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Heparan Sulfate and Heparan Sulfate Proteoglycans in Cancer Initiation and Progression

Arvindhan Nagarajan, Parmanand Malvi, Narendra Wajapeyee

Frontiers in Endocrinology · 2018 · Review

doi:10.3389/fendo.2018.00483

Abstract

Heparan sulfate (HS) are complex unbranched carbohydrate chains that are heavily modified by sulfate and exist either conjugated to proteins or as free, unconjugated chains. Proteins with covalently bound Heparan sulfate chains are termed Heparan Sulfate Proteoglycans (HSPGs). Both HS and HSPGs bind to various growth factors and act as co-receptors for different cell surface receptors. They also modulate the dynamics and kinetics of various ligand-receptor interactions, which in turn can influence the duration and potency of the signaling. HS and HSPGs have also been shown to exert a structural role as a component of the extracellular matrix, thereby altering processes such as cell adhesion, immune cell infiltration and angiogenesis. Previous studies have shown that HS are deregulated in a variety of solid tumors and hematological malignancies and regulate key aspects of cancer initiation and progression. HS deregulation in cancer can occur as a result of changes in the level of HSPGs or due to changes in the levels of HS biosynthesis and remodeling enzymes. Here, we describe the major cell-autonomous (proliferation, apoptosis/senescence and differentiation) and cell-non-autonomous (angiogenesis, immune evasion, and matrix remodeling) roles of HS and HSPGs in cancer. Finally, we discuss therapeutic opportunities for targeting deregulated HS biosynthesis and HSPGs as a strategy for cancer treatment.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 27, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Normal cells acquire series of genetic and epigenetic aberrations to become cancerous. The acquired cancer growth and progression enabling attributes are collectively referred to as hallmarks of cancer. Several hallmarks of cancer, such as sustained growth signaling, suppression of apoptosis, deregulated metabolism, immune evasion and angiogenesis can also be enhanced through pathological alterations of normal physiological processes.

Heparan sulfates (HS) are unbranched chains of disaccharide repeats that are heavily sulfated at various positions on their sugar residues. HS can occur either conjugated to amino acids, creating heparan sulfate proteoglycans (HSPGs), or as unconjugated chains. Both HS and HSPGs play important roles in cancer initiation and progression. Previous studies have implicated the role of HS and HSPGs in several types of solid tumors as well as hematological malignancies.

HSPGs are complex biopolymers whose synthesis is orchestrated by many enzymes, which catalyze the various steps of HS synthesis with very little redundancy (Figure 1). The majority of HS deregulation in cancer occurs due to alterations in the expression of HS-synthesizing and HS-modifying enzymes, however, alterations in HSPGs can also contribute to HS deregulation (also see Table 1).

In this review, we provide an overview of the cell-autonomous and cell-non-autonomous roles of HS and HSPGs in cancer initiation and progression. In addition, we will also discuss opportunities to develop cancer therapies by targeting the HS and HSPG axis.

Cell-autonomous role of HS and HSPGs in cancer initiation and progression

HS and HSPGs regulate diverse cell-autonomous functions, including oncogenic signaling, apoptosis, and cellular differentiation. In this section, we describe the cell-autonomous functions of HS and HSPGs in cancer initiation and progression.

Growth factor signaling and regulation of proliferation

Previous studies have shown important roles of HS and HSPGs in oncogenic signaling. In this regard, FGF binding interactions are best characterized by the role of HS in altered Receptor Tyrosine Kinase (RTK) signaling. For example, HS-modified HSPGs bind FGF ligands and receptors to form a ternary complex and enhance signaling by promoting FGF receptor (FGFR) dimerization. This in turn results in receptor activation and enhanced FGFR signaling, which consequentially promotes tumor growth. In addition to FGF, HS binds to several different mitogenic growth factors such as PDGF, Heparin-Binding Epidermal Growth Factor-like Growth Factor (HB-EGF), and Hepatocyte Growth Factor (HGF) and modulates their signaling in a context dependent manner.

Breast cancer cells are also shown to overexpress HSPGs, such as Glypican 1 (GPC1) and Syndecan 1 (SDC1), which enhance the proliferative response after treatment with various growth factors due to prolonged signaling. Similar to breast cancer, GPC1 also has been shown to have growth-promoting effects in pancreatic cancer and gliomas. Collectively, these studies highlight wide-spread deregulation of HSPGs in different cancers that exert tumor promoting roles.

Additionally, HSPGs also influence cell-matrix interactions by binding matrix proteins such as fibronectin, laminin, thrombospondin, and collagen. For example, SDC2 has been shown to be overexpressed in colon cancer cell lines and inhibition of SDC2 in these cells results in cell cycle arrest. Similarly, RKIP and HMGB2-dependent breast cancer survival and metastasis was shown to be regulated in SDC2 dependent manner. However, it is important to note that in addition to the pro-tumorigenic effects, some HSPGs, such as SDC2, exert tumor suppressive effects depending on the cancer type.

Interestingly, HSPGs on the cell surface can also shed, generating soluble proteins that influence cellular proliferation by accumulating in intercellular spaces and sequestering growth factors. HSPGs are also often expressed in the tumor stroma and affect several cancer cell growth-enabling features. For example, stromal SDC1 that is released into the tumor microenvironment promotes breast carcinoma growth by enhancing FGF2 signaling. Interestingly, SDC1 shedding into the stroma is enhanced by heparanase expression, in part through removal and reduction of heparan sulfate chains. Thus, various components of the HS signaling pathway coordinate to promote carcinogenesis.

HSPGs secreted into the stroma can also inhibit cancer cell proliferation. For example, increased FGF2 signaling due to soluble HSPGs suppresses neuroblastoma proliferation. Specifically, it has been shown that growing neuroblastoma cells with soluble HSPGs promote its differentiation by enhancing both basal and FGF1 mediated phosphorylation of ERK1/2 and expression of transcription factor ID1. Another study has shown that the HSPG, type III TGF-β receptor (TGFBR3) acts as a co-receptor in FGF2 mediated neuroblastome differentiation. Similarly, SDC1 that is expressed in multiple myeloma has been shown to activate WNT signaling by two mechanisms. First, Wnts bind to the SDC1 HS side chains and activates WNT pathway in a paracrine manner via Frizzled. Second, SDC1 binds to R-spondins produced in osteoblast and stabilizes Frizzled in a LGR4-dependent manner. In other instances, soluble HSPGs sequester growth factors, reducing certain pro-proliferative signals. For example, GPC3 promotes hepatocellular carcinoma growth by activating WNT signaling. However, contrary to this, soluble GPC3 has been shown to block hepatocellular carcinoma growth by blocking WNT signaling and MAP kinase and AKT pathways. Taken together, these studies underpin that HS and HSPGs can exert diverse cancer promoting or inhibitory functions depending upon the context.

