Relationship between Glycocalyx and Tumor Microenvironment: Comparison
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Please note this is a comparison between Version 2 by Bingmei M Fu and Version 3 by Sirius Huang.

The glycocalyx is a fluffy sugar coat covering the surface of all mammalian cells. While glycocalyx at endothelial cells is a barrier to tumor cell adhesion and transmigration, glycocalyx at tumor cells promotes tumor metastasis. Extracellular vesicles (EVs) secreted by the tumor cells and tumor-associated endothelial cells are the components of tumor microenvironment. They can modify glycocalyx of endothelial and tumor cells, as well as tumor vasculature, extracellular matrix (ECM) and fibroblasts. On the other hand, glycocalyx at both cells mediates the secretion and uptake of EVs that affect tumor microenvironment.

  • extracellular vesicles
  • glycocalyx
  • microenvironment
  • angiogenesis
  • metastasis

1. Introduction

Malignant tumors remain a major threat to human health. Two key challenges facing conventional oncology therapies such as surgery, radiation, and chemotherapy are the local invasion of primary tumors and the metastasis of primary tumors to form secondary tumors, and the development of tumor cell tolerance to therapies [1]. Angiogenesis is a crucial process in tumor growth and progression. In fact, solid tumors do not grow beyond 2–3 mm3 without angiogenesis. Moreover, the vascular system has important functions such as maintaining nutrient and oxygen supply, waste removal, and immune surveillance. Therefore, anti-angiogenic therapies (AATs) that target tumor vasculature to inhibit the growth and metastasis of solid tumors have been widely used in the clinic [2]. However, AATs such as vascular pruning, disruption, and normalization have failed to achieve the desired therapeutic outcomes [1]. After the termination of AATs, the angiogenic process is reactivated and the tumor vascular system is reconstructed, leading to rapid tumor recurrence and metastasis. For example, tumors grow more rapidly in patients with metastatic colorectal cancer after the termination of bevacizumab treatment [3]. Surgical treatments may also increase plasma vascular endothelial growth factor (VEGF) levels and accelerate colorectal cancer growth and metastasis [3]. Discontinuous treatment with bevacizumab promoted tumor growth and revascularization in colorectal cancer xenograft mice [4]. Although sunitinib and bevacizumab reduced microvessel density in the primary tumor tissue of patients with renal cell carcinoma, however, sunitinib promoted endothelial cell (EC) proliferation in tumor tissues [5]. Angiogenesis in tumor growth and tumor progression involves a series of complex changes in the microenvironment. But the mechanism of AAT resistance remains unclear at present. In particular, the mechanisms by which AATs modulate the tumor microenvironment remain unclear.
The tumor microenvironment provides a suitable soil for tumor angiogenesis and growth. Tumor vasculature is disorganized and tortuous, with abnormal vascular ECs and leaky vascular walls. Tumor angiogenesis arises from the stimulation of a complex set of genetic and microenvironmental factors. Interstitial fluid pressure, hypoxia, and acidosis can regulate tumor angiogenesis [6]. EVs are important components of the tumor microenvironment and share many common biological properties, although they can be classified into different types, such as exosomes, apoptotic vesicles, and matrix vesicles, according to their origin and characteristics. EVs perform their biological functions by carrying and transporting ribonucleic acids, proteins, and lipids [7]. EVs are important targets of microenvironmental modification and play an important role in tumor angiogenesis [8]. Compared to normal vascular ECs, tumor ECs are heterogeneous, and AAT can induce tumor ECs to secrete exosomes carrying VEGF, which is defined as VEGF exosomes that could in turn induce angiogenesis and the progression of hepatocellular carcinoma (HCC) [9].
Vascular ECs and their luminal side of the endothelial glycocalyx layer (EGL) are the basic barrier and regulator of material exchange between circulating blood and tissues [10]. Previous studies have shown that the intercellular space between vascular ECs is an important pathway for material exchange in the microcirculation and an important site for tumor cell adhesion and extravasation [11][12][13][14][15]. The EGL also acts as a natural barrier for tumor cells to metastasize across the endothelium [11][12][13][14] and mediates the secretion and uptake of EVs [16][17]. AATs triggered tumor endothelial VEGF exosomes, which are potential modifiers of the tumor stromal microenvironment, are an important linkage between vascular ECs and tumor cells [9]. On the other hand, many components carried by EVs can modify the EGL, which finally facilitates the development of the tumor microenvironment.

