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Journal ArticleDOI

Proteoglycans in cancer biology, tumour microenvironment and angiogenesis

TL;DR: Decorin and growth control, and genetic evidence for a role for decorin in carcinogenesis and mechanism of decorin action: suppression of β‐catenin and Myc levels are presented.
Abstract: Proteoglycans, key molecular effectors of cell surface and pericellular microenvironments, perform multiple functions in cancer and angiogenesis by virtue of their polyhedric nature and their ability to interact with both ligands and receptors that regulate neoplastic growth and neovascularization. Some proteoglycans such as perlecan, have pro- and anti-angiogenic activities, whereas other proteoglycans, such as syndecans and glypicans, can also directly affect cancer growth by modulating key signalling pathways. The bioactivity of these proteoglycans is further modulated by several classes of enzymes within the tumour microenvironment: (i) sheddases that cleave transmembrane or cell-associated syndecans and glypicans, (ii) various proteinases that cleave the protein core of pericellular proteoglycans and (iii) heparanases and endosulfatases which modify the structure and bioactivity of various heparan sulphate proteoglycans and their bound growth factors. In contrast, some of the small leucine-rich proteoglycans, such as decorin and lumican, act as tumour repressors by physically antagonizing receptor tyrosine kinases including the epidermal growth factor and the Met receptors or integrin receptors thereby evoking anti-survival and pro-apoptotic pathways. In this review we will critically assess the expanding repertoire of molecular interactions attributed to various proteoglycans and will discuss novel proteoglycan functions modulating cancer progression, invasion and metastasis and how these factors regulate the tumour microenvironment.
Citations
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Journal ArticleDOI
TL;DR: The complex ECM structure is emphasized as to provide a better understanding of its dynamic structural and functional multipotency and the implication of the various families of ECM macromolecules in health and disease is presented.

1,379 citations


Cites background from "Proteoglycans in cancer biology, tu..."

  • ...mainly, through their GAG side chains participating in several cell functional properties, such as cell signaling, proliferation, migration, differentiation, apoptosis and adhesion [14, 16-19]....

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  • ...PGs and GAGs play important roles in normal physiology and development of various diseases since their biosynthesis is markedly modified during ECM remodeling in all pathologies [14, 16-19]....

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Journal ArticleDOI
TL;DR: The proposed nomenclature encompasses forty-three distinct proteoglycan-encoding genes and many alternatively-spliced variants and is based on three criteria: Cellular and subcellular location, overall gene/protein homology, and the utilization of specific protein modules within their respective protein cores.

856 citations


Cites background from "Proteoglycans in cancer biology, tu..."

  • ...Perlecan is a complex regulator of vascular biology and tumor angiogenesis [33,140,141] by performing a dual function: via the N-terminal HS chains, perlecan is pro-angiogenic [96] by binding and presenting VEGFA and various FGFs to their cognate receptors [33,141– 152]....

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Journal ArticleDOI
TL;DR: This review focuses on the remodeling of the ECM under the influence of a primary solid tumor mass, primed by soluble factors of the primary tumor, which may be remodeled in a way to facilitate the engraftment of metastasizing cancer cells.
Abstract: The extracellular matrix (ECM) constitutes the scaffold of tissues and organs. It is a complex network of extracellular proteins, proteoglycans and glycoproteins, which form supramolecular aggregates, such as fibrils and sheet-like networks. In addition to its biochemical composition, including the covalent intermolecular cross-linkages, the ECM is also characterized by its biophysical parameters, such as topography, molecular density, stiffness/rigidity and tension. Taking these biochemical and biophysical parameters into consideration, the ECM is very versatile and undergoes constant remodeling. This review focusses on this remodeling of the ECM under the influence of a primary solid tumor mass. Within this tumor stroma, not only the cancer cells but also the resident fibroblasts, which differentiate into cancer-associated fibroblasts (CAFs), modify the ECM. Growth factors and chemokines, which are tethered to and released from the ECM, as well as metabolic changes of the cells within the tumor bulk, add to the tumor-supporting tumor microenvironment. Metastasizing cancer cells from a primary tumor mass infiltrate into the ECM, which variably may facilitate cancer cell migration or act as barrier, which has to be proteolytically breached by the infiltrating tumor cell. The biochemical and biophysical properties therefore determine the rates and routes of metastatic dissemination. Moreover, primed by soluble factors of the primary tumor, the ECM of distant organs may be remodeled in a way to facilitate the engraftment of metastasizing cancer cells. Such premetastatic niches are responsible for the organotropic preference of certain cancer entities to colonize at certain sites in distant organs and to establish a metastasis. Translational application of our knowledge about the cancer-primed ECM is sparse with respect to therapeutic approaches, whereas tumor-induced ECM alterations such as increased tissue stiffness and desmoplasia, as well as breaching the basement membrane are hallmark of malignancy and diagnostically and histologically harnessed.

