Cancer Metastasis: The Role of the Extracellular Matrix and the Heparan Sulfate Proteoglycan Perlecan

Elgundi, Zehra; Papanicolaou, Michael; Major, Gretel; Cox, Thomas R.; Melrose, James; Whitelock, John M.; Farrugia, Brooke L.

doi:10.3389/fonc.2019.01482

Cited by 122 publications

(101 citation statements)

References 265 publications

(244 reference statements)

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“…The authors could interfere with intoxication of cells by addition of surfen (14). HSPGs are extracellular matrix components (27), they are found in secreted vesicles of mast cells (serglycin, (28)), described as sequestering co-receptors for growth factors and cytokines (fibroblast growth factor (FGF), (29,30)) or binding partners for molecules undergoing transcellular transport (31). In principle, HSPG binding could be sufficient for endocytosis of the toxin.…”

Section: Discussionmentioning

confidence: 99%

Glycosaminoglycans are specific endosomal receptors forYersinia pseudotuberculosisCytotoxic Necrotizing Factor

Schmidt

Kowarschik

Schöllkopf

et al. 2020

Preprint

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The Cytotoxic Necrotizing Factor Y (CNFY) is produced by the gram-negative, enteric pathogen Yersinia pseudotuberculosis. The bacterial toxin belongs to a family of deamidases, which constitutively activate Rho GTPases, thereby balancing inflammatory processes. We identified heparan sulfate proteoglycans as essential host cell factors for intoxication with CNFY. Using flow cytometry, microscopy, knockout cell lines, pulsed electron-electron double resonance and bio-layer interferometry, we studied the role of glucosaminoglycans in the intoxication process of CNFY. To analyze toxin-glucosaminoglycan interaction we utilized a truncated CNFY (CNFY 709-1014 ).Especially this C-terminal part of CNFY, which encompasses the catalytic activity, binds with high affinity to heparan sulfates. CNFY binding with the N-terminal domain to its protein receptor seems to induce a first conformational change supporting the interaction between the C-terminal domain and heparan sulfates, which seems sterically hindered in the full toxin. A second conformational change occurs by acidification of the endosome, probably allowing insertion of the hydrophobic regions of the toxin into the endosomal membrane. Our findings suggest that heparan sulfates play a major role for intoxication within the endosome, rather than being relevant for an interaction at the cell surface. Lastly, cleavage of heparin sulfate chains by heparanase is likely required for efficient uptake of the toxic enzyme into the cytosol of mammalian cells. Author SummaryThe RhoA deamidating Cytotoxic Necrotizing Factor Y (CNFY) from Yersinia pseudotuberculosis is a crucial virulence factor that is important for successful infection 3 of mammalian cells by the pathogen. The mode of action by which CNFY is able to intoxicate cells can be divided into the following steps: Binding to the cell surface, internalization, translocation from the endosome to the cytosol and deamidation of RhoA. We show, that CNFY uses heparan sulfates to maximize the amount of molecules entering the cytosol. While not being necessary for toxin binding and uptake, the sugars hold a key role in the intoxication process. We show that CNFY undergoes a conformational change at a low endosomal pH, allowing the C-terminal domain to be released from the endosomal membrane by the action of heparanase. This study reveals new insights into the CNFY-host interaction and promotes understanding of the complex intoxication process of bacterial toxins.

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Section: Discussionmentioning

confidence: 99%

Glycosaminoglycans are specific endosomal receptors forYersinia pseudotuberculosisCytotoxic Necrotizing Factor

Schmidt

Kowarschik

Schöllkopf

et al. 2020

Preprint

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“…[7,8,[10][11][12][13][14][15]17,18]. In addition to a well-established role in development [20,23,26,104,[165][166][167], HSPG-ligand interactions play major roles in tumor stroma and tumor microenvironment by regulating cellular proliferation, differentiation, adhesion, migration, apoptosis, angiogenesis, inflammation, invasion, and metastasis [3,22,24,25,28,[33][34][35][36][37][38][39][40]107,143,165,168] (Figure 1). modulation of ligand distribution and function, the restriction of ligand range of action on target cells, the prevention of ligand degradation, the generation of morphogen gradients, the proper presentation of growth factors to their cognate receptors, the transactivation of receptors in adjacent cells, the promotion of endocytosis and vesicular trafficking, etc.…”

Section: Functional Properties Of Hspgs In Tumor Microenvironmentmentioning

confidence: 99%

“…However, a significant reduction of cell surface tethered SDC1 and an increase of shed SDC1 in the ECM has been observed as a function of tumor progression and aggressiveness, suggesting the involvement of post-transcriptional mechanisms in SDC1 expression in this type of tumor. Differential regulation of SDC1 expression as well as of the other SDC isoforms, GPCs, and the other HSPGs has been found in several tumors ( Table 3 ) [ 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 ].…”

