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

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Review

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

Zehra Elgundi et al. Front Oncol.

Abstract

Cancer metastasis is the dissemination of tumor cells to new sites, resulting in the formation of secondary tumors. This process is complex and is spatially and temporally regulated by intrinsic and extrinsic factors. One important extrinsic factor is the extracellular matrix, the non-cellular component of tissues. Heparan sulfate proteoglycans (HSPGs) are constituents of the extracellular matrix, and through their heparan sulfate chains and protein core, modulate multiple events that occur during the metastatic cascade. This review will provide an overview of the role of the extracellular matrix in the events that occur during cancer metastasis, primarily focusing on perlecan. Perlecan, a basement membrane HSPG is a key component of the vascular extracellular matrix and is commonly associated with events that occur during the metastatic cascade. Its contradictory role in these events will be discussed and we will highlight the recent advances in cancer therapies that target HSPGs and their modifying enzymes.

Keywords: cancer metastasis; heparan sulfate proteoglycan; heparanase; perlecan; therapeutic.

Figures

Figure 1
Figure 1
Role of the extracellular matrix in driving progression through stages of the metastatic cascade. (a) Primary tumor cells may undergo epithelial-mesenchymal transition (EMT) (Box 1) and invade through basement membranes (BM) into the surrounding stroma. Tumor cell local invasion and metastatic dissemination is often facilitated by cancer-associated fibroblasts (CAFs) or specific ECM components, which may enhance invasion or modulate the immune system. (b) To disseminate to a secondary site, tumor cells must access the vascular system and intravasate through the endothelial BM. This occurs in part through the release of proteases and heparanase, which disrupt BM integrity (Box 2). (c) The circulating tumor cells (CTCs) must then survive transit to secondary sites of metastasis and can be assisted by platelet activation as well as accompanying CAFs. (d) To exit the vessel, cells extravasate into the surrounding tissue and seed at distinctly different tissues from the primary tumor. Overt colonization of secondary sites by disseminating tumor cells (DTCs) is greatly enhanced through extravasation at premetastatic niches. (e) Extravasated cancer cells typically have three fates, either colonize and proliferate to form overt metastases, enter a reversible state of dormancy or, in most cases, die.
Figure 2
Figure 2
Schematic diagram of the HSPG perlecan and HS. The different domains of perlecan are depicted by roman numerals. The insert depicts a schematic of HS represented by the repeating disaccharide of N-acetyl glucosamine and glucuronic acid (or iduronic acid) and sulfate moieties that can occur. Enzymatic modification of HS can occur via heparanase cleavage, resulting in smaller molecular weight fragments, or cleaving the 6-O sulfate on glucosamine via sulfatase.

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