Flipping the Molecular Switch: Influence of Perlecan and Its Modifiers in the Tumor Microenvironment

Cruz, Lissette A.; Tellman, Tristen V.; Farach‐Carson, Mary C.

doi:10.1007/978-3-030-40146-7_6

Cited by 19 publications

(23 citation statements)

References 82 publications

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“…The cleavage of GPC1 by ADAM17 plays a role in the adhesion, proliferation and migration of oral squamous cell carcinoma cells [159]. At the basement membrane of the cells, perlecan can undergo shedding through heparanase, MMPs, and other proteases [145]. The C-terminal fragment of perlecan, known as endorepellin, resulting from the proteolytic cleavage of perlecan, may undergo further proteolysis that leads to the release of the C-terminal endorepellin fragment LG3 whose levels are reduced in breast cancer [160].…”

Section: Collagen Type VIII Col8a1mentioning

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%

“…Overexpression of GPC6 is associated with gastric adenocarcinoma and metastatic progression of cutaneous melanoma [ 140 ]. 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 ].…”

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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Section: Collagen Type VIII Col8a1mentioning

confidence: 99%

Section: Structural Features Biosynthesis and Enzymatic Modificamentioning

confidence: 99%

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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“…Moreover, the release of growth factors bound to perlecan HS chains likewise contributes to various tumor-related processes, including angiogenesis [ 123 ]. Indeed, Cruz et al suggest that modifications of perlecan-abundant TME, such as bone, “flip the molecular switch” and transform the “hostile” stroma into a permissive environment with the ability to facilitate cancer dissemination and metastasis [ 124 ].…”

Section: Role Of Pgs In Hormone-dependent Cancer Growth Metastasimentioning

confidence: 99%

“…Here, it was demonstrated that the degradation of HS chains of basement membrane PGs enhances the extravasation of inflammatory cells [ 218 ]. Another example of PG involvement in the formation of a “permissive” tumor microenvironment is the action of perlecan, whose inflammation-mediated modifications have the role of being a “switch” between tumor permissive and prohibiting states [ 124 ].…”

Section: The Contribution Of Pgs To the Immunobiology Of Hormone-dmentioning

confidence: 99%

Proteoglycans in the Pathogenesis of Hormone-Dependent Cancers: Mediators and Effectors

Tzanakakis

Giatagana

Kuskov

et al. 2020

Cancers

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Hormone-dependent cancers exhibit high morbidity and mortality. In spite of advances in therapy, the treatment of hormone-dependent cancers remains an unmet health need. The tumor microenvironment (TME) exhibits unique characteristics that differ among various tumor types. It is composed of cancerous, non-cancerous, stromal, and immune cells that are surrounded and supported by components of the extracellular matrix (ECM). Therefore, the interactions among cancer cells, stromal cells, and components of the ECM determine cancer progression and response to therapy. Proteoglycans (PGs), hybrid molecules consisting of a protein core to which sulfated glycosaminoglycan chains are bound, are significant components of the ECM that are implicated in all phases of tumorigenesis. These molecules, secreted by both the stroma and cancer cells, are crucial signaling mediators that modulate the vital cellular pathways implicated in gene expression, phenotypic versatility, and response to therapy in specific tumor types. A plethora of deregulated signaling pathways contributes to the growth, dissemination, and angiogenesis of hormone-dependent cancers. Specific inputs from the endocrine and immune systems are some of the characteristics of hormone-dependent cancer pathogenesis. Importantly, the mechanisms involved in various aspects of cancer progression are executed in the ECM niche of the TME, and the PG components crucially mediate these processes. Here, we comprehensively discuss the mechanisms through which PGs affect the multifaceted aspects of hormone-dependent cancer development and progression, including cancer metastasis, angiogenesis, immunobiology, autophagy, and response to therapy.

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Proteoglycans in mechanobiology of tissues and organs: Normal functions and mechanopathology

Farach‐Carson,

Wu,

França

2024

Proteoglycan Research

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Proteoglycans (PGs) are a diverse class of glycoconjugates that serve critical functions in normal mechanobiology and mechanopathology. Both the protein cores and attached glycosaminoglycan (GAG) chains function in mechanically sensitive processes, and loss of either can contribute to development of pathological conditions. PGs function as key components of the extracellular matrix (ECM), where they can serve as mechanosensors in mechanosensitive tissues including bone, cartilage, tendon, blood vessels, and soft organs. The mechanical properties of these tissues depend on the presence and function of PGs, which play important roles in tissue elasticity, osmolarity, and pressure sensing, and response to physical activity. Tissue responses depend on cell surface mechanoreceptors that include integrins, CD44, voltage‐sensitive ion channels, transient receptor potential, and piezo channels. PGs contribute to cell and molecular interplay in wound healing, fibrosis, and cancer, where they transduce the mechanical properties of the ECM and influence the progression of various context‐specific conditions and diseases. The PGs that are most important in mechanobiology vary depending on the tissue and its functions and functional needs. Perlecan, for example, is important in the mechanobiology of basement membranes, cardiac muscle, and skeletal muscle, while aggrecan plays a primary role in the mechanical properties of cartilage and joints. A variety of techniques have been used to study the mechanobiology of PGs, including atomic force microscopy, mouse knockout models, and in vitro cell culture experiments with three‐dimensional organoid models. These studies have helped to elucidate the tissue‐specific roles that PGs play in cell‐level mechanosensing and tissue mechanics. Overall, the study of PGs in mechanobiology is yielding fundamental new concepts in the molecular basis of mechanosensing that can open the door to the development of new treatments for a host of conditions related to mechanopathology.

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Flipping the Molecular Switch: Influence of Perlecan and Its Modifiers in the Tumor Microenvironment

Cited by 19 publications

References 82 publications

Heparan Sulfate Proteoglycan Signaling in Tumor Microenvironment

Heparan Sulfate Proteoglycan Signaling in Tumor Microenvironment

Proteoglycans in the Pathogenesis of Hormone-Dependent Cancers: Mediators and Effectors

Proteoglycans in mechanobiology of tissues and organs: Normal functions and mechanopathology

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