Section: Structural Features Biosynthesis and Enzymatic Modificamentioning

confidence: 99%

“…Increased expression levels of perlecan have been found in hepatocellular carcinoma, melanoma, pancreatic and prostate cancer, whereas the upregulation of the expression of agrin has been demonstrated in oral squamous cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, lung carcinoma, oral squamous cell carcinoma, and rectal cancer [ 35 , 38 , 144 , 145 , 146 , 148 , 149 , 150 , 151 , 152 ]. Reduced levels of perlecan correlate with the progression of breast cancer, colorectal cancer, lung cancer, ovarian cancer, and fibrosarcoma [ 35 , 38 , 105 , 143 , 144 , 147 ]. Finally, type VIII collagen results in being elevated in melanoma, lung, breast, ovary, prostate, and pancreatic cancers [ 35 , 38 , 153 ].…”

Section: Structural Features Biosynthesis and Enzymatic Modificamentioning

confidence: 99%

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Heparan Sulfate Proteoglycan Signaling in Tumor Microenvironment

Pasquale

Pavone

2020

IJMS

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In the last few decades, heparan sulfate (HS) proteoglycans (HSPGs) have been an intriguing subject of study for their complex structural characteristics, their finely regulated biosynthetic machinery, and the wide range of functions they perform in living organisms from development to adulthood. From these studies, key roles of HSPGs in tumor initiation and progression have emerged, so that they are currently being explored as potential biomarkers and therapeutic targets for cancers. The multifaceted nature of HSPG structure/activity translates in their capacity to act either as inhibitors or promoters of tumor growth and invasion depending on the tumor type. Deregulation of HSPGs resulting in malignancy may be due to either their abnormal expression levels or changes in their structure and functions as a result of the altered activity of their biosynthetic or remodeling enzymes. Indeed, in the tumor microenvironment, HSPGs undergo structural alterations, through the shedding of proteoglycan ectodomain from the cell surface or the fragmentation and/or desulfation of HS chains, affecting HSPG function with significant impact on the molecular interactions between cancer cells and their microenvironment, and tumor cell behavior. Here, we overview the structural and functional features of HSPGs and their signaling in the tumor environment which contributes to tumorigenesis and cancer progression.

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“…HIF activation can transcriptionally regulate genes involved in epithelial-to-mesenchymal transition (EMT) [8]. Breakdown of the cell-extracellular matrix (ECM) and metastases thus plays a pivotal role in these processes [9]. The role of HIF-1α and HIF-2α in promoting tumorigenesis of melanoma has also been reported.…”

Section: Introductionmentioning

confidence: 99%

HIF-1α and HIF-2α Mediated PARVB Expression Promotes Tumor Growth and Metastasis in Malignantmelanoma

Wang

et al. 2020

Preprint

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BackgroundMalignant melanoma is the leading cause of skin cancer-related death. The role of PARVB in malignant melanoma remains unclear. Hypoxia is a hallmark of solid tumors including melanoma. But the regulation role of hypoxia in PARVB expression has not been reported.MethodsHuman malignant melanoma tissues, cell lines and their controls were collected. IHC staining, qRT-PCR and Western blot were performed to reveal the differential PARVB expression. The role of PARVB in tumor growth and metastasis of malignant melanoma was evaluated in vitro and in vivo. The regulation role and mechanism of hypoxia and HIFs in PARVB expression was validated by qRT-PCR, Western blot, ChIP-PCR and Luciferase reporter assays.ResultsPARVB was upregulated in malignant melanoma and correlated with patient survival. OverexpressionofPARVB promoted tumor growth and metastasis of malignant melanoma. Furthermore, hypoxia induced HIF-1α and HIF-2α expression activated PARVB transcription and expression through binding to the specific hypoxia-responsive element (HRE) in the promoter region of PARVB.ConclusionsIn malignant melanoma, Hypoxia induced HIF-1α and HIF-2α expression could directly activate PARVB expression, which further promoted tumor growth and metastasis, inducing poor prognosis. These results indicated that PARVB might be a potential therapeutic target for malignant melanoma.

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Cancer Metastasis: The Role of the Extracellular Matrix and the Heparan Sulfate Proteoglycan Perlecan

Cited by 122 publications

References 265 publications

Glycosaminoglycans are specific endosomal receptors forYersinia pseudotuberculosisCytotoxic Necrotizing Factor

Glycosaminoglycans are specific endosomal receptors forYersinia pseudotuberculosisCytotoxic Necrotizing Factor

Heparan Sulfate Proteoglycan Signaling in Tumor Microenvironment

HIF-1α and HIF-2α Mediated PARVB Expression Promotes Tumor Growth and Metastasis in Malignantmelanoma

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