Apoptosis and cellular senescence regulation

HS and HSPGs can also play important role in the regulation of apoptosis and cellular senescence. For example, the upregulation of the RTK signaling pathway by HSPGs induces an anti-apoptotic effect through upregulating phosphatidylinositol 3-kinase (PI3K)- and Mitogen-Activated Protein Kinase (MAPK)-mediated survival pathways. Additionally, HS and chondroitin sulfate directly inhibit H2O2-induced apoptosis by blocking cytochrome c release and caspase-3 and -9 activation. Death receptor-mediated apoptosis pathway, which is mediated through the cell surface receptors for Fas ligand (FasL) and Tumor Necrosis Factor-related Apoptosis-Inducing Ligand (TRAIL) can also be regulated by HSPGs. For example, SDC1 suppresses TRAIL-mediated apoptosis in multiple myeloma cells. The same study also reported that SDC1 knockdown in lymphoma cells protected them against FasL-mediated apoptosis. In addition to the regulation of apoptosis, a recent study also revealed that heparan sulfation is essential for preventing senescence. This study revealed that the depletion of 3'-phosphoadenosine 5′-phosphosulfate synthetase 2 (PAPSS2), an enzyme that synthesizes the sulfur donor PAPS, and the small molecule inhibitor-mediated repression of HS sulfation led to premature cell senescence. Collectively, these studies further demonstrate the importance of HS and HSPGs in the regulation of cancer growth relevant cellular processes, such as apoptosis and senescence.

Cellular differentiation regulation

HS, HSPGs, and HS modifiers have also been shown to determine the cellular differentiation state. In this regard, the role of HS modifiers in regulating epithelial-to-mesenchymal transition (EMT) is noteworthy. EMT plays an important role in metastatic progression and drug resistance. Cells overexpressing the HS modifier sulfatase 2 (SULF2) present with reduced levels of the trisulfated disaccharide UA(2S)-GlcNS(6S). This reduction is followed by an increase in EMT markers and WNT signaling. Tumor cell-mediated tumor stroma modulation can also suppress differentiation and increase proliferation. The expression of several HSPGs is low in neuroblasts and high in the Schwannian stroma, and neuroblastomas with a high TβRIII, GPC1, and SDC3 expression have improved prognosis. The same study also found that soluble HSPGs and heparin promoted differentiation and decreased proliferation through FGFR1 and ERK phosphorylation. Similarly, another study has shown that neuroblastoma differentiation is promoted by release of a GPI-anchored HSPG, Glypican-6 (GPC6) through via Glycerophosphodiesterase (GDE2). This study also found that high GDE2 or low GPC6 level in neuroblastoma predicted significantly increased patient survival. These studies are of high significance as they make two major points; first, that the differentiation state of the cancer cells predict survival, and second, that HS and HSPGs are among the key regulators of cancer differentiation states.

Cell-non-autonomous roles of HS signaling in cancer

Several features of cancer such as sustained angiogenesis, tissue invasion and migration and immune evasion require a complex interplay between more than one cell type and involve multiple organ systems. In this section, we describe the cell-non-autonomous functions of HS and HSPGs in cancer initiation and progression.

Role in angiogenesis

Angiogenesis is considered a key requirement for cancer growth and progression. This is highlighted by the fact that several angiogenesis inhibitors are in clinical trials for cancer treatment. HS and HSPGs modify angiogenesis due to their effect on angiogenic factors, such as FGF, PDGF, and VEGF. For exmaple, SDC1 binds to VEGF, and SDC1 shedding increases the VEGF concentration in the matrix and promotes angiogenesis in myeloma. The same study also showed that heparanase expression increases SDC1 shedding. SDC1 is overexpressed in endothelial cells derived from patients with multiple myeloma. In addition to suppressing cell proliferation, RNAi silencing of SDC1 in patient-derived endothelial cells reduces capillary-like structure organization, which is correlated with reduced VEGF receptor (VEGFR)-2 surface expression. Other members of the syndecan family, such as SDC2 and SDC3, also affect tumor angiogenesis.

Another HSPG with an opposing effect on angiogenesis is Perlecan. Perlecan is a secreted HSPG which is also found on cancer cell surface and in cancer microenvironment. Perlecan is shown to promotes angiogenesis in its intact form. However, Perlecan can also be partially cleaved by proteases, which results in a C-terminal fragment, called endorepellin, which has been shown to exert anti-angiogenic effects. Thus, HSPGs modulate tumor angiogenesis in multiple ways: they increase the tumor microenvironment VEGF concentration, affect VEGFR surface localization, and fine-tune interaction of VEGF with its receptor and co-receptor.

Role in immune evasion

Immune response is the first line of systemic defense against tumorigenesis. Recent success of immunotherapeutic approaches to treat cancer further highlights the importance of immune evasion mechanisms for cancer initiation and progression. HSPGs can serve as cancer biomarkers, which can also be used to target antibodies for immunotherapies. At the same time, evidence suggests that HSPGs in the extracellular matrix (ECM) or those expressed on bystander cells are involved in reducing immune signaling to dendritic cells (DCs). One of the well-studied HSPGs roles in melanoma immunity involves myeloid-derived suppressor cells (MDSCs) that suppresses immunity against melanoma. Previous studies have shown that melanoma immune evasion involves myeloid-derived suppressor cells (MDSCs) that express an immune-suppressive molecule called dendritic cell-associated, HSPG-dependent integrin ligand (DC-HIL). DL-HIL engages Syndecan-4 on effector T cell causing anergy. Furthermore, targeting DC-HIL with neutralizing antibody or its genetic knockout delayed the growth of transplantable B16 melanoma in syngeneic mice, which further strengthen the role of DC-HIL as a potential target for enhancing the immune response and cause tumor eradication.

HSPGs also affect innate immune response against cancer cells by modulating Natural Killer (NK) cell-mediated activity against cancer cells. NK cells exert their cytotoxic activity on cancer cells through recognition of specific ligands, one group of which is called the natural cytotoxicity receptors (NCR). The NCRs bind to HSPGs and their interaction promotes NK cell-mediated cancer cell eradication. Additionally, it has been shown that cancer cells upregulate heparanase through activation of bromodomain PHD finger transcription factor (BPTF), leading to reduced NCR-HSPG interaction, which results in dampened NK cell response. Collectively, these studies demonstrate that by activating immune tolerance, enhancing signaling pathways, and interfering with immune cell-tumor interactions, HSPGs regulate immune evasion functions in cancer cells.

