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Controlled Delivery of Angiogenic Proteins
Published in Emmanuel Opara, Controlled Drug Delivery Systems, 2020
Binita Shrestha, Jacob Brown, Eric M. Brey
Vascular Endothelial Growth Factors (VEGFs) are a family of factors that are required for angiogenesis and/or lymphangiogenesis (formation of lymphatic vessels). The VEGF family consists of a number of members, including VEGF-A (which has many isoforms), VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PIGF) [20]. Each of these members play important, but often different, roles in biological processes. For example, VEGF-A binds with VEGFR-1 to regulate normal and pathological angiogenesis. VEGF-A also binds with VEGFR-2 to modulate growth, migration, survival, and permeability of ECs [21] and stimulates ECs to release other growth factors essential to activate surrounding cells [22]. VEGF-C and VEGF-D and their receptor VEGFR-3 have been reported to regulate lymphangiogenesis. There is also a subgroup of VEGF isolated from snake venom, VEGF-F. VEGF-F regulates vascular permeability, angiogenesis, and blood pressure [23]. PIGF binds specifically to VEGFR-1 and regulates vascular events in both angiogenesis and vasculogenesis [24].
Biomimetic Microsystems for Blood and Lymphatic Vascular Research
Published in Hyun Jung Kim, Biomimetic Microengineering, 2020
PROX1 expressed in the cardinal vein endothelial cells leads to expression of VEGFR receptor 3 (VEGFR3), Neuropilin 2 (NRP2), and Podoplanin, which are major regulators of lymphatic budding and lymphatic separation (Petrova et al. 2002). VEGFR3 is a key receptor for lymphangiogenesis, a new lymphatic vessel formation that can be driven by prolymphangiogenic growth factors, such as VEGF-C and VEGF-D (Achen et al. 1998). In addition to VEGFR3, NRP2 serves as a co-receptor of VEGF-C/D to facilitate prolymphangiogenic signal transduction through the VEGFR3 (Xu et al. 2010). While VEGFR3 and NRP2 promote lymphatic budding (Yang et al. 2012), podoplanin (PDPN) makes LECs separated from the cardinal vein endothelium (Herzog et al. 2013). Once lymphatic budding sprouts out from the vein endothelium, blood in the veins makes a contact with PDPN in LECs, which initiates blood coagulation by activation of CLEC2 (C-type lectin-like receptor 2) in platelets through the lymphatic PDPN interaction to CLEC2 at the conjunction area of blood and lymphatic vessels (Uhrin et al. 2010) (Figure 2.2a).
Understanding the complex microenvironment in oral cancer: the contribution of the Faculty of Dentistry, University of Otago over the last 100 years
Published in Journal of the Royal Society of New Zealand, 2020
Alison Mary Rich, Haizal Mohd Hussaini, Benedict Seo, Rosnah Bt Zain
A typical feature of neoplasia is the secretion of angiogenic factors via a complex balance of pro- and anti-angiogenic mechanisms (Folkman and Shing 1992). It is known that endothelial cells in the TME participate in cross talk with tumour cells themselves and promote invasion. In a study in our laboratory angiogenic factors (vascular endothelial growth factor [VEGF], VEGF receptor 2 [KDR] and vasohibin-1 [VASH-1]) were expressed differently in the endothelial cells and the epithelial cells of inflamed hyperplastic oral tissues compared with OSCC and normal oral mucosa (NOM) (Allsobrook 2014). The malignant keratinocytes of OSCC were strongly VEGF+. Gene expression in three immortal OSCC cell lines (SCC4, SCC15 and SCC25) and three normal epithelial cell lines (OKF4, OKF6 and OKP7) showed differential regulation of VEGF in OSCC compared with normal epithelial cells (Allsobrook 2014). Likewise, lymphangiogenesis is a key component of carcinogenesis with loss of control of lymphangiogenic regulation leading to the formation of new lymph vessels within and around the tumour. This may increase the likelihood of lymphatic metastasis. Using IHC with reliable lymphatic endothelial cell (LEC) antibody markers, we were able to establish that the OSCC TME possessed significantly more lymphatic vessels expressing D2-40 (Figure 6) podoplanin (D2-40) and prospero-homeobox protein (Prox)-1 than the control groups (Chutipongpisit 2016). Overexpression of the lymphatic markers in the malignant tissues was significantly greater than in the inflamed connective tissue as well as the normal controls, i.e. increased lymphangiogenesis associated with non-specific inflammation was controlled for. This increase in lymphatic vessels density (LVD) may play a role in facilitating lymphatic invasion and later metastases. These molecular entities may serve as potential anti-oral cancer therapeutic targets. D2-40 expression on the tumour cells themselves has been associated with a role in tumour progression in experimental and human carcinogenesis (Schacht et al. 2005; Ugorski et al. 2016) including in oral cancer (Martin-Villar et al. 2005; Yuan et al. 2006; Cueni et al. 2010; Tsuneki et al. 2013) and OPMD (Kawaguchi et al. 2008; Mei et al. 2014). In OPMD, the basal cell layer of the dysplastic epithelium was D2-40+ (Kawaguchi et al. 2008), a phenomenon also observed in our study in dysplastic epithelium adjacent to OSCC (Chutipongpisit 2016). Multivariate analysis found that epithelial D2-40 positivity was an independent predictor of progression of OPMD to OSCC and that it can be used to further stratify oral cancer development risk (Kawaguchi et al. 2008).