2. The Relationship between Glycocalyx and Tumor Microenvironment

The intercellular cleft between vascular ECs is a major pathway for water and hydrophilic molecule exchange in microcirculation and a major site for tumor cell adhesion and transmigration. The endothelial glycocalyx layer is located at the vascular luminal surface, in direct contact with blood, covers the intercellular cleft, and is a natural barrier for tumor cells to metastasize across the vascular wall or endothelium. EGL has a complex structure and is comprised of many components. Heparan sulfate proteoglycan (HSPGs), syndecan-1 (SDC1), syndecan-2 (SDC2), syndecan-4 (SDC4), and glypican-1 (GPC1), and their glycosaminoglycan side chains, including heparan sulfate (HS), hyaluronic acid (HA), and chondroitin sulfate (CS), are important components of EGL [18].
Both vascular endothelial and tumor cells in the tumor microenvironment are involved in tumorigenesis and metastasis. The microenvironmental modification and glycocalyx remodeling of vascular endothelium and tumor cells are prerequisites for tumor angiogenesis, tumor cell invasion, and metastasis. Tumor cell adhesion to and transmigration across the vessel wall are accompanied by the degradation of endothelial glycocalyx and disruption of EC junctions [11][12][13][14]. At the branches and turns of microvessels, the endothelial glycocalyx is more likely to be destroyed by flow-induced factors, which increase vascular permeability and make it easier for tumor cells to adhere to the exposed adhesion molecules either on the ECs or in the ECM [11][12][13][14][15]. In contrast, tumor cell glycocalyx is closely associated with its ability of migration [19]. A most recent study found that a tumor secretion, VEGF, while disrupting the glycocalyx of human cerebral microvascular endothelial cells, significantly enhances heparan sulfate and hyaluronic acid coverage on malignant breast cancer cells MDA-MB-231 [20]. Tumor cell surface glycocalyx promotes the uptake and internalization of EVs [16]. The secretion of syntenin exosomes also requires glycocalyx [21][22]. Disruption of the tumor cell surface glycocalyx reduces the metastatic tumor cells by 95% [19]. These findings suggest that glycocalyx is a potential mediator for vascular endothelium-tumor cell interaction. It is thus important to elucidate the regulatory role of cell surface glycocalyx in tumor microenvironment modulation. Table 1 summarizes the association of glycocalyx components with the tumor microenvironment in various cancers. Before specifying each role of the glycocalyx, the next subsection first reviews the modification of the glycocalyx by the EVs with various cargos.

2.1. Modification of Glycocalyx by EVs

The glycocalyx on different cells may have different changes in response to external stimuli. Vascular ECs co-cultured with tumor cells secrete EVs carrying vascular endothelial cadherin (VE-cadherin), which are reused by tumor cells and promote tumor angiogenesis [8]. VE-cadherin is closely linked to the vascular endothelial glycocalyx. Degradation of the vascular endothelial glycocalyx inhibits circumferential strain-induced VE-cadherin transcription [23], while VE-cadherin knockdown can result in a reduction of the vascular endothelial glycocalyx [24]. Plasma-derived EVs secreted by linoleic acid-induced tumor cells or EVs from the serum of cancer patients promote MMPs secretion and angiogenesis [25]. Previous studies have shown that MMPs can degrade the vascular endothelial glycocalyx [26]. These findings indicate that the glycocalyx can be modified by EVs.
Table 1.
Components of glycocalyx and its association with tumor microenvironment.
Cancer Type Components Pathway Function Ref.
Multiple myeloma SDC1 HGF/c-met/IL-11 ECM remodeling [27]
Breast cancer SDC1 TGF-β ECM remodeling [28]
Breast cancer SDC1 FGF2, SDF1 Growth signal [29]
Bladder cancer SDC4 NF-κB ECM deposition of Tenascin-C [30]
Pancreatic ductal adenocarcinoma SDC1 CCL5 Mediate the T cells crosstalk with tumor cells [31]
Breast cancer SDC2 TGF-β Immune evasion [32]
Melanoma SDC3   Proinflammatory response [33]
Colon cancer SDC1 VEGFR2 Angiogenesis [34]
Colon cancer SDC2 VEGF Angiogenesis [35]

