-1 subsequently activates an endocytic/exocytic trans-tissue transport pathway, leading to a transient increase in tumor penetration of nanoparticles and small-molecule drugs [15]. This mechanism works especially well in starved tumors due to dependence of the transport process on metabolism.
Angiogenesis in Hematological Malignancies
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Alida C. Weidenaar, Hendrik J. M. de Jonge, Arja ter Elst, Evelina S. J. M. de Bont
The VEGF family includes VEGFA, placental growth factor (PLGF), VEGFB, VEGFC, VEGFD, VEGFE and VEGFF (32–36). These proteins can bind to and exert their effect on two cell surface receptor families: the tyrosine kinase receptors (VEGFR) and the neuropilin (NRP) receptors. Three VEGF receptors have been identified, namely VEGF receptor 1 (FLT1), VEGF receptor 2 (KDR), and VEGF receptor 3 (FLT4) (37–39). Until now, two neuropilins (NRP1 and NRP2) have been described (40,41). Members of the VEGF family exert their effects by binding to the transmembrane receptors, resulting in the formation of dimers in the plasma membrane. Interaction between dimers is thought to stimulate autophosphorylation of the receptor. In response to phosphorylation of the receptors, intracellular signals are transmitted via signaling pathways such as mitogen activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI 3-K/Akt) cascades, or the signal transducers and activators of transcription (STAT) pathway (42–44). These signals are essential to various cellular processes including control of cell growth, differentiation, and migration (45).
Targeted Therapies
Published in Loredana G. Marcu, Iuliana Toma-Dasu, Alexandru Dasu, Claes Mercke, Radiotherapy and Clinical Radiobiology of Head and Neck Cancer, 2018
Loredana G. Marcu, Iuliana Toma-Dasu, Alexandru Dasu, Claes Mercke
Angiogenesis is intrinsically dependent on the development of hypoxia in the tumour microenvironment, when a cascade of proangiogenic molecules is released determining the formation of neovasculature. Vascular endothelial growth factor A (VEGF-A) is the most known of these molecules. It is a vascular permeability factor belonging to the platelet derived growth factor (PDGF) superfamily which also includes VEGF-B, VEGF-C, VEGF-D and placental growth factor (PIGF) (Ferrara 2005; Christopoulos et al. 2011). The expression of VEGF has been reported in many solid tumours, including squamous cell carcinomas of the head and neck. The overexpression of this molecule has been associated with increased tumour progression, increased resistance to chemotherapy, positive lymph node metastasis and poor prognosis (Riedel et al. 2000; Smith et al. 2000; Tse et al. 2007; Boonkitticharoen et al. 2008). The key mediator modulating VEGF expression in solid tumours is hypoxia-inducible factor (HIF-1α). The VEGF family signals through a group of cell surface receptor tyrosine kinases that include VEGFR-1, VEGFR-2 and VEGFR-3. Of these, VEGFR-2 has been identified as the principal angiogenic receptor. VEGF also interacts with neuropilins, a family of coreceptors that include NRP-1 and NRP-2. The neuropilins are thought to form complexes with the VEGF receptors, thus enhancing their biological activities (Ferrara, Gerber & LeCouter 2003; Christopoulos et al. 2011).
Semaphorin 3A Inhibits Endoplasmic Reticulum Stress Induced by High Glucose in Müller Cells
Published in Current Eye Research, 2023
Mengyang Li, Enzhong Jin, Li Zhu, Chi Ren, Zhiqiao Liang, Mingwei Zhao, Jinfeng Qu
Semaphorins, originally discovered by Kolodkin et al. in 1992,7 constitute a large family of endogenous secreted and transmembrane-associated proteins.8 Semaphorins have been characterized as repulsive axonal and vessel network guidance signals that regulate cellular interactions as well as cell differentiation, morphology, and function.9 The secreted protein Sema3A (collapsin-1) was the first vertebrate Semaphorin identified, and its role is to induce contraction and collapse of structures on axon growth cones.10 During signaling, Sema3A binds to the Plexin A 1-4 receptor, and Neuropilins 1 (Nrp-1) acts as a coreceptor to stabilize the Semaphorin-Plexin interaction.9 Since the discovery of Sema3A, the most studied function of Sema3A has been the effect on axon growth and neural repair during development and wound healing.11 A variety of studies have reported the effects of Sema3A on other physiological processes, including the immune response, organogenesis, tumor formation, and bone tissue remodeling.12 However, the effects of Sema3A on Müller cells in DR have not been documented.
Ganoderma lucidum polysaccharides ameliorate lipopolysaccharide-induced acute pneumonia via inhibiting NRP1-mediated inflammation
Published in Pharmaceutical Biology, 2022
Xuelian Zhang, Daoshun Wu, Yu Tian, Xiangdong Chen, Jin Lan, Fei Wei, Ye Li, Yun Luo, Xiaobo Sun
Neuropilin-1 (NRP1), an encoded transmembrane protein, is expressed in many human tissues, notably in the lung (Saiz et al. 2021). In addition, NRP1 is a surface receptor found on cancer cells, immune cells and many other cell types (Chuckran et al. 2020; Liu et al. 2020). Mainly, it has been reported that NRP1 was found to be effective in diverse immune cells, including macrophages, dendritic cells and T cell subpopulations, which indicated the vital effect of NRP1 on the regulation of immune response as well as respiratory diseases (Tordjman et al. 2002; Roy et al. 2017; Wilson Ariel et al. 2018). Notably, it has been reported that SARS-CoV-2 Spike protein can bind to the b1b2 domain of NRP1, and NRP1 is an essential mediator to assist the entry of SARS-CoV-2 into normal cells and lead to cell infectivity (Cantuti-Castelvetri et al. 2020; Daly James et al. 2020). At present, the inhibition of NRP1 expression is considered an effective strategy for blocking viral infectivity and spreading (Kolarič et al. 2022).
Enteroviruses and coronaviruses: similarities and therapeutic targets
Published in Expert Opinion on Therapeutic Targets, 2021
Varpu Marjomäki, Kerttu Kalander, Maarit Hellman, Perttu Permi
Coronavirus spike protein binds to the host cell receptors on the plasma membrane. Those receptors include human aminopeptidase N for HCoV-229E and angiotensin-converting enzyme2 (ACE2) for SARS-Cov and SARS CoV-2 [12]. The Spike-ACE2 complex has been solved by Cryo-EM and shows that 16 residues from the S and 20 residues from ACE-2 are involved in the binding [32,33]. The binding residues are conserved between SARS viruses,but due to having more interactions with ACE-2, SARS-CoV-2 was suggested to bind ACE-2 with higher affinity than SARS-CoV [32,33]. Recently, a new player was shown to be involved in binding to the host cells, namely neuropilin receptor (NRP1 and NRP2) [34]. Specific to SARS-CoV-2 and some other highly virulent pathogenic viruses such as Ebola and avian influenza, their spike proteins have a polybasic cleavage site, which, after proteolytic cleavage, exposes a conserved C-terminal motif (RXXROH) which is able to bind and activate neuropilin receptors. Neuropilin receptors are known to be abundantly expressed in the olfactory system, including the neuronal cells, suggesting that neuropilins may truly promote successful infection in the upper respiratory tract and may be the basis of the neurological symptoms in several infected subjects.