Shedding; towards a new paradigm of syndecan function in cancer

Choi, So Joong; Lee, Ha Won; Choi, Jung Ran; Oh, Eok Soo

doi:10.5483/bmbrep.2010.43.5.305

Cited by 30 publications

(21 citation statements)

References 52 publications

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“…HSPGs including syndecans-1 are actively shed from epithelial cells via the activity of a variety of MMP sheddases including, but not limited to, MMP7, MMP9, MT1MMP, ADMTS1, ADAM17, and LasA (Figure 1A i ) [25], [31]. Therefore, we hypothesized that HSPG-bound HPV particles would be released from cells in complex with HSPGs and syndecan-1.…”

Section: Resultsmentioning

confidence: 99%

“…The large number of MMPs important for epithelial cell HSPG ectodomain shedding and fact that many posses overlapping substrates in vitro make genetic knockdowns unfeasible [36]. Since we wished simply to determine if HSPG release was related to HPV16 infectivity, we tested broadly active MMP inhibitors, batimastat (BM) marimastat (MM), and tissue inhibitor of metalloproteinases 3 (TIMP3) that are typically used to assay the functional consequences of inhibiting MMP activity and the release of their substrates [25], [31]. Whereas TIMP3 broadly inhibits ADAM-TS4 and ADAM-TS5 and all MMPS tested to date, BM is specific to MMP -1, -2, -3, -7 and -9; MM blocks function of MMP -1, -2, -7, -9, -14.…”

Section: Resultsmentioning

confidence: 99%

“…Extracellular domain shedding of proteins is involved in the control of diverse cellular functions such as development, growth, differentiation, and wound healing as well as various pathologies like cancer [21], [23], [25], [28], [63]. For example, it has recently been recognized that ectodomain shedding functions to control the availability of EGFR ligands, TGF-beta receptor, TNF-alpha, and cell adhesion molecules (L-selectin, E-cadherin).…”

Section: Discussionmentioning

confidence: 99%

“…A prominent characteristic of syndecans is that their extracellular domains can be cleaved to release intact HS-containing ectodomains decorated with bioactive molecules that act as soluble effectors [25], [26]. All syndecan ectodomains are shed constitutively as a normal part of turnover, but this process is also regulated (e.g., certain GFs accelerate shedding).…”

Section: Introductionmentioning

confidence: 99%

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Essential Roles for Soluble Virion-Associated Heparan Sulfonated Proteoglycans and Growth Factors in Human Papillomavirus Infections

2012

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A subset of human papillomavirus (HPV) infections is causally related to the development of human epithelial tumors and cancers. Like a number of pathogens, HPV entry into target cells is initiated by first binding to heparan sulfonated proteoglycan (HSPG) cell surface attachment factors. The virus must then move to distinct secondary receptors, which are responsible for particle internalization. Despite intensive investigation, the mechanism of HPV movement to and the nature of the secondary receptors have been unclear. We report that HPV16 particles are not liberated from bound HSPG attachment factors by dissociation, but rather are released by a process previously unreported for pathogen-host cell interactions. Virus particles reside in infectious soluble high molecular weight complexes with HSPG, including syndecan-1 and bioactive compounds, like growth factors. Matrix mellatoproteinase inhibitors that block HSPG and virus release from cells interfere with virus infection. Employing a co-culture assay, we demonstrate HPV associated with soluble HSPG-growth factor complexes can infect cells lacking HSPG. Interaction of HPV-HSPG-growth factor complexes with growth factor receptors leads to rapid activation of signaling pathways important for infection, whereas a variety of growth factor receptor inhibitors impede virus-induced signaling and infection. Depletion of syndecan-1 or epidermal growth factor and removal of serum factors reduce infection, while replenishment of growth factors restores infection. Our findings support an infection model whereby HPV usurps normal host mechanisms for presenting growth factors to cells via soluble HSPG complexes as a novel method for interacting with entry receptors independent of direct virus-cell receptor interactions.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Essential Roles for Soluble Virion-Associated Heparan Sulfonated Proteoglycans and Growth Factors in Human Papillomavirus Infections