Role in the regulation of extracellular matrix modification

HSPGs, free HS chains and heparin are structural components of extracellular matrix (ECM). The ECM is a major part of the tumor microenvironment and influences tumor progression by several mechanisms, including growth factor concentrations, angiogenesis, and immune infiltration. The changes in HSPGs and HS metabolizing enzymes vary widely with cancer type and have varying context dependent roles.

Right-sided colorectal cancers show that the expression of the HSPGs glypican-1,-3, and -6 and betaglycan are altered in non-metastatic tumors, whereas in metastatic tumors, only glypican-1 and SDC1 are modified. Interestingly, alterations were found in only non-metastatic tumors, affecting N-sulfation, and the isoforms of heparan sulfate 6-O-sulfotransferase 1 (HS6ST1), heparan sulfate-glucosamine 3-sulfotransferase 3B1 (HS3ST3B1) and heparan sulfate-glucosamine 3-sulfotransferase 5 (HS3ST5). The HSPG SDC2 induces MMP-7-mediated E-cadherin shedding in colorectal cancer. E-Cadherin shedding led to reduced cell-to-cell contacts and the acquisition of a fibroblast-like morphology, which are both associated with cancer metastasis. Another important study showed that SDC1-positive human mammary fibroblasts (HMF) induced extracellular matrix remodeling by promoting an aligned fiber architecture, which promoted directional migration and invasion of breast cancer cells.

Apart from syndecans, perlecan and agrin, two other basement membrane constituents are also involved in cancer progression. Antisense RNA against perlecan inhibits tumor growth and angiogenesis in colon carcinoma. Moreover, the ECM protein agrin stimulated osteosarcoma cell growth and migration. Agrin also induces a switch from topoisomerase I to topoisomerase II. Therefore, these studies collectively reveal the role of HSPG ECM constituents and cell surface HSPGs in regulating cell-to-cell and cell-matrix adhesion, which in turn control tumor cell migration and shedding.

Targeting HS and HSPGs for cancer treatment

Understanding the biology behind HS and HSPG deregulation in cancers has enabled the development of various therapeutic strategies aimed at various HS- and HSPG-mediated cancer growth and progression enabling features. Small molecule inhibitors, which interfere with the activities of various enzymes involved in HSPG synthesis and modification, have been developed. Additionally, small molecule inhibitors and monoclonal antibodies, which target interactions between HSPGs and their targets, are being developed. Below, we describe some of these agents and their value as anti-cancer agents.

Antibody and small molecule targeting HS-modifying enzymes, HS, and HSPGs

Among the enzymes involved in HS synthesis and modifications, heparanases, and sulfatases are considered good drug targets. Heparanase is overexpressed in a wide-variety of solid tumors and hematological malignancies. A previous study assessed the therapeutic value of heparanase targeting using heparanse-neutralizing antibodies for the treatment of diffuse non-Hodgkin's B-cell lymphoma and follicular lymphoma. This study found that heparanase inhibition blocked xenograft tumors and growth of lymphoma cells in the bones of mice. Additional studies have shown that antibody-mediated anti-heparanase-therapies inhibit cell invasion and tumor metastasis. Recently, a small molecule inhibitor of hepranase was developed and was shown to reduce metastatic attributes in a model of hepatocellular carcinoma. Thus, these studies collectively establish heparanase as a potential drug target for cancer therapy.

Small molecule inhibitors, which prevent growth hormone binding to HSPG, reduce the proliferative HSPG-mediated signal. A similarity-based screening of small molecule libraries identified bi-naphthalenic compounds, which can inhibit FGF binding to both, HSPGs and FGFR1 binding. In vitro and ex vivo, these compounds inhibit FGF2 activity in angiogenesis models, with improved therapeutic potency. Monoclonal antibodies developed against the HS chain on GPC3 inhibit Wnt3a/β-catenin activation, recapitulating GPC3 knockdown by reducing HCC migration and motility.

Small molecule inhibitors against sulfatases have shown promise in inhibiting tumor growth. A disulfonyl derivative of phenyl–tert–butyl nitrone (PBN) called OKN-007 inhibited Sulf2 activity in hepatocellular carcinoma (HCC) cell lines and blocked HCC tumor xenograft growth in mice.

HS signaling modulation also affects immune cell trafficking and associated immune responses. Deletion of the glycosyltransferase gene exostosin glycosyltransferase 1 (Ext1), which is essential for HS chain formation, in myxovirus resistance-1 (Mx-1)-expressing bone marrow stromal cells increased hematopoietic stem cells (HSCs) efflux from the bone marrow to the spleen in response to granulocyte colony-stimulating factor. Thus, a therapeutic that targets Ext1 may help mobilize immune cells to target cancer cells. For detailed review on the role of different enzymes in HS synthesis and modification readers are referred to a review by Bishop et al..

Heparan sulfate mimetics

HS mimetics were also used as anti-cancer agents. HS mimetics induce an immune response against lymphoma through activation of natural killer (NK) cells. The HS mimetic PG545, in addition to its anti-heparanase and anti-angiogenic effect shows pleiotropic effect by enhancing toll-like receptor 9 (TLR9) activation through increasing the TLR9 ligand CpG in DCs. It was shown that treatment with PG545 resulted in the accumulation of CpG in the lysosomal compartment of DCs. This in turn enhanced the IL-12 production, which was essential for the ability of PG545 to activate NK cells. Furthermore, PG545 was also shown to directly bind to WNT3A and WNT7A and inhibits WNT/β-catenin signaling, inhibiting proliferation in pancreatic tumor cell lines. These studies further highlight the possibility of using heparin sulfate mimetics as agents for cancer therapy.

HSPGs as immunotherapeutic targets

Some recent studies have also indicated that the upregulation of HSPGs on cancer cells can be used as unique biomarkers that can be targeted to selectively deliver cytotoxic drugs. A recent study that analyzed differential expression of cell surface proteins on neuroblastoma identified the HSPG, Glypican-2 (GPC2) as selectively expressed on neuroblastoma where it enhances neuroblastoma proliferation. The researchers were able to develop an antibody drug conjugate that selectively eradicated GPC2 positive neuroblastoma. This is another exciting area of emerging research where HSPGs can be exploited to serve as targets for selective drug delivery to cancer cells.

