Abstract
Pancreatic ductal adenocarcinoma (PDAC) stands as the poorest prognostic tumor of the digestive tract, with a 5-year survival rate of less than 5 %. Therapeutic options for unresectable PDAC are extremely limited and there is a pressing need for expanded therapeutic approaches to improve current options available with gemcitabine-based regimens. With PDAC displaying one of the most prominent desmoplastic stromal reactions of all carcinomas, recent research has focused on the microenvironment surrounding PDAC cells. Secreted protein acid and rich in cysteine (SPARC), which is overexpressed in PDAC, may display tumor suppressor functions in several cancers (e.g., in colorectal, ovarian, prostate cancers, and acute myelogenous leukemia) but also appears to be overexpressed in other tumor types (e.g., breast cancer, melanoma, and glioblastoma). The apparent contradictory functions of SPARC may yield inhibition of angiogenesis via inhibition of vascular endothelial growth factor, while promoting epithelial-to-mesenchymal transition and invasion through matrix metalloprotease expression. This feature is of particular interest in PDAC where SPARC overexpression in the stroma stands along with inhibition of angiogenesis and promotion of cancer cell invasion and metastasis. Several therapeutic strategies to deplete stromal tissue have been developed. In this review, we focused on key preclinical and clinical data describing the role of SPARC in PDAC biology, the properties, and mechanisms of delivery of drugs that interact with SPARC and discuss the proof-of-concept clinical trials using nab-paclitaxel.
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1 Introduction
Pancreatic ductal adenocarcinoma (PDAC) accounts for 2–3 % of all cancers but is the fifth leading cause of cancer deaths in Western countries (the fourth in the USA), with a 5-year survival rate of less than 5 % [1, 2]. Most patients are diagnosed at advanced stages; 80 % having distant metastases or inoperable locoregional involvement [3, 4]. Furthermore, most patients with apparently localized disease who undergo complete surgical resection may rapidly develop local relapse and/or metastases [3, 4]. Therapeutic options for inoperable PDAC are limited. In 1997, gemcitabine became the reference chemotherapy following phase III studies showing an improvement in median overall survival (OS) of approximately 3 months compared to best supportive care [5]. Several drugs used as single agents or combined with gemcitabine subsequently failed to demonstrate significant survival benefit over gemcitabine, with the exception of erlotinib, which gave a significant but modest 2-week improvement in OS [6, 7]. In 2011, the FOLFIRINOX regimen combining 5-FU, irinotecan, and oxaliplatin demonstrated a survival benefit over gemcitabine alone in PDAC; however, this benefit was restricted to a selected patient population with good prognosis (performance status 0–1, absence of cholestasis) [8]. Therefore, new therapeutic options to improve gemcitabine-based regimen activity are urgently needed.
Over the last decade, research has increasingly focused on the microenvironment surrounding PDAC cells. The desmoplastic reaction seen with PDAC is dramatic, and the extent of its outcome is often greater than the epithelial component of the tumor itself [3]. Activated pancreatic stellate cells (PSCs), resident cells which are normally quiescent, take on a myofibroblastic phenotype and produce excessive quantities of several extracellular matrix (ECM) components [9]. This dense and fibrotic stroma may be responsible for the low vascularization of PDACs. This, along with increased interstitial pressure, may contribute to poorer tumor drug delivery and chemotherapy resistance [9]. Few drugs depleting stromal tissue in PDAC are available, and novel anticancer agents taking advantage of this fibrotic component are under development [10]. Proof-of-concept clinical data have been recently reported in metastatic PDAC patients using secreted protein acid and rich in cysteine (SPARC) as a target for the albumin-bound paclitaxel (nab-paclitaxel) [11].
In this review, we provide an overview of SPARC’s physiological functions and summarize key preclinical and clinical data on the role of SPARC as a target for therapeutic intervention in PDAC.
2 SPARC
2.1 Expression and structure
SPARC, also known as osteonectin and basement membrane-40 protein, is a member of the matricellular family of proteins [12]. Two groups of ECM-related proteins have been described: (1) the structural proteins, such as collagens, laminins, fibronectin, and vitronectin, which are intrinsic components of the ECM, and (2) nonstructural or matricellular proteins, including SPARC, osteopontin, thrombospondin, tenascin, and galectin. Matricellular proteins are transiently secreted into the ECM and modulate cell functions, cell–cell, and cell–ECM interactions.
SPARC expression was first identified in bone and endothelial cells and is also highly expressed in embryonic tissues, playing a role during development and in the differentiation of chondrocytes and megakaryocytes [13, 14]. In addition, SPARC is abundantly secreted at sites of tissue injury, playing a role in wound healing, and is expressed in response to various forms of cellular stress [14].
SPARC is the best characterized member of its family which is composed of several proteins including Hevin/SPL-1, SPOCKs/Testicans-1/2/3, SMOCs-1/2, and Fstl1 [15]. Their sequences have been highly conserved and they share similar structure. The SPARC gene is located on human chromosome 5q [16]. CpG islands in the promoter region may be methylated, inhibiting SPARC expression [17]. SPARC is a glycoprotein, varying in size from 32 to 43 kDa, depending on its glycosylation status [18]. It is divided into three domains (Fig. 1): (1) the N-terminus (NT) acidic domain, which binds calcium ions with low affinity and hydroxyapatite; (2) the follistatin-like (FS) domain, which is rigidly stabilized by five disulphide bonds, comprising a very twisted β-hairpin sub-domain, with structural homology to the epidermal growth factor (EGF)-like domain of the blood coagulation factor IX, and a sub-domain with similarity to the Kazal family of serine proteases; and (3) the C-terminus extracellular (EC) domain, almost entirely composed of α-helices and containing two EF-hand motifs which bind calcium with high affinity [13, 14, 19, 20]. SPARC can be degraded by various proteases including matrix metalloproteinases (MMPs), plasmin, and trypsin [19, 21]. Rapid proteolysis of SPARC prevents its accumulation in the extracellular environment.