2.2. Regulation of ECM Remodeling by Glycocalyx

Chemotherapy-driven shedded SDC1 stimulates IL-11 via enhancing HGF/c-met signaling, and it might bind to bone marrow ECM molecules such as collagen and fibronectin, worsening the bone disease in myeloma [27]. SDC1 overexpression in senescent breast stromal fibroblasts induced by ionizing radiation treatment of breast cancer via an autocrine action of TGF-β reduces expression of COL1A1 and increases expression of several MMPs, i.e., MMP-1, -2, -3, and -9 [36]. T47D breast carcinoma cells induce expression of SDC1 in mammary fibroblasts, whereas shedding of SDC1 HS from the fibroblast surface mediates the paracrine growth signal of breast carcinomas [29]. An ECM component, Tenascin-C, which has been reported to compete with the binding sites of fibronectin with SDC4, is recently reported to activate NF-κB signaling by binding with SDC4 to promote tumor progression [37].

2.3. Regulation of Immune Landscape by Glycocalyx

A recent single-cell RNA-seq analysis demonstrated that CCL5-SDC1/4 receptor-ligand interaction mediates the T cells’ crosstalk with tumor cells in pancreatic ductal adenocarcinoma [31]. SDC2 enhances TGF-β signaling in tumor-associated stromal cells and mediates immune evasion in breast cancer [32]. SDC3 expressed on tumor-associated macrophages is promoted by hypoxia inducible factors (HIFs) and might link to a proinflammatory response [33].

2.4. Regulation of Angiogenesis by Glycocalyx

It has been shown that SDC1 promotes the transformation of tumor ECs into an angiogenic phenotype [34]. SDC1 silencing inhibits the organization of tumor ECs into patent vessels in severe combined immunodeficient (SCID) mice, reduces membrane expression of VEGFR2, and thus weakens the colocalization of VEGFR2 with SDC1 [34]. SDC2 is closely associated with cytoskeleton organization, integrin signaling, and developmental angiogenesis, and is required for the development of the vascular system. SDC2 promotes VEGF/VFGFR2 complex formation and VEGF-dependent neovascularization [38]. Global and inducible endothelial-specific deletion of SDC2 in mice markedly impairs VEGF signaling and leads to angiogenic defects [38]. The shed SDC2 enhances tumorigenic activity by increasing the crosstalk of cancer cells with tumor-associated macrophages and endothelial cells to enhance angiogenesis for colon cancer progression via producing VEGF [35]. VEGF is a central effector of angiogenesis and vascular permeability regulated by EVs. VEGF also activates MMPs [39], which can degrade the vascular endothelial glycocalyx [26]. The interplay among VEGF, MMPs, and endothelial glycocalyx is still unclear.
Moreover, whether vascular endothelial glycocalyx participates in the tumor angiogenesis and tumor metastasis remains unclear. Further investigation is required. VEGF not only selectively regulates the proliferation and motility of vascular ECs but also enhances vascular permeability, leading to fibrin gel deposition and providing a suitable microenvironment for tumor metastasis [40]. VEGF can disrupt EC junctions, promote the adhesion of tumor cells to microvessels, and enhance microvascular permeability through the VEGF receptor 2 (VEGFR2/FDR/Flk-1) pathway [14][41]. The role of the VEGFR2 pathway in mediating the disruption of vascular endothelial glycocalyx and cell junctions has attracted much attention recently.