308 citations

Journal ArticleDOI
TL;DR: Decorin was an early response gene evoked by septic inflammation, and protein concentrations of decorin were increased in the plasma of septic patients and mice, and this pathway operates in both pathogen-mediated and sterile inflammation.
Abstract: The mechanisms linking immune responses and inflammation with tumor development are not well understood. Here, we show that the soluble form of the extracellular matrix proteoglycan decorin controls inflammation and tumor growth through PDCD4 (programmed cell death 4) and miR-21 (microRNA-21) by two mechanisms. First, decorin acted as an endogenous ligand of Toll-like receptors 2 and 4 and stimulated production of proinflammatory molecules, including PDCD4, in macrophages. Second, decorin prevented translational repression of PDCD4 by decreasing the activity of transforming growth factor-β1 and the abundance of oncogenic miR-21, a translational inhibitor of PDCD4. Moreover, increased PDCD4 abundance led to decreased release of the anti-inflammatory cytokine interleukin-10, thereby making the cytokine profile more proinflammatory. This pathway operates in both pathogen-mediated and sterile inflammation, as shown here for sepsis and growth retardation of established tumor xenografts, respectively. Decorin was an early response gene evoked by septic inflammation, and protein concentrations of decorin were increased in the plasma of septic patients and mice. In cancer, decorin reduced the abundance of anti-inflammatory molecules and increased that of proinflammatory molecules, thereby shifting the immune response to a proinflammatory state associated with reduced tumor growth. Thus, by stimulating proinflammatory PDCD4 and decreasing the abundance of miR-21, decorin signaling boosts inflammatory activity in sepsis and suppresses tumor growth.

289 citations


Cites background from "Proteoglycans in cancer biology, tu..."

  • ...Multifunctional involvement of proteoglycans makes them both potential targets for cancer remedies and novel antitumoral therapeutic agents (57, 58)....

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  • ...Small leucine-rich proteoglycans, such as decorin and lumican, act as tumor repressors (57)....

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Journal ArticleDOI
TL;DR: The key molecular functions of syndecan-1 in modulating the onset, progression, and resolution of inflammatory diseases, cancer, and infection are discussed.

288 citations

References
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Journal ArticleDOI
24 Jan 1997-Cell
TL;DR: This work has identified endostatin, an angiogenesis inhibitor produced by hemangioendothelioma, a 20 kDa C-terminal fragment of collagen XVIII that specifically inhibits endothelial proliferation and potently inhibitsAngiogenesis and tumor growth.

4,613 citations


"Proteoglycans in cancer biology, tu..." refers background in this paper

  • ...Domain V of perlecan bound with high affinity to the non collagenous NC1 domain of collagen XVIII [76] which includes the well-established angiogenic inhibitor endostatin [77]....

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Journal ArticleDOI
TL;DR: Recent insights have shed light onto VEGFR signal transduction and the interplay between different V EGFRs and VEGF co-receptors in development, adult physiology and disease.
Abstract: Vascular endothelial growth-factor receptors (VEGFRs) regulate the cardiovascular system. VEGFR1 is required for the recruitment of haematopoietic precursors and migration of monocytes and macrophages, whereas VEGFR2 and VEGFR3 are essential for the functions of vascular endothelial and lymphendothelial cells, respectively. Recent insights have shed light onto VEGFR signal transduction and the interplay between different VEGFRs and VEGF co-receptors in development, adult physiology and disease.

2,894 citations


"Proteoglycans in cancer biology, tu..." refers background in this paper

  • ...This is interesting because the vascular abnormalities observed in the perlecan morphants are similar to those observed in VEGFA morphants [59], null mutants of VEGFR2 [60] or phospholypase C 1 [61], a downstream effector of VEGFR2 [62, 63]....