Conclusion

Recent cancer therapies have largely focused on targeting driver mutations and their downstream effectors. However, the emerging body of evidence now shows that driver-mutations are, in fact, enhanced and modified by a host of other modifications as cancer evolves. HS and HSPG deregulation are major contributing factors to cancer evolution. This review has covered some of the well-established and emerging roles of HS and HSPGs in cancer. However, new, non-canonical functions of HSPGs are still being discovered. For instance, in addition to modulating growth factors and RTK interactions, HSPGs also transport growth factors directly to the nucleus, where these factors modify gene regulation. HSPGs have also been shown to influence cancer exosome shedding and uptake, thereby modulating cell-to-cell communication between cancer and healthy fibroblasts, immune cells, and endothelial cells. HSPGs can also influence actin cytoskeleton remodeling and cancer cell motility. The HSPG, SDC2 binds Ezrin, a cytoskeletal protein and serves as adapter molecules for IGF1 mediated activation of ERK. Additionally, HSPGs are implicated in lipoprotein uptake and cellular stress signaling. As more researchers validate these findings, newer areas of HS- and HSPG-mediated regulation will be discovered. Additionally, as cancer treatment moves from single target to combination therapies, HS- and HSPG-targeting therapies will likely emerge as a major new direction for cancer therapeutics.

Author contributions

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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    Dietrich A Tanczos E Vanscheidt W Schopf E Simon JC. High CD44 surface expression on primary tumours of malignant melanoma correlates with increased metastatic risk and reduced survival. Eur J Cancer (1997 ) 33:926–30.

    Not in our library10.1016/s0959-8049(96)00512-6

  44. 44.

    Munchar MJ Sharifah NA Jamal R Looi LM. CD44s expression correlated with the International Neuroblastoma Pathology Classification (Shimada system) for neuroblastic tumours. Pathology (2003 ) 35:125–9.

    Not in our library10.1097/01268031-200335020-00005

  45. 45.

    Iozzo RV Zoeller JJ Nystrom A. Basement membrane proteoglycans: modulators par excellence of cancer growth and angiogenesis. Mol Cells (2009 ) 27:503–13.

    Not in our library10.1007/s10059-009-0069-0

  46. 46.

    O'Reilly MS Boehm T Shing Y Fukai N Vasios G Lane WS. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell (1997 ) 88:277–85.

    Not in our library10.1016/s0092-8674(00)81848-6

  47. 47.

    Huang G Ge G Izzi V Greenspan DS. alpha3 Chains of type V collagen regulate breast tumour growth via glypican-1. Nat Commun. (2017 ) 8:14351.

    Not in our library10.1038/ncomms14351

  48. 48.

    Tanaka M Ishikawa S Ushiku T Morikawa T Isagawa T Yamagishi M. EVI1 modulates oncogenic role of GPC1 in pancreatic carcinogenesis. Oncotarget (2017 ) 8:99552–66.

    Not in our library10.18632/oncotarget.20601

  49. 49.

    Su G Meyer K Nandini CD Qiao D Salamat S Friedl A. Glypican-1 is frequently overexpressed in human gliomas and enhances FGF-2 signaling in glioma cells. Am J Pathol. (2006 ) 168:2014–26.

    Not in our library10.2353/ajpath.2006.050800

  50. 50.

    Feng M Gao W Wang R Chen W Man YG Figg WD. Therapeutically targeting glypican-3 via a conformation-specific single-domain antibody in hepatocellular carcinoma. Proc Natl Acad Sci USA. (2013 ) 110:E1083–91.

    Not in our library10.1073/pnas.1217868110

  51. 51.

    Yamanaka K Ito Y Okuyama N Noda K Matsumoto H Yoshida H. Immunohistochemical study of glypican 3 in thyroid cancer. Oncology (2007 ) 73:389–94.

    Not in our library10.1159/000136159

  52. 52.

    Boily G Ouellet S Langlois S Lariviere M Drouin R Sinnett D. In vivo footprinting analysis of the Glypican 3 (GPC3) promoter region in neuroblastoma cells. Biochim Biophys Acta (2007 ) 1769:182–93.

    Not in our library10.1016/j.bbaexp.2007.01.014

  53. 53.

    Toretsky JA Zitomersky NL Eskenazi AE Voigt RW Strauch ED Sun CC. Glypican-3 expression in Wilms tumor and hepatoblastoma. J Pediatr Hematol Oncol. (2001 ) 23:496–9.

    Not in our library10.1097/00043426-200111000-00006

  54. 54.

    Esheba GE Pate LL Longacre TA. Oncofetal protein glypican-3 distinguishes yolk sac tumor from clear cell carcinoma of the ovary. Am J Surg Pathol. (2008 ) 32:600–7.

    Not in our library10.1097/pas.0b013e31815a565a

  55. 55.

    Lin Q Xiong LW Pan XF Gen JF Bao GL Sha HF. Expression of GPC3 protein and its significance in lung squamous cell carcinoma. Med Oncol. (2012 ) 29:663–9.

    Not in our library10.1007/s12032-011-9973-1

  56. 56.

    Midorikawa Y Ishikawa S Iwanari H Imamura T Sakamoto H Miyazono K. Glypican-3, overexpressed in hepatocellular carcinoma, modulates FGF2 and BMP-7 signaling. Int J Cancer (2003 ) 103:455–65.

    Not in our library10.1002/ijc.10856

  57. 57.

    Li Y Miao L Cai H Ding J Xiao Y Yang J. The overexpression of glypican-5 promotes cancer cell migration and is associated with shorter overall survival in non-small cell lung cancer. Oncol Lett. (2013 ) 6:1565–72.

    Not in our library10.3892/ol.2013.1622

  58. 58.

    Li Y Sheu CC Ye Y de Andrade M Wang L Chang SC. Genetic variants and risk of lung cancer in never smokers: a genome-wide association study. Lancet Oncol. (2010 ) 11:321–30.

    Not in our library10.1016/s1470-2045(10)70042-5

  59. 59.

    Datta S Pierce M Datta MW. Perlecan signaling: helping hedgehog stimulate prostate cancer growth. Int J Biochem Cell Biol. (2006 ) 38:1855–61.

    Not in our library10.1016/j.biocel.2006.03.022

  60. 60.

    Kadenhe-Chiweshe A Papa J McCrudden KW Frischer J Bae JO Huang J. Sustained VEGF blockade results in microenvironmental sequestration of VEGF by tumors and persistent VEGF receptor-2 activation. Mol Cancer Res. (2008 ) 6:1–9.

    Not in our library10.1158/1541-7786.mcr-07-0101

  61. 61.