References

  1. Ye Zeng; Bingmei M. Fu; Resistance Mechanisms of Anti-angiogenic Therapy and Exosomes-Mediated Revascularization in Cancer. Frontiers in Cell and Developmental Biology 2020, 8, 610661, 10.3389/fcell.2020.610661.
  2. Dorian Yarih Garcia-Ortega; Sara Aileen Cabrera-Nieto; Haydee Sarai Caro-Sánchez; Marlid Cruz-Ramos; An overview of resistance to chemotherapy in osteosarcoma and future perspectives. Cancer Drug Resistance 2022, 5, 762-93, 10.20517/cdr.2022.18.
  3. W. Cacheux; T. Boisserie; L. Staudacher; O. Vignaux; B. Dousset; O. Soubrane; B. Terris; C. Mateus; S. Chaussade; F. Goldwasser; et al. Reversible tumor growth acceleration following bevacizumab interruption in metastatic colorectal cancer patients scheduled for surgery. Annals of Oncology 2008, 19, 1659-1661, 10.1093/annonc/mdn540.
  4. Selma Becherirat; Fatemeh Valamanesh; Mojgan Karimi; Anne-Marie Faussat; Jean-Marie Launay; Cynthia Pimpie; Amu Therwath; Marc Pocard; Discontinuous Schedule of Bevacizumab in Colorectal Cancer Induces Accelerated Tumor Growth and Phenotypic Changes. Translational Oncology 2018, 11, 406-415, 10.1016/j.tranon.2018.01.017.
  5. Arjan W. Griffioen; Laurie A. Mans; Annemarie M.A. de Graaf; Patrycja Nowak-Sliwinska; Céline L.M.M. de Hoog; Trees A.M. de Jong; Florry A. Vyth-Dreese; Judy R. van Beijnum; Axel Bex; Eric Jonasch; et al. Rapid Angiogenesis Onset after Discontinuation of Sunitinib Treatment of Renal Cell Carcinoma Patients. Clinical Cancer Research 2012, 18, 3961-3971, 10.1158/1078-0432.ccr-12-0002.
  6. Rakesh K. Jain; Normalization of Tumor Vasculature: An Emerging Concept in Antiangiogenic Therapy. Science 2005, 307, 58-62, 10.1126/science.1104819.
  7. Ye Zeng; Yan Qiu; Wenli Jiang; Junyi Shen; Xinghong Yao; Xueling He; Liang Li; Bingmei Fu; Xiaoheng Liu; Biological Features of Extracellular Vesicles and Challenges. Frontiers in Cell and Developmental Biology 2022, 10, 816698, 10.3389/fcell.2022.816698.
  8. Maryam Rezaei; Ana C. Martins Cavaco; Martin Stehling; Astrid Nottebaum; Katrin Brockhaus; Michele F. Caliandro; Sonja Schelhaas; Felix Schmalbein; Dietmar Vestweber; Johannes A. Eble; et al. Extracellular Vesicle Transfer from Endothelial Cells Drives VE-Cadherin Expression in Breast Cancer Cells, Thereby Causing Heterotypic Cell Contacts. Cancers 2020, 12, 2138, 10.3390/cancers12082138.
  9. Ye Zeng; Xinghong Yao; Xiaoheng Liu; Xueling He; Liang Li; Xiaojing Liu; Zhiping Yan; Jiang Wu; Bingmei M. Fu; Anti-angiogenesis triggers exosomes release from endothelial cells to promote tumor vasculogenesis. Journal of Extracellular Vesicles 2019, 8, 1629865, 10.1080/20013078.2019.1629865.
  10. Ye Zeng; X. Frank Zhang; Bingmei M. Fu; John M. Tarbell; The Role of Endothelial Surface Glycocalyx in Mechanosensing and Transduction. null 2018, 1097, 1-27, 10.1007/978-3-319-96445-4_1.
  11. Bingmei M. Fu; Tumor Metastasis in the Microcirculation. null 2018, 1097, 201-218, 10.1007/978-3-319-96445-4_11.
