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Current Cancer Therapy Reviews, 2009, 5, 256-260
Heparan Sulfate Proteoglycans, Tumour Progression and the Cancer Stem Cell Niche Larisa M. Haupt and Lyn R. Griffiths* Genomics Research Centre and Griffith Institute for Health and Medical Research, Griffith University, Parklands Drive, Southport, Queensland 4215, Australia Abstract: The cancer stem cell hypothesis states that tumours arise from cells with the ability to self-renew and differentiate into multiple cell types, and that these cells persist in tumors as a distinct population that can cause disease relapse and hence metastasis. The crux of this hypothesis is that these cells are the only cells capable of, by themselves, giving rise to new tumours. What proportion of a tumour consists of these stem cells, where are they localised, how are they regulated, and how can we identify them? The stromal cells embedded within the extracellular matrix (ECM) not only provide a scaffold but also produce ECM constituents for use by stem cells. Heparan sulfate proteoglycans (HSPGs) are ubiquitous to this cell niche and interact with a large number of ligands including growth factors, their receptors, and ECM structural components. It is still unclear whether ECM degradation and subsequent metastasis is a result of proteases produced by the tumour cells themselves or by cells within the stromal compartment. The identification of the cellular origin of cancer stem cells along with microenvironmental changes involved in the initiation, progression and the malignant conversion of all cancers is critical to the development of targeted therapeutics. As ubiquitous members of the ECM microenvironment and hence the cancer cell niche, HSPGs are candidates for a central role in these processes.
Key Words: Stem cells, cancer, proteoglycan, metastasis, microenvironment. CANCER AND HYPOTHESIS
THE
CANCER
STEM
CELL
The majority of cancers are solid tumours, with eighty percent of these epithelial in origin and hence arising in tissues that include the breast, lung, colon, prostate and ovary [1]. The specific cellular origin of most tumours remains largely unknown, with speculation that tumour heterogeneity may reflect not only the specific cell of origin but also the microenvironment in which the tumour arises, and the varied responses to therapies observed across patient populations [2]. This tumour microenvironment or niche which includes the stroma, inflammatory cells and vasculature has a significant role in all stages of tumourigenesis. Tumours are generally characterised clinically at the gross level by histology and by their expression profile of known specific markers. This combination of detection has enabled the definition of distinct tumour subtypes, but has not yet produced distinctive markers of initiation or indeed progression. As no tumour-specific target antigens are available, monoclonal antibodies against various antigens including cytoskeletal markers, surface adhesion molecules, or growth factor receptors are used to determine tumourigeneity. Currently, there are two models for tumour heterogeneity: the cancer stem cell hypothesis and the clonal evolution model [1, 3, 4]. Cancer stem cells (CSCs) refer to a specific subset of tumour cells that have the ability to self-renew and generate the diversity of cells which make up the tumour. This model
*Address correspondence to this author at the Genomics Research Centre, Griffith University Gold Coast Campus, Parklands Drive, Southport 4215, Queensland, Australia; Tel: + 61 7555 29158; Fax + 61 7555 28908; E-mail:
[email protected] 1573-3947/09 $55.00+.00
implies a hierarchical structure where these CSCs, with stem-like properties, are able to initiate and sustain tumourigenesis [1, 5, 6]. The differentiated or non-CSC cells that make up the bulk of the tumour mass may have a high proliferative potential, but this is not unlimited [5]. The first evidence for the existence of CSCs came from leukemia in which a rare subset comprising 0.1-1% of the acute myeloid tumour cell population inducing leukemia following transplantation into immunodeficient mice [7]. In contrast, the clonal evolution model postulates that mutant tumour cells with a growth advantage are selected and expanded, with cells in the dominant population having potential for regenerating tumour growth. The acquisition of genetic events, epigenetic and other changes, along with microenvironmental changes are plausible contributors in both models. Indeed both models are not mutually exclusive, with both likely to exist in human cancer as demonstrated by leukemia cells and models of serial transplantation (resulting in more aggressive tumours). Indeed, the characteristics that define CSCs, including their long life and high proliferative capacity may increase the susceptibility of these cells to transformation [1, 5, 8]. The lack of specific markers used to define most normal stem cells and their progeny highlights the difficulty in isolating cells of tumour initiation, which is likely to include CSCs and their progeny. The identification of these cells within the tumour combined with extensive in vivo analysis to accurately determine the frequency of CSCs within solid tumours would provide targets for directed therapeutics. It follows that eliminating these differentiated progenies while sparing the cancer stem cells will ultimately result in relapse [1, 5]. To date, several cell surface markers have proved useful for the isolation of tumours enriched for CSCs, including CD133 (PROM1), CD44, CD24 and epithelial cell © 2009 Bentham Science Publishers Ltd.
