Elsevier

Drug Resistance Updates

Volume 11, Issue 6, December 2008, Pages 231-246
Drug Resistance Updates

SPARC in cancer biology: Its role in cancer progression and potential for therapy

https://doi.org/10.1016/j.drup.2008.08.005Get rights and content

Abstract

The ability to effectively target a tumor to achieve complete regression and cure is the ultimate goal that drives our need to better understand tumor biology. Recently, SPARC has generated considerable interest as a multi-faceted protein that belongs to a family of matricellular proteins. It functions not only to modulate cell–cell and cell–matrix interactions, but its de-adhesive and growth inhibitory properties in non-transformed cells have led to studies to assess its role in cancer. Its divergent actions reflect the complexity of this protein, because in certain types of cancers, such as melanomas and gliomas, SPARC is associated with a highly aggressive tumor phenotype, while in others, mainly ovarian, neuroblastomas and colorectal cancers, SPARC may function as a tumor suppressor. Recent studies have also demonstrated a role for SPARC in sensitizing therapy-resistant cancers. Here, the role of SPARC in cancer progression and its potential application in cancer therapy is discussed.

Introduction

Secreted protein and rich in cysteine, SPARC (also known as osteonectin; or basement-membrane-40, BM-40), is a member of a family of matricellular proteins, whose function is to modulate cell–matrix interactions and cell function without participating in the structural scaffold of the extracellular matrix (Bornstein and Sage, 2002, Brekken and Sage, 2001). It was initially identified as osteonectin by Termine et al. (1981) as a bone-specific phosphoprotein that binds to collagen fibrils and hydroxyapatite at distinct sites. Later the same protein was identified as a serum albumin-binding glycoprotein secreted by endothelial cells (Sage et al., 1984).

The full-length cDNA was cloned from a human placental cDNA library (Swaroop et al., 1988), using a mouse cDNA probe (Mason et al., 1986a), revealing its location on human chromosome 5q31–q33. Human SPARC contains 10 exons, spans 34.6 kb, and is highly conserved through evolution with sequence homology with D. melanogaster (Martinek et al., 2002), C. elegans (Schwarzbauer and Spencer, 1993) and other mammals (Mason et al., 1986a, Mason et al., 1986b, McVey et al., 1988). There are a total of seven members within the SPARC family of proteins, that include testican-1, -2, -3, SPARC-like 1 (or hevin, Mast9), and SPARC-related modular calcium binding (SMOC)-1, and -2. All members of this protein family share three similar domains: (1) N-terminus, (2) follistatin-like, and (3) C-terminus (Bradshaw and Sage, 2001, Brekken and Sage, 2000) (Fig. 1). SPARC protein is 32 kDa in size and has 303 amino acids, with the first 17 amino acids containing the signaling peptide sequence, which is removed during processing. The final mature SPARC protein has 286 amino acids with three distinct domains: NH2-terminal acidic domain (NT), follistatin-like domain (FS), and the C-terminus domain (EC). The NT domain, spanning the first 52 amino acids (Ala1-Glu52), binds hydroxyapatite and calcium ions. This is followed by the follistatin-like domain (FS), which comprises the next 85 aa (Asn53–Pro137). This region contains several internal disulfide bonds that stabilize two weakly interacting modules. The N-terminus region of the FS domain has a very twisted β-hairpin structure that is linked by disulfide bonds at cysteines 1–3, and 2–4. This distribution of disulfide bonds makes the FS-domain structurally homologous to epidermal growth factor (EGF)-like domain of factor IX, a coagulation factor (Hohenester et al., 1997). At the other end of the FS-domain, its C-terminus region has structural similarity to Kazal family of serine proteases. It has antiparallel α-helices connected to small three-stranded antiparallel β-sheets with disulfide bonds linking cysteines 5–9, 6–8, 7–10. The third domain, C-terminus domain, is 149 amino acids in length (Cys138–Ile286). It contains two EF-hand motifs that bind calcium with high affinity, and comprise almost entirely of α-helices.

In addition to its expression in bone and endothelial cells, where it was first identified, it is also highly expressed in developing tissues, such as the notochord, somites and the embryonic skeleton (Holland et al., 1987, Mason et al., 1986a); differentiating chondrocytes (Oshima et al., 1989); megakaryocytes (Kelm et al., 1992), and macrophages at sites of tissue injury (Raines et al., 1992, Reed et al., 1993). Therefore, its conservation during evolution implies that this protein may play an important physiological role, and in fact, multiple biological functions have been ascribed to this protein, including its involvement in tissue remodeling (Salonen et al., 1990, Tremble et al., 1993), morphogenesis (Damjanovski et al., 1997, Motamed and Sage, 1997, Tremble et al., 1993), and bone mineralization (Termine et al., 1981). Specifically, in vitro studies using primary cultured cells have demonstrated SPARC’s ability to modulate cell spreading and attachment, thereby giving it a counter-adhesive function (Sage and Bornstein, 1991). This, and its ability to not only influence cell shape and proliferation through its interaction with growth factors, such as platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and basic fibroblast growth factors (bFGF) (Hasselaar and Sage, 1992, Raines et al., 1992, Yan and Sage, 1999); its regulation of matrix remodeling via metalloproteinases (Tremble et al., 1993), together with its ability to inhibit G1 to S-phase cell cycle progression in primary cells (Funk and Sage, 1991) have led many to ask if SPARC could play a role in cancer initiation and progression. Interestingly, a glimpse into this possibility came from reports demonstrating that downregulation of SPARC expression in rat and chick embryo fibroblasts transformed with c-Jun and v-Src could lead to tumorigenesis (Mettouchi et al., 1994, Young et al., 1986). Conversely, its reintroduction resulted in inhibition of tumors—a very intriguing observation (Vial and Castellazzi, 2000). There are now several studies examining the potential role of SPARC in a variety of cancers.