    Gronborg M Kristiansen TZ Iwahori A Chang R Reddy R Sato N. Biomarker discovery from pancreatic cancer secretome using a differential proteomic approach. Mol Cell Proteomics (2006 ) 5:157–71.

    Not in our library10.1074/mcp.m500178-mcp200

  62. 62.

    Cohen IR Murdoch AD Naso MF Marchetti D Berd D Iozzo RV. Abnormal expression of perlecan proteoglycan in metastatic melanomas. Cancer Res. (1994 ) 54:5771–4.

    Not in our library

  63. 63.

    Malek-Hosseini Z Jelodar S Talei A Ghaderi A Doroudchi M. Elevated Syndecan-1 levels in the sera of patients with breast cancer correlate with tumor size. Breast Cancer (2017 ) 24:742–7.

    Not in our library10.1007/s12282-017-0773-0

  64. 64.

    Conejo JR Kleeff J Koliopanos A Matsuda K Zhu ZW Goecke H Syndecan-1 expression is up-regulated in pancreatic but not in other gastrointestinal cancers. Int J Cancer (2000 ) 88:12–20.

    Not in our library10.1002/1097-0215(20001001)88:1<12::aid-ijc3>3.0.co;2-t

  65. 65.

    Davies EJ Blackhall FH Shanks JH David G McGown AT Swindell R. Distribution and clinical significance of heparan sulfate proteoglycans in ovarian cancer. Clin Cancer Res. (2004 ) 10:5178–86.

    Not in our library10.1158/1078-0432.ccr-03-0103

  66. 66.

    Khotskaya YB Dai Y Ritchie JP MacLeod V Yang Y Zinn K. Syndecan-1 is required for robust growth, vascularization, and metastasis of myeloma tumors in vivo. J Biol Chem. (2009 ) 284:26085–95.

    Not in our library10.1074/jbc.m109.018473

  67. 67.

    Sun M Gomes S Chen P Frankenberger CA Sankarasharma D Chung CH. RKIP and HMGA2 regulate breast tumor survival and metastasis through lysyl oxidase and syndecan-2. Oncogene (2014 ) 33:3528–37.

    Not in our library10.1038/onc.2013.328

  68. 68.

    Popovic A Demirovic A Spajic B Stimac G Kruslin B Tomas D. Expression and prognostic role of syndecan-2 in prostate cancer. Prostate Cancer Prostatic Dis. (2010 ) 13:78–82.

    Not in our library10.1038/pcan.2009.43

  69. 69.

    Park H Kim Y Lim Y Han I Oh ES. Syndecan-2 mediates adhesion and proliferation of colon carcinoma cells. J Biol Chem. (2002 ) 277:29730–6.

    Not in our library10.1074/jbc.m202435200

  70. 70.

    Marzioni D Lorenzi T Mazzucchelli R Capparuccia L Morroni M Fiorini R. Expression of basic fibroblast growth factor, its receptors and syndecans in bladder cancer. Int J Immunopathol Pharmacol. (2009 ) 22:627–38.

    Not in our library10.1177/039463200902200308

  71. 71.

    Fears CY Gladson CL Woods A. Syndecan-2 is expressed in the microvasculature of gliomas and regulates angiogenic processes in microvascular endothelial cells. J Biol Chem. (2006 ) 281:14533–6.

    Not in our library10.1074/jbc.c600075200

  72. 72.

    Park H Han I Kwon HJ Oh ES. Focal adhesion kinase regulates syndecan-2-mediated tumorigenic activity of HT1080 fibrosarcoma cells. Cancer Res. (2005 ) 65:9899–905.

    Not in our library10.1158/0008-5472.can-05-1386

  73. 73.

    Yao J Li WY Li SG Feng XS Gao SG. Midkine promotes perineural invasion in human pancreatic cancer. World J Gastroenterol. (2014 ) 20:3018–24.

    Not in our library10.3748/wjg.v20.i11.3018

  74. 74.

    Gatza CE Holtzhausen A Kirkbride KC Morton A Gatza ML Datto MB. Type III TGF-beta receptor enhances colon cancer cell migration and anchorage-independent growth. Neoplasia (2011 ) 13:758–70.

    Not in our library10.1593/neo.11528

  75. 75.

    Bernabeu C Lopez-Novoa JM Quintanilla M. The emerging role of TGF-beta superfamily coreceptors in cancer. Biochim Biophys Acta (2009 ) 1792:954–73.

    Not in our library10.1016/j.bbadis.2009.07.003

  76. 76.

    Dong M How T Kirkbride KC Gordon KJ Lee JD Hempel N. The type III TGF-beta receptor suppresses breast cancer progression. J Clin Invest. (2007 ) 117:206–17.

    Not in our library10.1172/jci29293

  77. 77.

    Turley RS Finger EC Hempel N How T Fields TA Blobe GC. The type III transforming growth factor-beta receptor as a novel tumor suppressor gene in prostate cancer. Cancer Res. (2007 ) 67:1090–8.

    Not in our library10.1158/0008-5472.can-06-3117

  78. 78.

    Hempel N How T Dong M Murphy SK Fields TA Blobe GC. Loss of betaglycan expression in ovarian cancer: role in motility and invasion. Cancer Res. (2007 ) 67:5231–8.

    Not in our library10.1158/0008-5472.can-07-0035

  79. 79.

    Lambert KE Huang H Mythreye K Blobe GC. The type III transforming growth factor-beta receptor inhibits proliferation, migration, and adhesion in human myeloma cells. Mol Biol Cell. (2011 ) 22:1463–72.

    Not in our library10.1091/mbc.e10-11-0877

  80. 80.

    Finger EC Turley RS Dong M How T Fields TA Blobe GC. TbetaRIII suppresses non-small cell lung cancer invasiveness and tumorigenicity. Carcinogenesis (2008 ) 29:528–35.

    Not in our library10.1093/carcin/bgm289

  81. 81.

    Gordon KJ Dong M Chislock EM Fields TA Blobe GC. Loss of type III transforming growth factor beta receptor expression increases motility and invasiveness associated with epithelial to mesenchymal transition during pancreatic cancer progression. Carcinogenesis (2008 ) 29:252–62.

    Not in our library10.1093/carcin/bgm249

  82. 82.

    Copland JA Luxon BA Ajani L Maity T Campagnaro E Guo H. Genomic profiling identifies alterations in TGFbeta signaling through loss of TGFbeta receptor expression in human renal cell carcinogenesis and progression. Oncogene (2003 ) 22:8053–62.

    Not in our library10.1038/sj.onc.1206835

  83. 83.