Heparan Sulfate Proteoglycans, Tumour Progression
adhesion molecule (EpCAM, also known as epithelial specific antigen (ESA) and TACSTD1). Although useful in some contexts, more definitive markers are required as many antigens, including CD44, CD24 and CD133 are heterogeneous between and within tumours and widely expressed in many different types of CSCs as well as normal stem cells [1, 9, 10]. It is also important to keep the use of the current suite of cell surface markers in context. Although markers of tumourigenic cells in established cell lines, they may differ from CSCs in primary tumours. Thus, observations made in cancer cell lines must be extended to primary tumours and in contextual models in order to validate their significance [1, 11]. As an example, recent work demonstrates the previously described CD44+CD24- stem cell phenotype is associated with basal-type breast cancers in human patients; in particular BRCA1 inherited cancers, but this has been shown not to correlate with clinical outcome. The use of tumour cells cultured in spheroids and other three-dimensional systems, allows the multicellular in vivo format to be mimicked in vitro, and have already demonstrated morphological, functional and gene expression differences with their traditional two-dimensional cell cultures [11-17]. These findings caution that the success of our efforts in translating cancer stem cell research into clinical practice depends on the thorough characterisation of CSCs and their surrounding microenvironment [5]. For epithelial malignancies, the epithelial-mesenchymal transition (EMT) is considered to be a crucial event in the metastatic process, which involves disruption of epithelial cell homeostasis and the acquisition of a migratory mesenchymal phenotype. In many epithelial tumours, an EMT appears to be controlled by canonical pathways such as the Wnt and TGF pathways, both of which can be aberrantly activated during neoplasia [1, 18-20]. It is conceivable that CSCs may have also play a role in the formation of a particular niche for metastasis, for example primary tumour cells can generate a pre-metastatic niche by recruiting haematopoietic progenitor cells to tumour-specific niches. Evidence for this comes from work demonstrating that the site of transplantation influences tumour initiating frequency in xenograft and in vivo models [1, 21, 22]. Critical to improving cancer models currently in use is the improved understanding of the cellular niche including the elucidation of markers specific for tumour type. HEPARAN SULFATE PROTEOGLYCANS (HSPG)S Proteoglycan (PGs) are a large family of proteins characteristically composed of a core protein to which one or more glycosaminoglycans (GAGs) attach. They include the heparan sulfate (HS) proteoglycans (HSPGs) and chondroitin sulfate (CS) proteoglycans (CSPGs). CS side chains are predominantly found on matrix localised PGs, whereas membrane PGs such as glypicans and syndecans contain mostly HS side chains. Precursor HS chains are synthesised in the golgi as non-sulfated copolymers attached to a HSPG core protein. Following chain initiation, several modification steps are required to complete the specific HS sulfation pattern. Polymerisation is the first step of HS biosynthesis, the beginning of chain assembly, and the commitment of the PG toward a HSPG and not a CSPG. The alternating addition of glucuronic acid and N-acetylglucosamine residues is cata-
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lysed by members of the Ext family (Ext1 and Ext2). Following completion of chain assembly, further sequential modifications occur within the golgi. The NDST (N-deacetylase/Nsulfotransferase) family of enzymes removes acetyl groups from the N-acetylglucosamine residues, generating free amino groups sulfated via N-sulfotransferase activity. All subsequent modifications of the HS chain depend on the presence of these residues, making NDSTs responsible for the overall design of the polysaccharide [23-25]. As substrate recognition by most enzymes during HS chain modification is generally dependant on structural modifications introduced in previous reactions [26], there appears to be coordinated temporal interaction. The final HS chain contains clusters of N- and -sulfated sugar residues separated by non-sulfated regions of varying length, with ligand binding properties of the HS chain determined by the density of sulfated domains [24, 26, 27]. HSPGs are ubiquitous to the cell surface and in the extracellular matrix (ECM), including basement