Herein, we will provide an overview of SPARC expression and its potential role in several types of human cancers, followed by an examination of recent studies that demonstrate a novel function for SPARC in modulating chemotherapy response. These interesting findings from several groups lend support to the possibility of utilizing SPARC in cancer therapy.

Section snippets

SPARC in cancer

Although there is growing evidence for an important role for SPARC in a variety of cancers, there is no unifying model, which explains all facets of its function and contribution to the development and progression of cancer. SPARC is differentially expressed in tumors and its surrounding stroma in various cancers in comparison to the normal tissue, yet, its pattern of expression is variable depending on the type of cancer. For example, higher levels of SPARC expression have been reported in

SPARC in breast cancer

The involvement of SPARC in the development and progression of breast cancer is unclear. Recent in vitro studies revealed SPARC’s ability to inhibit breast cancer cell proliferation without stimulating metastasis (Dhanesuan et al., 2002). A similar inhibition of metastasis was also suggested following ectopic expression of SPARC in MDA-MB231 cells—there was inhibition of the metastatic capacity of these SPARC-overexpressing cells to different organs, including lungs and bones (Koblinski et al.,

SPARC in melanoma

Cutaneous melanoma is a common cancer among young adults that is associated with a poor prognosis if not detected in its early stages because of its highly invasive and metastatic nature (Clark et al., 1989). Strong SPARC expression is found in advanced primary and metastatic melanomas, in comparison to nevus or normal melanocytes (Ledda et al., 1997a). It may play a role in melanoma progression (Ledda et al., 1997b) because downregulation of SPARC reduced the invasive and adhesive capacities

SPARC in brain and neurological cancers

Brain and neurological cancers include gliomas, meningiomas and neuroblastomas. Gliomas account for more than 40% of all neurological neoplasms (Kleihues et al., 1995); while meningiomas are considered the second most common (Esiri, 2000). Neuroblastomas (NBs) are the most common pediatric neoplasm (Alvarado et al., 2000). Even in these types of cancers, the effect of SPARC can be very divergent. The discussion below will highlight the different effects of SPARC on gliomas and neuroblastomas.

SPARC in prostate cancer

Higher levels of SPARC were found in metastatic prostate cancers in comparison to normal prostate (Thomas et al., 2000). However, a more recent study using metastatic subclones of human prostate cancer cell line PC-3 (Wong et al., 2007) showed variability in SPARC expression in different clones based on its metastatic potential. For example, there was high SPARC expression in poorly metastatic PC3-#78 cells, while it was significantly lower in highly metastatic PC3-#82 cells and its expression

SPARC in colorectal cancer

The expression of SPARC in human colorectal cancer has been assessed in a number of studies. Initial reports based on six cases of colorectal cancer appeared to suggest that SPARC was localized to the basement membrane (4 of 6 cases), while some cytoplasmic staining was observed in the remaining cases (Wewer et al., 1988). Positive SPARC expression was reported in the four cases of colorectal cancer examined (Porter et al., 1995) without localization of its expression. By comparing the

SPARC in ovarian cancer

SPARC expression is differentially expressed between normal and ovarian carcinoma cell lines (Mok et al., 1996). Downregulation of SPARC was not only detected in a large panel of ovarian cancer cell lines, but its endogenous overexpression promoted cellular growth arrest in vitro and suppressed the growth of tumor xenografts in vivo. This was the first indication of an inhibitory effect of SPARC in ovarian cancers. In an attempt to assess the effect of SPARC in relation to metastasis in ovarian

Mechanistic aspects of SPARC action in cancer biology

Although there appears to be inconsistent patterns in both the expression and biological activity of SPARC in malignancies, our evolving understanding of the mechanisms mediating SPARC’s various functions may shed light into the role(s) of this complex multifunctional protein in cancer.

SPARC as therapeutic and chemosensitizer

SPARC’s ability to inhibit cell proliferation and to enhance apoptosis in certain types of cancer, such as those of the ovary, colorectum, pancreas, neuroblastoma and leukemia leads to the idea that this molecule itself is a potential therapeutic for the treatment of these malignancies. As previously noted, SPARC not only inhibits cell proliferation and promotes apoptosis in ovarian cancers in vitro and in vivo (Yiu et al., 2001), but also reduces metastasis by significantly reducing peritoneal

SPARC peptides

In order to understand how the different regions of SPARC contribute to this multi-functional protein, Lane and Sage used synthetic 20-mer peptides spanning the mouse SPARC amino acid (designated peptides 1.1–4.2; Table 1, Fig. 2) to assess their ability to modulate cell shape. They found that two peptides at either end of the SPARC protein, peptides 1.1 and 4.2, which contain calcium-binding sites, inhibited cell spreading in endothelial cells and fibroblasts in a dose-dependent fashion (Lane

Conclusion and future directions

The studies on SPARC have demonstrated an important role for this protein in the development of malignancies, but there is still limited understanding of its varied and contradictory roles in tumorigenesis. This may be explained, in part by the different methodologies used in various studies: in vitro studies using different cancer cell lines; the use of xenografts of cancer cell lines in SPARC-null or immunocompromised mice; studies of clinical samples that failed to distinguish if alterations

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