    Hanks BA Holtzhausen A Evans KS Jamieson R Gimpel P Campbell OM. Type III TGF-beta receptor downregulation generates an immunotolerant tumor microenvironment. J Clin Invest. (2013 ) 123:3925–40.

    Not in our library10.1172/jci65745

  84. 84.

    Raman K Kuberan B. Chemical tumor biology of heparan sulfate proteoglycans. Curr Chem Biol. (2010 ) 4:20–31.

    Not in our library10.2174/187231310790226206

  85. 85.

    Higashiyama S Abraham JA Klagsbrun M. Heparin-binding EGF-like growth factor stimulation of smooth muscle cell migration: dependence on interactions with cell surface heparan sulfate. J Cell Biol. (1993 ) 122:933–40.

    Not in our library10.1083/jcb.122.4.933

  86. 86.

    Matsuda K Maruyama H Guo F Kleeff J Itakura J Matsumoto Y. Glypican-1 is overexpressed in human breast cancer and modulates the mitogenic effects of multiple heparin-binding growth factors in breast cancer cells. Cancer Res. (2001 ) 61:5562–9.

    Not in our library

  87. 87.

    Lindblom P Gerhardt H Liebner S Abramsson A Enge M Hellstrom M. Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev. (2003 ) 17:1835–40.

    Not in our library10.1101/gad.266803

  88. 88.

    Paine-Saunders S Viviano BL Economides AN Saunders S. Heparan sulfate proteoglycans retain Noggin at the cell surface: a potential mechanism for shaping bone morphogenetic protein gradients. J Biol Chem. (2002 ) 277:2089–96.

    Not in our library10.1074/jbc.m109151200

  89. 89.

    Whitelock JM Iozzo RV. Heparan sulfate: a complex polymer charged with biological activity. Chem Rev. (2005 ) 105:2745–64.

    Not in our library10.1021/cr010213m

  90. 90.

    Turner N Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer. (2010 ) 10:116–29.

    Not in our library10.1038/nrc2780

  91. 91.

    Spivak-Kroizman T Lemmon MA Dikic I Ladbury JE Pinchasi D Huang J. Heparin-induced oligomerization of FGF molecules is responsible for FGF receptor dimerization, activation, and cell proliferation. Cell (1994 ) 79:1015–24.

    Not in our library10.1016/0092-8674(94)90032-9

  92. 92.

    Iozzo RV Sanderson RD. Proteoglycans in cancer biology, tumour microenvironment and angiogenesis. J Cell Mol Med. (2011 ) 15:1013–31.

    Not in our library10.1111/j.1582-4934.2010.01236.x

  93. 93.

    Aikawa T Whipple CA Lopez ME Gunn J Young A Lander AD. Glypican-1 modulates the angiogenic and metastatic potential of human and mouse cancer cells. J Clin Invest. (2008 ) 118:89–99.

    Not in our library10.1172/jci32412

  94. 94.

    Carey DJ Crumbling DM Stahl RC Evans DM. Association of cell surface heparan sulfate proteoglycans of Schwann cells with extracellular matrix proteins. J Biol Chem. (1990 ) 265:20627–33.

    Not in our library

  95. 95.

    Mytilinaiou M Nikitovic D Berdiaki A Kostouras A Papoutsidakis A Tsatsakis AM. Emerging roles of syndecan 2 in epithelial and mesenchymal cancer progression. IUBMB Life. (2017 ) 69:824–33.

    Not in our library10.1002/iub.1678

  96. 96.

    Afratis NA Nikitovic D Multhaupt HA Theocharis AD Couchman JR Karamanos NK. Syndecans - key regulators of cell signaling and biological functions. FEBS J. (2017 ) 284:27–41.

    Not in our library10.1111/febs.13940

  97. 97.

    Maeda T Desouky J Friedl A. Syndecan-1 expression by stromal fibroblasts promotes breast carcinoma growth in vivo and stimulates tumor angiogenesis. Oncogene (2006 ) 25:1408–12.

    Not in our library10.1038/sj.onc.1209168

  98. 98.

    Knelson EH Gaviglio AL Tewari AK Armstrong MB Mythreye K Blobe GC. Type III TGF-beta receptor promotes FGF2-mediated neuronal differentiation in neuroblastoma. J Clin Invest. (2013 ) 123:4786–98.

    Not in our library10.1172/jci69657

  99. 99.

    Ren Z van Andel H de Lau W Hartholt RB Maurice MM Clevers H. Syndecan-1 promotes Wnt/beta-catenin signaling in multiple myeloma by presenting Wnts and R-spondins. Blood (2017 ) 131:982–94.

    Not in our library10.1182/blood-2017-07-797050

  100. 100.

    Gao W Ho M. The role of glypican-3 in regulating Wnt in hepatocellular carcinomas. Cancer Rep. (2011 ) 1:14–9.

    Not in our library

  101. 101.

    Zittermann SI Capurro MI Shi W Filmus J. Soluble glypican 3 inhibits the growth of hepatocellular carcinoma in vitro and in vivo. Int J Cancer (2010 ) 126:1291–301.

    Not in our library10.1002/ijc.24941

  102. 102.

    Lemmon MA Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell (2010 ) 141:1117–34.

    Not in our library10.1016/j.cell.2010.06.011

  103. 103.

    Yue XL Lehri S Li P Barbier-Chassefiere V Petit E Huang QF. Insights on a new path of pre-mitochondrial apoptosis regulation by a glycosaminoglycan mimetic. Cell Death Diff. (2009 ) 16:770–81.

    Not in our library10.1038/cdd.2009.9

  104. 104.

    Wu YH Yang CY Chien WL Lin KI Lai MZ. Removal of syndecan-1 promotes TRAIL-induced apoptosis in myeloma cells. J Immunol. (2012 ) 188:2914–21.

    Not in our library10.4049/jimmunol.1102065

  105. 105.

    Jung SH Lee HC Yu DM Kim BC Park SM Lee YS. Heparan sulfation is essential for the prevention of cellular senescence. Cell Death Differ. (2016 ) 23:417–29.

    Not in our library10.1038/cdd.2015.107

  106. 106.

    Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer (2002 ) 2:442–54.

    Not in our library10.1038/nrc822

  107. 107.

    Vicente CM Lima MA Nader HB Toma L. SULF2 overexpression positively regulates tumorigenicity of human prostate cancer cells. J Exp Clin Cancer Res. (2015 ) 34:25.

    Not in our library10.1186/s13046-015-0141-x

  108. 108.