membranes, where they mediate cell-cell and cell-ECM interactions [28]. The exact mechanism of these interactions is still not fully elucidated, but is thought to include regulation of the activity and stability of the ligands [29, 30]. As HS sequences are not directly encoded by genes, but are created by an elaborate posttranslational biosynthesis [23, 25], the tissue specificity of these interactions are due, at least in part, to the fine structure of HS characterised by the sulfation pattern [27, 29]. The sulfation of HS has been associated with roles both in differentiation [29, 31] and transformation of cells [32, 33]. Examples include mutated or inactivated Ext1 resulting in inappropriate bone growth [34]; sulfateless, the Drosophila NDST analog and its effect on multiple signalling pathways mediated by wingless, hedgehog, and the FGF/FGFR, breathless and branchless [35, 36]; and developmental studies in embryonic brain demonstrating a HSmediated growth factor activity switch from FGF2 to FGF1, accompanied by alterations in 6--sulfation patterns, total chain length, and the number of sulfated domains of the HS species. These data demonstrate the specificity of the HS produced by the cell may be mediated by distinct stimuli and hence can be up or down regulated dependent on the cell type and its niche [26, 37-39]. HSPGS, THE NICHE AND CANCER The extracellular matrix (ECM) is a reservoir of cellular and non-cellular material including binding proteins and growth factors that mediate cellular processes [40, 41]. The stromal cell components of the ECM are integral participants in these signaling mechanisms. Stromal cells are a diverse population consisting of fibroblasts, smooth muscle cells, endothelial cells and others. These cells provide a scaffold to the developing stem and progenitor cells, but also produce transmembrane ligands, extracellular matrix components and soluble proteins [2, 29, 31, 42]. Within the ECM, levels of gene expression vary, but the presence of specific combinations of growth factors and their receptors, may prime certain cells for induction when and if they are exposed to specific combinations in this microenvironment or niche. Due in part to their high negative charge, HS chains of PGs interact with
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a large number of ligands including growth factors and morphogens (FGF, Wnts, VEGFs), their receptors (FGFRs), as well as enzymes and enzyme inhibitors, lipases, apolipoproteins, ECM structural molecules (collagen, fibronectin, laminin) and plasma proteins [43-46]. It has been well established that the ECM and its constituents modulate cellular phenotypes, cell-cell interactions and signalling cascades. Recent evidence suggests that PGs may sequester growth factors through their core proteins to simultaneously modulate growth factor receptor activity and signalling efficacy. Dependant on type, expression pattern, and accessibility to ligands, PGs can either promote or inhibit cell proliferation and hence tumourigenesis. This tumour growth-promoting or tumour-suppressing-activity may be dependent on any aspect or indeed the combination of the specific HSPG (the core protein, its ligand/growth factor specificity or the tumour cell characteristics). PGs localised in the ECM may be upregulated in the tumour cells themselves and participate in the cells response to growth factor stimuli. Indeed GAG dysregulation in cancer has been correlated with prognosis in several malignancies [2, 47]. It is unclear whether these specific interactions occur at the level of the ECM or at the plasma membrane [2]. Members of the glypican and syndecan families of HSPGs have been implicated in the promotion of local tumour cell growth in some cancer tissues, but to inhibit tissue invasion and metastasis in others [2, 48, 49]. The mechanism/s by which this duality occurs is still unclear. Previous reports have demonstrated expression of glypican-1 is induced in human pancreatic tumour cells and surrounding fibroblasts, and in breast cancer cells, with the mitogenic response of the pancreatic tumour cells to FGF2 and EGF abolished by specific downregulation of this HSPG [2, 50]. Syndecan-4 overexpression has been shown to enhance FGF2 signalling, and is thought to regulate erb-B2 and erbB3 levels in colon carcinoma. In terms of HSPG interactions, syndecan-1 shedding is involved in the initial FGF2 response for glypican-dependent cells and is thought to modulate the long-term FGF2 response of glypican-independent cells [2]. However, the