Molecular mechanisms underlying the divergent roles of SPARC in human carcinogenesis (original) (raw)
Related papers
Secreted Protein Acidic and Rich in Cysteine (Sparc) in Cancer
Journal of carcinogenesis & mutagenesis, 2013
The local tissue microenvironment "niche" is composed of cellular and non-cellular components and plays an important role in regulating cell behaviour, during embryogenesis, and in physiologic and pathologic contexts including cancer. The cellular component is formed of specialized cell types endowed for the biological functions of the organ and tissues. The non-cellular component of the niche comprises the extracellular matrix (ECM) which functions not only as a scaffold for the cellular component maintaining tissue morphology, but dynamically influences fundamental aspects of cell behaviour. Matricellular proteins are a group of extracellular matrix (ECM) molecules that are not components of the structural scaffold of the ECM but serve as cell regulators and modulators of cellular behaviour and signaling. Secreted Protein Acidic and Rich in Cysteine (SPARC) is one of the matricellular proteins and is implicated in myriad physiological and pathological conditions characterized by extensive remodelling and plasticity. The role of SPARC in cancer is being increasingly recognized as it plays multi-faceted contextual roles depending on the cancer type, cell of origin and the surrounding milieu. The role of SPARC in the multistep cascades of carcinogenesis, cancer progression and metastasis has been studied retrospectively in human tumors, preclinical models using cell lines and models of oncogene-driven and carcinogen-induced cancers. Below we review several of these tumor types where SPARC biology has been evaluated.
The American journal of pathology, 2007
The matricellular glycoprotein SPARC (secreted protein acidic and rich in cysteine) has been accorded major roles in regulation of cell adhesion and proliferation, as well as tumorigenesis and metastasis. We have recently reported that in addition to its potent antiproliferative and proapoptotic functions, SPARC also abrogates ovarian carcinoma cell adhesion, a key step in peritoneal implantation. However, the underlying molecular mechanism through which SPARC ameliorates peritoneal ovarian carcinomatosis seems to be multifaceted and has yet to be delineated. Herein, we show that SPARC significantly inhibited integrin-mediated ovarian cancer cell adhesion to extracellular matrix proteins, as well as to peritoneal mesothelial cells. This counteradhesive effect of SPARC was shown to be mediated in part through significant attenuation of cell surface expression and clustering of alpha(v)-integrin subunit, alpha(v)beta(3)- and alpha(v)beta(5)-heterodimers, and beta(1)-subunit, albeit to...
Macrophage-Derived SPARC Bridges Tumor Cell-Extracellular Matrix Interactions toward Metastasis
Cancer Research, 2008
Other than genetic imprinting and epithelial to mesenchymal transition, cancer cells need interaction with the nearby stroma toward metastasis. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein known to regulate extracellular matrix (ECM) deposition and cell-ECM interaction. Gene expression profiles associate SPARC to malignant progression. Using reciprocal bone marrow chimeras between SPARC knockout and wild-type mice, we show that SPARC produced by inflammatory cells is necessary for spontaneous, but not experimental, i.v. metastasis. Macrophage-derived SPARC induces cancer cell migration and enhances their migration to other ECM proteins at least through A v B 5 integrin. Indeed, RNA interference knockdown of B 5 integrin expression reduces cell migration in vitro and metastasis in vivo. Together these results show that macrophage-derived SPARC takes part in metastasis, acting at the step of integrin-mediated migration of invasive cells. [Cancer Res 2008;68(21):9050-9]
Tumor Microenvironment: Extracellular Matrix Alterations Influence Tumor Progression
Frontiers in Oncology
The tumor microenvironment (TME) is composed of various cell types embedded in an altered extracellular matrix (ECM). ECM not only serves as a support for tumor cell but also regulates cell-cell or cell-matrix cross-talks. Alterations in ECM may be induced by hypoxia and acidosis, by oxygen free radicals generated by infiltrating inflammatory cells or by tumor-or stromal cell-secreted proteases. A poorer diagnosis for patients is often associated with ECM alterations. Tumor ECM proteome, also named cancer matrisome, is strongly altered, and different ECM protein signatures may be defined to serve as prognostic biomarkers. Collagen network reorganization facilitates tumor cell invasion. Proteoglycan expression and location are modified in the TME and affect cell invasion and metastatic dissemination. ECM macromolecule degradation by proteases may induce the release of angiogenic growth factors but also the release of proteoglycan-derived or ECM protein fragments, named matrikines or matricryptins. This review will focus on current knowledge and new insights in ECM alterations, degradation, and reticulation through cross-linking enzymes and on the role of ECM fragments in the control of cancer progression and their potential use as biomarkers in cancer diagnosis and prognosis.