    Matas-Rico E van Veen M Leyton-Puig D van den Berg J Koster J Kedziora KM Glycerophosphodiesterase GDE2 promotes neuroblastoma differentiation through glypican release and is a marker of clinical outcome. Cancer Cell (2016 ) 30:548–62.

    Not in our library10.1016/j.ccell.2016.08.016

  109. 109.

    De Palma M Biziato D Petrova TV. Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer (2017 ) 17:457–74.

    Not in our library10.1038/nrc.2017.51

  110. 110.

    Jayson GC Hicklin DJ Ellis LM. Antiangiogenic therapy–evolving view based on clinical trial results. Nat Rev Clin Oncol. (2012 ) 9:297–303.

    Not in our library10.1038/nrclinonc.2012.8

  111. 111.

    Lamorte S Ferrero S Aschero S Monitillo L Bussolati B Omede P. Syndecan-1 promotes the angiogenic phenotype of multiple myeloma endothelial cells. Leukemia (2012 ) 26:1081–90.

    Not in our library10.1038/leu.2011.290

  112. 112.

    Purushothaman A Uyama T Kobayashi F Yamada S Sugahara K Rapraeger AC. Heparanase-enhanced shedding of syndecan-1 by myeloma cells promotes endothelial invasion and angiogenesis. Blood (2010 ) 115:2449–57.

    Not in our library10.1182/blood-2009-07-234757

  113. 113.

    Noguer O Villena J Lorita J Vilaro S Reina M. Syndecan-2 downregulation impairs angiogenesis in human microvascular endothelial cells. Exp Cell Res. (2009 ) 315:795–808.

    Not in our library10.1016/j.yexcr.2008.11.016

  114. 114.

    De Rossi G Whiteford JR. A novel role for syndecan-3 in angiogenesis. F1000Res (2013 ) 2:270.

    Not in our library10.12688/f1000research.2-270.v1

  115. 115.

    Douglass S Goyal A Iozzo RV. The role of perlecan and endorepellin in the control of tumor angiogenesis and endothelial cell autophagy. Connect Tissue Res. (2015 ) 56:381–91.

    Not in our library10.3109/03008207.2015.1045297

  116. 116.

    Goyal A Pal N Concannon M Paul M Doran M Poluzzi C. Endorepellin, the angiostatic module of perlecan, interacts with both the alpha2beta1 integrin and vascular endothelial growth factor receptor 2 (VEGFR2): a dual receptor antagonism. J Biol Chem. (2011 ) 286:25947–62.

    Not in our library10.1074/jbc.m111.243626

  117. 117.

    Disis ML. Immune regulation of cancer. J Clin Oncol. (2010 ) 28:4531–8.

    Not in our library10.1200/jco.2009.27.2146

  118. 118.

    Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer (2012 ) 12:252–64.

    Not in our library10.1038/nrc3239

  119. 119.

    Vanneman M Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer (2012 ) 12:237–51.

    Not in our library10.1038/nrc3237

  120. 120.

    Feng M Ho M. Glypican-3 antibodies: a new therapeutic target for liver cancer. FEBS Lett. (2014 ) 588:377–82.

    Not in our library10.1016/j.febslet.2013.10.002

  121. 121.

    Haruyama Y Kataoka H. Glypican-3 is a prognostic factor and an immunotherapeutic target in hepatocellular carcinoma. World J Gastroenterol. (2016 ) 22:275–83.

    Not in our library10.3748/wjg.v22.i1.275

  122. 122.

    Wang J Chen L. Myeloid cells' evasion of melanoma immunity. J Invest Dermatol. (2014 ) 134:2675–7.

    Not in our library10.1038/jid.2014.251

  123. 123.

    Chung JS Tamura K Cruz PD Jr Ariizumi K. DC-HIL-expressing myelomonocytic cells are critical promoters of melanoma growth. J Invest Dermatol. (2014 ) 134:2784–94.

    Not in our library10.1038/jid.2014.254

  124. 124.

    Kruse PH Matta J Ugolini S Vivier E. Natural cytotoxicity receptors and their ligands. Immunol Cell Biol. (2014 ) 92:221–9.

    Not in our library10.1038/icb.2013.98

  125. 125.

    Hecht ML Rosental B Horlacher T Hershkovitz O De Paz JL Noti C. Natural cytotoxicity receptors NKp30, NKp44 and NKp46 bind to different heparan sulfate/heparin sequences. J Proteome Res. (2009 ) 8:712–20.

    Not in our library10.1021/pr800747c

  126. 126.

    Mayes K Elsayed Z Alhazmi A Waters M Alkhatib SG Roberts M. BPTF inhibits NK cell activity and the abundance of natural cytotoxicity receptor co-ligands. Oncotarget (2017 ) 8:64344–57.

    Not in our library10.18632/oncotarget.17834

  127. 127.

    Kreuger J Kjellen L. Heparan sulfate biosynthesis: regulation and variability. J Histochem Cytochem. (2012 ) 60:898–907.

    Not in our library10.1369/0022155412464972

  128. 128.

    Fernandez-Vega I Garcia-Suarez O Garcia B Crespo A Astudillo A Quiros LM. Heparan sulfate proteoglycans undergo differential expression alterations in right sided colorectal cancer, depending on their metastatic character. BMC Cancer (2015 ) 15:742.

    Not in our library10.1186/s12885-015-1724-9

  129. 129.

    Jang B Jung H Chung H Moon BI Oh ES. Syndecan-2 enhances E-cadherin shedding and fibroblast-like morphological changes by inducing MMP-7 expression in colon cancer cells. Biochem Biophys Res Commun. (2016 ) 477:47–53.

    Not in our library10.1016/j.bbrc.2016.06.019

  130. 130.

    Yang N Friedl A. Syndecan-1-induced ECM fiber alignment requires integrin αvβ3 and syndecan-1 ectodomain and heparan sulfate chains. PLoS ONE (2016 ) 11:e0150132.

    Not in our library10.1371/journal.pone.0150132

  131. 131.

    Chakraborty S Njah K Pobbati AV Lim YB Raju A Lakshmanan M. Agrin as a mechanotransduction signal regulating YAP through the Hippo Pathway. Cell Rep. (2017 ) 18:2464–79.

    Not in our library10.1016/j.celrep.2017.02.041

  132. 132.

    Kalluri R. Basement membranes: structure, assembly and role in tumour angiogenesis. Nat Rev Cancer (2003 ) 3:422–33.

    Not in our library10.1038/nrc1094

  133. 133.

    Kawahara R Granato DC Carnielli CM Cervigne NK Oliveria CE Rivera C. Agrin and perlecan mediate tumorigenic processes in oral squamous cell carcinoma. PLoS ONE (2014 ) 9:e115004.