  12. Bin Cai; Jie Fan; Min Zeng; Lin Zhang; Bingmei M. Fu; Adhesion of malignant mammary tumor cells MDA-MB-231 to microvessel wall increases microvascular permeability via degradation of endothelial surface glycocalyx. Journal of Applied Physiology 2012, 113, 1141-1153, 10.1152/japplphysiol.00479.2012.
  13. Bingmei M. Fu; Jinlin Yang; Bin Cai; Jie Fan; Lin Zhang; Min Zeng; Reinforcing endothelial junctions prevents microvessel permeability increase and tumor cell adhesion in microvessels in vivo. Scientific Reports 2015, 5, 15697, 10.1038/srep15697.
  14. Jie Fan; Bingmei M. Fu; Quantification of Malignant Breast Cancer Cell MDA-MB-231 Transmigration Across Brain and Lung Microvascular Endothelium. Annals of Biomedical Engineering 2015, 44, 2189-2201, 10.1007/s10439-015-1517-y.
  15. Lin Zhang; Min Zeng; Bingmei M. Fu; Inhibition of endothelial nitric oxide synthase decreases breast cancer cell MDA-MB-231 adhesion to intact microvessels under physiological flows. American Journal of Physiology-Heart and Circulatory Physiology 2016, 310, H1735-H1747, 10.1152/ajpheart.00109.2016.
  16. Pedro Fuentes; Marta Sesé; Pedro J. Guijarro; Marta Emperador; Sara Sánchez-Redondo; Héctor Peinado; Stefan Hümmer; Santiago Ramón Y Cajal; ITGB3-mediated uptake of small extracellular vesicles facilitates intercellular communication in breast cancer cells. Nature Communications 2020, 11, 1-15, 10.1038/s41467-020-18081-9.
  17. Josiah Ochieng; Gladys Nangami; Amos Sakwe; Tanu Rana; Shalonda Ingram; Jeffrey S. Goodwin; Cierra Moye; Philip Lammers; Samuel E. Adunyah; Extracellular histones are the ligands for the uptake of exosomes and hydroxyapatite‐nanoparticles by tumor cellsviasyndecan‐4. FEBS Letters 2018, 592, 3274-3285, 10.1002/1873-3468.13236.
  18. Sheldon Weinbaum; Limary M. Cancel; Bingmei M. Fu; John M. Tarbell; The Glycocalyx and Its Role in Vascular Physiology and Vascular Related Diseases. Cardiovascular Engineering and Technology 2020, 12, 37-71, 10.1007/s13239-020-00485-9.
  19. Henry Qazi; Zhong-Dong Shi; Jonathan W. Song; Limary M. Cancel; Peigen Huang; Ye Zeng; Sylvie Roberge; Lance L. Munn; John M. Tarbell; Heparan sulfate proteoglycans mediate renal carcinoma metastasis. International Journal of Cancer 2016, 139, 2791-2801, 10.1002/ijc.30397.
  20. Yifan Xia; Yunfei Li; Bingmei M. Fu; Differential effects of vascular endothelial growth factor on glycocalyx of endothelial and tumor cells and potential targets for tumor metastasis. APL Bioengineering 2022, 6, 016101, 10.1063/5.0064381.
  21. Maria Francesca Baietti; Zhe Zhang; Eva Mortier; Aurélie Melchior; Gisèle Degeest; Annelies Geeraerts; Ylva Ivarsson; Fabienne Depoortere; Christien Coomans; Elke Vermeiren; et al.Pascale ZimmermannGuido David Syndecan–syntenin–ALIX regulates the biogenesis of exosomes. Nature cell biology 2012, 14, 677-685, 10.1038/ncb2502.
  22. Bart Roucourt; Sofie Meeussen; Jie Bao; Pascale Zimmermann; Guido David; Heparanase activates the syndecan-syntenin-ALIX exosome pathway. Cell Research 2015, 25, 412-428, 10.1038/cr.2015.29.