A prototypic matricellular protein in the tumor microenvironment—where there's SPARC, there's fire
2008
Within the tumor microenvironment is a dynamic exchange between cancer cells and their surrounding stroma. This complex biologic system requires carefully designed models to understand the role of its stromal components in carcinogenesis, tumor progression, invasion, and metastasis. Secreted protein acidic and rich in cysteine (SPARC) is a prototypic matricellular protein at the center of this exchange. Two decades of basic science research combined with recent whole genome analyses indicate that SPARC is an important player in vertebrate evolution, normal development, and maintenance of normal tissue homeostasis. Therefore, SPARC might also play an important role in the tumor microenvironment. Clinical evidence indicates that SPARC expression correlates with tumor progression, but tightly controlled animal models have shown that the role of SPARC in tumor progression is dependent on tissue and tumor cell type. In this Prospectus, we review the current understanding of SPARC in the tumor microenvironment and discuss current and future investigations of SPARC and tumor-stromal interactions that require careful consideration of growth factors, cytokines, proteinases, and angiotropic factors that might influence SPARC activity and tumor progression.
International Journal of Cancer, 2006
Secreted protein, acidic and rich in cysteine (SPARC), is a multifunctional matricellular glycoprotein. In vitro, SPARC has antiangiogenic properties, including the ability to inhibit the proliferation and migration of endothelial cells stimulated by bFGF and VEGF. Previously, we demonstrated that platelet-derived SPARC also inhibits angiogenesis and impairs the growth of neuroblastoma tumors in vivo. In the present study, we produced rhSPARC in the transformed human embryonic kidney cell line 293 and show that the recombinant molecule retains its ability to inhibit angiogenesis. Although 293 cell proliferation was not affected by exogenous expression of SPARC in vitro, growth of tumors formed by SPARC-transfected 293 cells was significantly impaired compared to tumors comprised of wild-type cells or 293 cells transfected with a control vector. Consistent with its function as an angiogenesis inhibitor, significantly fewer blood vessels were seen in SPARC-transfected 293 tumors compared to controls, and these tumors contained increased numbers of apoptotic cells. Light microscopy revealed small nests of tumor cells surrounded by abundant stromal tissue in xenografts with SPARC expression, whereas control tumors were comprised largely of neoplastic cells with scant stroma. Mature, covalently cross-linked collagen was detected in SPARC-transfected 293 xenografts but not in control tumors. Our studies suggest that SPARC may regulate tumor growth by inhibiting angiogenesis, inducing tumor cell apoptosis and mediating changes in the deposition and organization of the tumor microenvironment. ' 2005 Wiley-Liss, Inc.