2012

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“…Shed syndecan-1 is present at high levels in some disease states including inflammation, microbial infections, and cancer (Choi et al, 2010; Manon-Jensen et al, 2010). In murine models of inflammation, high levels of shed syndecan-1 direct neutrophil migration, chemokine signaling and the subsequent disease outcome (Kliment et al, 2009; Li et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Chemotherapy stimulates syndecan-1 shedding: A potentially negative effect of treatment that may promote tumor relapse

Ramani

Sanderson

2014

Matrix Biology

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In patients with multiple myeloma, the heparan sulfate proteoglycan syndecan-1 (CD138) is shed from the surface of tumor cells and accumulates in the serum and within the extracellular matrix of the bone marrow where it promotes tumor growth and metastasis. In the present study we discovered that commonly used anti-myeloma drugs stimulate syndecan-1 shedding both in vitro and in animals bearing myeloma tumors. Enhanced shedding is accompanied by increased syndecan-1 synthesis prior to drug induced tumor cell death. Addition of a caspase inhibitor blocks the drug-induced shedding of syndecan-1 in vitro indicating that shedding is linked to the onset of apoptosis. ADAMs inhibitors or siRNA targeting ADAMs blocked drug-induced shedding suggesting that up regulation or activation of ADAMs is responsible for cleaving syndecan-1 from the tumor cell surface. These results reveal that myeloma chemotherapy stimulates synthesis and shedding of syndecan-1, a potentially negative side effect that may lead to accumulation of high levels of syndecan-1 to establish a microenvironment that nurtures relapse and promotes tumor progression. Interestingly, we also found that chemotherapeutic drugs stimulated syndecan-1 shedding from pancreatic cancer cells as well, indicating that drug-induced shedding of syndecan-1 may occur in many cancer types. Overall, our results indicate that use of metalloproteinase inhibitors (to inhibit syndecan-1 shedding) in combination with chemotherapy may represent a novel therapeutic strategy to prevent re-establishment of a microenvironment conducive for tumor relapse.

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Exploring the potential role of palladin in modulating human CAF/ECM functional units

Dolskii,

Alcantara dos Santos,

Andrake

et al. 2024

Cytoskeleton

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Fibroblasts, crucial for maintaining tissue homeostasis, significantly shape the tumor microenvironment (TME). In pancreatic cancer, a highly aggressive malignancy, cancer‐associated fibroblast (CAF)/extracellular matrix (ECM) units dominate the TME, influencing tumor initiation, progression, and treatment responses. Palladin, an actin‐associated protein, is vital for fibroblast structural integrity and activation, playing a key role in CAF/ECM functionality. Palladin interacts with cytoskeletal proteins such as alpha‐actinin (α‐Act) and can therefore regulate other proteins like syndecans, modulating cytoskeletal features, cell adhesion, integrin recycling, and signaling. In this review, we propose that targeting the palladin/α‐Act/syndecan interaction network could modulate CAF/ECM units, potentially shifting the TME from a tumor‐promoting to a tumor‐suppressive state. In silico data and reported studies to suggest that stabilizing palladin‐α‐Act interactions, via excess palladin, influences syndecan functions; potentially modulating integrin endocytosis via syndecan engagement with protein kinase C alpha as opposed to syndecan binding to α‐Act. This mechanism can then affect the distribution of active α5β1‐integrin between the plasma membrane and known intracellular vesicular compartments, thereby influencing the tumor‐suppressive versus tumor‐promoting functions of CAF/ECM units. Understanding these interactions offers likely future therapeutic avenues for stroma normalization in pancreatic and other cancers, aiming to inhibit tumor progression and improve future treatment outcomes.

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Shedding; towards a new paradigm of syndecan function in cancer

Cited by 30 publications

References 52 publications

Essential Roles for Soluble Virion-Associated Heparan Sulfonated Proteoglycans and Growth Factors in Human Papillomavirus Infections

Essential Roles for Soluble Virion-Associated Heparan Sulfonated Proteoglycans and Growth Factors in Human Papillomavirus Infections

Chemotherapy stimulates syndecan-1 shedding: A potentially negative effect of treatment that may promote tumor relapse

Exploring the potential role of palladin in modulating human CAF/ECM functional units

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