    Not in our library10.1371/journal.pone.0115004

  134. 134.

    Sharma B Handler M Eichstetter I Whitelock JM Nugent MA Iozzo RV. Antisense targeting of perlecan blocks tumor growth and angiogenesis in vivo. J Clin Invest. (1998 ) 102:1599–608.

    Not in our library10.1172/jci3793

  135. 135.

    Harisi R Dudas J Timar F Pogany G Timar J Kovalszky I. Invasive growth and topoisomerase-switch induced by tumorous extracellular matrix in osteosarcoma cell culture. Cell Biol Int. (2005 ) 29:959–67.

    Not in our library10.1016/j.cellbi.2005.08.010

  136. 136.

    Zheng X Gai X Han S Moser CD Hu C Shire AM. The human sulfatase 2 inhibitor 2,4-disulfonylphenyl-tert-butylnitrone (OKN-007) has an antitumor effect in hepatocellular carcinoma mediated via suppression of TGFB1/SMAD2 and Hedgehog/GLI1 signaling. Genes Chromosomes Cancer. (2013 ) 52:225–36.

    Not in our library10.1002/gcc.22022

  137. 137.

    Gao W Kim H Ho M. Human monoclonal antibody targeting the heparan sulfate chains of glypican-3 inhibits HGF-mediated migration and motility of hepatocellular carcinoma cells. PLoS ONE (2015 ) 10:e0137664.

    Not in our library10.1371/journal.pone.0137664

  138. 138.

    Weissmann M Arvatz G Horowitz N Feld S Naroditsky I Zhang Y. Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis. Proc Natl Acad Sci USA. (2016 ) 113:704–9.

    Not in our library10.1073/pnas.1519453113

  139. 139.

    Zhang YF Tang XD Gao JH Fang DC Yang SM. Heparanase: a universal immunotherapeutic target in human cancers. Drug Discov Today (2011 ) 16:412–7.

    Not in our library10.1016/j.drudis.2011.02.015

  140. 140.

    Chen T Tang XD Wan Y Chen L Yu ST Xiong Z. HLA-A2-restricted cytotoxic T lymphocyte epitopes from human heparanase as novel targets for broad-spectrum tumor immunotherapy. Neoplasia (2008 ) 10:977–86.

    Not in our library10.1593/neo.08576

  141. 141.

    Baburajeev CP Mohan CD Rangappa S Mason DJ Fuchs JE Bender A. Identification of novel class of triazolo-thiadiazoles as potent inhibitors of human heparanase and their anticancer activity. BMC Cancer (2017 ) 17:235.

    Not in our library10.1186/s12885-017-3214-8

  142. 142.

    Foglieni C Pagano K Lessi M Bugatti A Moroni E Pinessi D. Integrating computational and chemical biology tools in the discovery of antiangiogenic small molecule ligands of FGF2 derived from endogenous inhibitors. Sci Rep. (2016 ) 6:23432.

    Not in our library10.1038/srep23432

  143. 143.

    Saez B Ferraro F Yusuf RZ Cook CM Yu VW Pardo-Saganta A. Inhibiting stromal cell heparan sulfate synthesis improves stem cell mobilization and enables engraftment without cytotoxic conditioning. Blood (2014 ) 124:2937–47.

    Not in our library10.1182/blood-2014-08-593426

  144. 144.

    Brennan TV Lin L Brandstadter JD Rendell VR Dredge K Huang X. Heparan sulfate mimetic PG545-mediated antilymphoma effects require TLR9-dependent NK cell activation. J Clin Invest. (2016 ) 126:207–19.

    Not in our library10.1172/jci76566

  145. 145.

    Jung DB Yun M Kim EO Kim J Kim B Jung JH. The heparan sulfate mimetic PG545 interferes with Wnt/beta-catenin signaling and significantly suppresses pancreatic tumorigenesis alone and in combination with gemcitabine. Oncotarget (2015 ) 6:4992–5004.

    Not in our library10.18632/oncotarget.3214

  146. 146.

    Gao W Tang Z Zhang YF Feng M Qian M Dimitrov DS. Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis. Nat Commun. (2015 ) 6:6536.

    Not in our library10.1038/ncomms7536

  147. 147.

    Li N Fu H Hewitt SM Dimitrov DS Ho M. Therapeutically targeting glypican−2 via single-domain antibody-based chimeric antigen receptors and immunotoxins in neuroblastoma. Proc Natl Acad Sci USA. (2017 ) 114:E6623–E31.

    Not in our library10.1073/pnas.1706055114

  148. 148.

    Bosse KR Raman P Zhu Z Lane M Martinez D Heitzeneder S. Identification of GPC2 as an oncoprotein and candidate immunotherapeutic target in high-risk neuroblastoma. Cancer Cell (2017 ) 32:295–309.e12.

    Not in our library10.1016/j.ccell.2017.08.003

  149. 149.

    Christianson HC Belting M. Heparan sulfate proteoglycan as a cell-surface endocytosis receptor. Matrix Biol. (2014 ) 35:51–5.

    Not in our library10.1016/j.matbio.2013.10.004

  150. 150.

    Fares J Kashyap R Zimmermann P. Syntenin: key player in cancer exosome biogenesis and uptake? Cell Adh Migr. (2017 ) 11:124–6.

    Not in our library10.1080/19336918.2016.1225632

  151. 151.

    Friand V David G Zimmermann P. Syntenin and syndecan in the biogenesis of exosomes. Biol Cell (2015 ) 107:331–41.

    Not in our library10.1111/boc.201500010

  152. 152.

    Granes F Berndt C Roy C Mangeat P Reina M Vilaro S. Identification of a novel Ezrin-binding site in syndecan-2 cytoplasmic domain. FEBS Lett. (2003 ) 547:212–6.

    Not in our library10.1016/s0014-5793(03)00712-9

  153. 153.

    Kasza I Suh Y Wollny D Clark RJ Roopra A Colman RJ. Syndecan-1 is required to maintain intradermal fat and prevent cold stress. PLoS Genet. (2014 ) 10:e1004514.

    Not in our library10.1371/journal.pgen.1004514

  154. 154.

    Menard JA Christianson HC Kucharzewska P Bourseau-Guilmain E Svensson KJ Lindqvist E. Metastasis stimulation by hypoxia and acidosis-induced extracellular lipid uptake is mediated by proteoglycan-dependent endocytosis. Cancer Res. (2016 ) 76:4828–40.

    Not in our library10.1158/0008-5472.can-15-2831

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