  23. Maria Nikmanesh; Limary M. Cancel; Zhong‐Dong Shi; John M. Tarbell; Heparan sulfate proteoglycan, integrin, and syndecan‐4 are mechanosensors mediating cyclic strain‐modulated endothelial gene expression in mouse embryonic stem cell‐derived endothelial cells. Biotechnology & Bioengineering 2019, 116, 2730-2741, 10.1002/bit.27104.
  24. Liqun Li; Qiang Liu; Tongyao Shang; Wei Song; Dongmei Xu; Thaddeus D. Allen; Xia Wang; James Jeong; Corrinne G. Lobe; Ju Liu; et al. Aberrant Activation of Notch1 Signaling in Glomerular Endothelium Induces Albuminuria. Circulation Research 2021, 128, 602-618, 10.1161/circresaha.120.316970.
  25. Alejandra Garcia-Hernandez; Elizabeth Leal-Orta; Javier Ramirez-Ricardo; Pedro Cortes-Reynosa; Rocio Thompson-Bonilla; Eduardo Perez Salazar; Linoleic acid induces secretion of extracellular vesicles from MDA-MB-231 breast cancer cells that mediate cellular processes involved with angiogenesis in HUVECs. Prostaglandins & other lipid mediators 2020, 153, 106519, 10.1016/j.prostaglandins.2020.106519.
  26. Ye Zeng; Roger H. Adamson; Fitz-Roy E. Curry; John M. Tarbell; Sphingosine-1-phosphate protects endothelial glycocalyx by inhibiting syndecan-1 shedding. American Journal of Physiology-Heart and Circulatory Physiology 2014, 306, H363-H372, 10.1152/ajpheart.00687.2013.
  27. Vishnu C. Ramani; Ralph D. Sanderson; Chemotherapy stimulates syndecan-1 shedding: A potentially negative effect of treatment that may promote tumor relapse. Matrix Biology 2014, 35, 215-222, 10.1016/j.matbio.2013.10.005.
  28. Eleni Liakou; Eleni Mavrogonatou; Harris Pratsinis; Sophia Rizou; Konstantinos Evangelou; Petros N. Panagiotou; Nikos K. Karamanos; Vassilis G. Gorgoulis; Dimitris Kletsas; Ionizing radiation-mediated premature senescence and paracrine interactions with cancer cells enhance the expression of syndecan 1 in human breast stromal fibroblasts: the role of TGF-β. Aging 2016, 8, 1650-1669, 10.18632/aging.100989.
  29. Gui Su; Stacy A. Blaine; Dianhua Qiao; Andreas Friedl; Shedding of Syndecan-1 by Stromal Fibroblasts Stimulates Human Breast Cancer Cell Proliferation via FGF2 Activation. Journal of Biological Chemistry 2007, 282, 14906-14915, 10.1074/jbc.m611739200.
  30. Zhenfeng Guan; Yi Sun; Liang Mu; Yazhuo Jiang; Jinhai Fan; Tenascin-C promotes bladder cancer progression and its action depends on syndecan-4 and involves NF-κB signaling activation. BMC Cancer 2022, 22, 1-14, 10.1186/s12885-022-09285-x.
  31. Kai Chen; Yazhou Wang; Yuting Hou; Qi Wang; Di Long; Xinxin Liu; Xiaodong Tian; Yinmo Yang; Single cell RNA-seq reveals the CCL5/SDC1 receptor-ligand interaction between T cells and tumor cells in pancreatic cancer. Cancer letters 2022, 545, 215834, 10.1016/j.canlet.2022.215834.
  32. Loftus, P.G.; Watson, L.; Deedigan, L.M.; Camarillo-Retamosa, E.; Dwyer, R.M.; et al.; Targeting stromal cell Syndecan‐2 reduces breast tumour growth, metastasis and limits immune evasion. International Journal of Cancer 2020, 148, 1245-1259, 10.1002/ijc.33383.