expression profile of the core proteins (syndecans, glypicans etc) along with the side-chain modification enzymes (NDSTs, Exts etc) has yet to be fully determined in most human cancers. The growth factor signalling associated with tumourigenesis has been postulated to be controlled, at least on one level, by an autoregulatory loop that may involve HSPGs expression levels on the cell surface and their role in the endocytosis of receptor/ligand complexes [48]. The aberrant distribution of PGs on tumour lesions could be correlated with the possibility that the stromal compartment of the tumour may be enriched in these macromolecules. Patterns of HSPG expression are believed to mirror those of ligands that require HSPGs to elicit cellular responses. As a result, the presentation and/or release of growth factors may aid in establishing the coordination of growth factors and the required HSPG to facilitate and direct tumour cell motility. Increased knowledge of the tumour niche and its role in the initiation, proliferation and progression of tumours is one of the major objectives in cancer research [2, 48].
Haupt and Griffiths
HSPGS AND METASTASIS Cancers are diagnosed and classified histologically as invasive or non-invasive. Invasive carcinomas extend into the surrounding ECM, whilst in non-invasive carcinoma tumour cells are confined to the primary tumour. Currently, most solid primary tumours are resected, with these patients at risk from metastatic relapse as a result of residual tumour cells [4]. During the invasive phase of malignant tumours, the metastatic cells break into the basal lamina and enter the underlying connective tissue, which concurrently undergoes extensive modifications [2]. The processes of intravastation from the primary lesion, avoidance of immune surveillance and extravastation at the secondary site defines metastasis as an active process [51]. Malignant tumour cells degrade ECM constituents essentially involving proteolytic enzymes produced either by the tumour cells themselves or by the surrounding stromal cells. The identification of the cellular origin of genetic and microenvironmental changes involved in the initiation, progression and the malignant conversion; the understanding of processes occurring during the establishment of secondary tumour sites; along with strategies to limit the cancer to the primary site are of medical and social interest. As ubiquitous members of the ECM microenvironment and hence cancer cell niche, HSPGs and their regulators are candidates for a central role in these processes. At the beginning of the invasive phase, several cascade processes start to be activated, both at the cellular and extracellular levels. The host stroma undergoes modifications of the ECM composition and recruitment of host cells [2]. The process of matrix disassembly for reorganisation during the processes of tissue remodeling and cell movement, including cancer progression, metastasis and angiogenesis is operated by the complex machinery of extracellular proteases, including members of the matrix metalloproteinase family and heparanase. Heparanase is the predominant mammalian enzyme degrading HS and cleaves HS side-chains into large molecular weight fragments. With heparanase gene expression shown to tightly correlate with enzyme activity [24, 52], recent data has emerged linking heparanase overexpression with prostate cancers, gastric cancers and lymph node metastasis, including a tight correlation with grade and levels of heparanase expression [53-55]. In vivo, heparanase has been associated with remodelling of the bone microenvironment in both the developmental and metastatic context [56, 57]. In breast cancers, heparanase has been shown to be induced by tamoxifen [58] and implicated in both primary tumours and metastasis [59]. HSPGs are well-suited to play a pivotal role in these processes, as syndecans are actively shed from the cell surface by heparanase, potentially providing the required HSPG mediated ligand/receptor interactions for downstream signalling [48]. HSPGs, their site-specific sulfation patterns and their interactions are pivotal in these processes and are becoming more heavily investigated and understood. A better understanding of these HSPG-mediated biological events of not only cancer initiation, but progression and metastasis is fundamental to biomarker discovery and their application in effective tumour limitation strategies.
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Revised: April 05, 2009
Accepted: July 14, 2009