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  • ...Moreover, a significant proportion of the perlecan morphants could be rescued by intra-embryonic injections of human VEGFA, suggesting that perlecan acts upstream of VEGFA/VEGFR2 axis [58]....

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  • ...SHP-1 then dephosphorylates a number of RTKs including VEGFR2, thereby blocking endothelial cell migration, survival and proliferation....

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  • ...Concomitantly, there is vascular expression of VEGFR2 and sustained VEFGR2 activation, suggesting that, like in the zebrafish model described above, perlecan might represent a potent reservoir of growth factors that can be presented to and utilized by VEGFR2 [67]....

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  • ...This concept is further supported by the discovery that heparan sulphate proteoglycans in trans can potentiate VEGFR2 signalling and thus angiogenesis by evoking a sustained signal transduction due to heparan sulphate-dependent trapping of the active VEGFR2 signalling complex [69]....

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Journal ArticleDOI
TL;DR: WNT signalling has been studied primarily in developing embryos, but WNTs also have important functions in adults, and aberrant signalling by WNT pathways is linked to a range of diseases, most notably cancer.
Abstract: WNT signalling has been studied primarily in developing embryos, in which cells respond to WNTs in a context-dependent manner through changes in survival and proliferation, cell fate and movement. But WNTs also have important functions in adults, and aberrant signalling by WNT pathways is linked to a range of diseases, most notably cancer. What is the full range of diseases that involve WNT pathways? Can inhibition of WNT signalling form the basis of an effective therapy for some cancers? Could activation of WNT signalling provide new therapies for other clinical conditions? Finally, on the basis of recent experiments, might WNTs normally participate in self-renewal, proliferation or differentiation of stem cells? If so, altering WNT signalling might be beneficial to the use of stem cells for therapeutic means.

1,660 citations


"Proteoglycans in cancer biology, tu..." refers background in this paper

  • ...Both -catenin and Myc translocate to the nucleus where they activate a large number of genes including Myc itself [240, 241], thereby establishing a positive feedback loop that favours growth and survival (Fig....

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Journal ArticleDOI
TL;DR: The basement membrane (BM) as mentioned in this paper is a specialized form of extracellular matrix (ECM) which mediates tissue compartmentalization and sends signals to epithelial cells about the external microenvironment.
Abstract: In recent years, the basement membrane (BM)--a specialized form of extracellular matrix (ECM)--has been recognized as an important regulator of cell behaviour, rather than just a structural feature of tissues. The BM mediates tissue compartmentalization and sends signals to epithelial cells about the external microenvironment. The BM is also an important structural and functional component of blood vessels, constituting an extracellular microenvironment sensor for endothelial cells and pericytes. Vascular BM components have recently been found to be involved in the regulation of tumour angiogenesis, making them attractive candidate targets for potential cancer therapies.

1,560 citations

Journal ArticleDOI
19 Jul 1990-Nature
TL;DR: The ability of decorin to bind transforming growth factor-β, an autocrine factor that stimulates the growth of Chinese hamster ovary cells, is reported, suggesting that decorin may be a component of a feedback system regulating cell growth.
Abstract: Decorin is a small chondroitin-dermatan sulphate proteoglycan consisting of a core protein and a single glycosaminoglycan chain. Eighty per cent of the core protein consists of 10 repeats of a leucin-rich sequence of 24 amino acids. Similar repeats have been found in two other proteoglycans, biglycan and fibromodulin, and in several other proteins including Drosophila morphogenetic proteins. Expression of high levels of decorin in Chinese hamster ovary cells has a dramatic effect on their morphology and growth properties. We now report that this effect is due at least in part to the ability of decorin to bind transforming growth factor-beta, an autocrine factor that stimulates the growth of Chinese hamster ovary cells. As transforming growth factor-beta induces synthesis of decorin in many cell types, our results suggest that decorin may be a component of a feedback system regulating cell growth.

1,494 citations


"Proteoglycans in cancer biology, tu..." refers background in this paper

  • ...It was subsequently found that decorin secreted by the transgenic CHO cells bound with high affinity to TGF- thereby blocking the growth-stimulatory activity of the growth factor [196]....

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