  33. Endika Prieto-Fernández; Leire Egia-Mendikute; Alexandre Bosch; Ana García Del Río; Borja Jimenez-Lasheras; Asier Antoñana-Vildosola; So Young Lee; Asis Palazon; Hypoxia Promotes Syndecan-3 Expression in the Tumor Microenvironment. Frontiers in Immunology 2020, 11, 586977, 10.3389/fimmu.2020.586977.
  34. S Lamorte; S Ferrero; S Aschero; L Monitillo; B Bussolati; P Omedè; M Ladetto; G Camussi; Syndecan-1 promotes the angiogenic phenotype of multiple myeloma endothelial cells. Leukemia 2011, 26, 1081-1090, 10.1038/leu.2011.290.
  35. Bohee Jang; Hyun-Kuk Song; Jisun Hwang; Seohyeon Lee; Eunhye Park; Areum Oh; Eun Sook Hwang; Jee Young Sung; Yong-Nyun Kim; Kyunghye Park; et al.You Mie LeeEok-Soo Oh Shed syndecan-2 enhances colon cancer progression by increasing cooperative angiogenesis in the tumor microenvironment. Matrix Biology 2022, 107, 40-58, 10.1016/j.matbio.2022.02.001.
  36. Eleni Liakou; Eleni Mavrogonatou; Harris Pratsinis; Sophia Rizou; Konstantinos Evangelou; Petros N. Panagiotou; Nikos K. Karamanos; Vassilis G. Gorgoulis; Dimitris Kletsas; Ionizing radiation-mediated premature senescence and paracrine interactions with cancer cells enhance the expression of syndecan 1 in human breast stromal fibroblasts: the role of TGF-β. Aging 2016, 8, 1650-1669, 10.18632/aging.100989.
  37. Zhenfeng Guan; Yi Sun; Liang Mu; Yazhuo Jiang; Jinhai Fan; Tenascin-C promotes bladder cancer progression and its action depends on syndecan-4 and involves NF-κB signaling activation. BMC Cancer 2022, 22, 1-14, 10.1186/s12885-022-09285-x.
  38. Federico Corti; Yingdi Wang; John M. Rhodes; Deepak Atri; Stephanie Archer-Hartmann; Jiasheng Zhang; Zhen W. Zhuang; Dongying Chen; Tianyun Wang; Zhirui Wang; et al.Parastoo AzadiMichael Simons N-terminal syndecan-2 domain selectively enhances 6-O heparan sulfate chains sulfation and promotes VEGFA165-dependent neovascularization. Nature Communications 2019, 10, 1562, 10.1038/s41467-019-09605-z.
  39. Miri Morgulis; Mark R. Winter; Ligal Shternhell; Tsvia Gildor; Smadar Ben-Tabou De-Leon; VEGF signaling activates the matrix metalloproteinases, MmpL7 and MmpL5 at the sites of active skeletal growth and MmpL7 regulates skeletal elongation. Developmental biology 2021, 473, 80-89, 10.1016/j.ydbio.2021.01.013.
  40. Harold F. Dvorak; Tumors: Wounds That Do Not Heal—A Historical Perspective with a Focus on the Fundamental Roles of Increased Vascular Permeability and Clotting. Seminars in thrombosis and hemostasis 2019, 45, 576-592, 10.1055/s-0039-1687908.
  41. Shang Shen; Jie Fan; Bin Cai; Yonggang Lv; Min Zeng; Yanyan Hao; Filippo G. Giancotti; Bingmei M. Fu; Vascular endothelial growth factor enhances cancer cell adhesion to microvascular endotheliumin vivo. Experimental Physiology 2009, 95, 369-379, 10.1113/expphysiol.2009.050260.
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