The interplay between tumor cells and the microenvironment has been recognized as one of the hallmarks of cancer biology. To assess the role of extracellular matrix (ECM) in the modulation of tissue homeostasis and tumorigenesis, we developed a protocol for the purification of tissue-derived ECM using mucosae from healthy human colon, perilesional area, and colorectal carcinoma (CRC). Matched specimens were collected from the left colon of patients undergoing CRC resection surgery. ECMs were obtained from tissues that were decellularized with hypotonic solutions containing ionic and nonionic detergents, hypertonic solution, and endonuclease in the absence of denaturing agents. Mucosae-derived ECMs maintained distribution and localization of proteins and glycoproteins typical of the original tissues, and showed different three-dimensional (3D) structures among normal versus perilesional and tumor-derived stroma. The three types of ECM differentially regulated the localization and organization of seeded monocytes and cancer cells that were located and organized as in the original tissue. Specifically, healthy, perilesional, and CRC-derived ECMs sustained differentiation and polarization of cancer epithelial cells. In addition, healthy, but not perilesional and CRC-derived ECM constrained invasion of cancer cells. All three ECMs sustained turnover between cell proliferation and death up to 40 days of culture, although each ECM showed different ability in supporting cell proliferation, with tumor > perilesional > healthy-derived ECMs. Healthy-, perilesional-and CRC-derived ECM differently modulated cell homeostasis, spreading in the stroma and turnover between proliferation and death, and equally supported differentiation and polarization of cancer epithelial cells, thus highlighting the contribution of different ECMs modulating some features of tissue homeostasis and tumorigenesis. Moreover, these ECMs provide competent scaffolds useful to assess efficacy of antitumor drugs in a 3D setting that more closely recapitulates the native microenvironment. Further, ECM-based scaffolds may also be beneficial for future studies seeking prognostic and diagnostic stromal markers and targets for antineoplastic drugs.
Anticancer Research, 2016
Background: Cancer cells grown in a 3D culture are more resistant to anticancer therapy treatment compared to those in a monolayer 2D culture. Emerging evidence has suggested that the key reasons for increased cell survival could be gene expression changes in cell-extracellular matrix (ECM) interaction-dependent manner. Materials and Methods: Global gene-expression changes were obtained in human colorectal carcinoma HT29 and DLD1 cell lines between 2D and laminin-rich (lr) ECM 3D growth conditions by gene-expression microarray analysis. The most significantly altered functional categories were revealed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Results: The microarray data revealed that 841 and 1190 genes were differentially expressed in colorectal carcinoma DLD1 and HT29 cells. KEGG analysis indicated that the most significantly altered categories were cell adhesion, mitogen-activated protein kinase and immune response. Conclusion: Our results indicate altered pathways related to cancer development and progression and suggest potential ECM-regulated targets for the development of anticancer therapies. Traditionally, the most common cancer cell-based in vitro assays are performed using 2D cell cultures, often growing on plastic substrates. Although data obtained using 2D cell cultures have revealed critical knowledge related to the complex nature of tumor cells, monolayer cell cultures poorly mimic biological processes occurring in tumor tissue due to the artificial environment and standardized growing conditions (1). Moreover, important cell functions such as proliferation or morphology can be dramatically altered in 2D cell cultures (2). The extracellular matrix (ECM), as a key component of the tumor microenvironment, has a high impact on tumor development and cancer cell features (3). The ECM not only structurally supports cancer cells, but also affects other cellular functions, such as cell differentiation, migration, survival or proliferation (4-7). Moreover, gene and protein expression levels are regulated in a cell-ECM interactiondependent manner (8). The ECM is also implicated in tumor cell response to external stimuli (9). Hence, an ECM-based (3D) cell culture, as a model closer to tumor tissue, has been suggested to represent tumor properties better than 2D cell culture does. Previous studies have shown that the morphology of cancer cells cultivated in 2D and ECM-based 3D cultures can differ dramatically (10). Cells grown in a 3D culture are also more resistant to anticancer therapy treatment compared to those in a monolayer culture (11, 12). Emerging evidence suggests that the key reasons for increased cell survival or reduced cell death could be changes in gene expression in cell-ECM interaction-dependent manner (13). Analysis of ECM dependent gene-expression changes is expected to reveal potential targets for more efficient anticancer therapies. Therefore, in order to investigate which cellular pathways that are altered in an ECM-dependent manner are potential targets for the development of new anticancer therapy strategies and in order to establish a model for these investigations, we compared genome-wide transcriptome changes of two human colon carcinoma cell DLD1 and HT29 lines grown in laminin-rich (lr) ECM 3D cell culture compared to conventional 2D monolayer conditions following 48 h of cultivation.
The extracellular matrix in tumor progression and metastasis
Clinical & Experimental Metastasis, 2019
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.