SPARC interacts with a variety of molecular partners via its different domains (Fig. 1), including ECM structural proteins, growth factors, and cell surface receptors, resulting in a broad spectrum of biological effects [20]. Interestingly, truncated forms resulting from SPARC cleavage exhibit specific biological activity and modified affinity for molecular partners [13, 22].
2.2 Matrix remodeling
SPARC has been shown to play a crucial role in tissue homeostasis in murine models. SPARC-deficient mice exhibit profound osteopenia, reduced tensile strength of skin tissue, increased risk of cardiac rupture after myocardial infarction, defects in the lens capsule with early onset cataracts, and increased deposition of adipose tissue [12, 21, 23–27].
SPARC regulates ECM assembly, organization, and turnover by binding to multiple structural components. It acts as a chaperone for collagens, is necessary for fibril formation, and also binds vitronectin, thrombospondin, and fibrinogen fragments [15, 20]. Of note, glycosylation, presence or absence of calcium ions, and proteases may modulate these interactions.
SPARC is also able to regulate MMP activity [15, 20]. MMPs are necessary for ECM proteolysis and turnover and are mainly released by macrophages during inflammation and fibroblasts during tissue remodeling. Exogenous SPARC can induce the expression of MMP-1 and MMP-9 in fibroblasts and MMP-1, MMP-3, and MMP-9 in peripheral blood monocytes [28, 29].
2.3 Growth factor signaling modulation
In animal models, SPARC is able to inhibit angiogenesis by modulating pathways involved in endothelial cell stimulation [15, 20, 30]. It inhibits vascular endothelial growth factor (VEGF) signaling through direct binding to VEGF, thereby preventing VEGF interaction with its receptor VEGFR [31]. SPARC can also directly bind platelet-derived growth factor (PDGF) [32]. On the other hand, it antagonizes the angiogenic effects of basic fibroblast growth factor (bFGF) on endothelial cells without a direct binding mechanism [33]. FGFR1 is required for SPARC-induced inhibition of fibroblast growth factor (FGF) signaling, suggesting that modulation of FGF actions by SPARC is mediated by this receptor. The CT domain of SPARC is particularly important for its function in angiogenesis modulation: specifically, peptide 4.2, from this region, has been shown to inhibit endothelial cell stimulation by VEGF, bFGF, and PDGF, leading to decreased angiogenesis [31, 33, 34].
In fibroblastic cells, SPARC stimulates bFGF-induced migration (and probably ECM production) and inhibits PDGF-induced proliferation [20, 32, 35]. TGFβ and SPARC display complex mutual regulatory effects. Treatment of fibroblasts with TGFβ induces SPARC expression [36]. Reciprocally, SPARC modulates TGFβ expression and activity [37]. Although SPARC does not directly bind TGFβ or its receptor, it can increase downstream SMAD2 phosphorylation [38, 39]. Administration of TGFβ normalizes ECM deposition deficiency and infarct healing in SPARC-deficient mice [26]. However, despite enhancing SMAD signaling, SPARC can inhibit activation of fibroblasts by TGFβ in vitro and in xenograft models [40].
2.4 Cell surface receptor signaling modulation
SPARC binds various cell surface receptors including integrins and VCAM-1, influencing cell adhesion and migration [20, 41, 42], an aspect of particular interest for immune response. SPARC expression can interfere with transendothelial migration and recruitment of inflammatory cells (macrophages, polymorphonuclear leucocytes), and its deregulation can lead to inappropriate immune response [12, 43].
During epithelial-to-mesenchymal transition (EMT), epithelial cells undergo a phenotype shift from cells expressing epithelial markers such as E-cadherin with tight junctions, clear basal and apical polarity, and sheet-like growth architecture into spindle-like fusiform, motile cells expressing mesenchymal markers such as vimentin and N-cadherin. This process is important during embryonic development but also plays a role in cancer, being associated with enhanced migration, invasion, and resistance to anticancer treatments. In vitro, SPARC induces cell shape modifications toward an “anti-adhesive” phenotype [44]. Integrin-linked kinase (ILK) interacts with integrin subunit β in focal adhesion complexes, connecting integrins with the actin cytoskeleton and multiple signaling pathways. SPARC modulates ILK by direct protein–protein interaction. This may lead to the loss of E-cadherin and cell adhesion, thus contributing to EMT [45].
2.5 Intracellular signaling modulation
By mediating changes in ECM organization and assembly, modulating extracellular signaling, and inducing EMT, SPARC can impact multiple downstream signaling pathways, including the MAPK, PI3K-AKT, and Wnt/β-catenin pathways [20]. The overall effect is an inhibition of cell proliferation through inhibition of ERK signaling triggered by growth factor receptors, leading to a G1-cell cycle block. The effect on survival through modulation of the PI3K/AKT pathway is more controversial, since SPARC expression has been reported to be associated with both activation and inhibition of AKT signaling depending on the models considered [20].
3 SPARC in PDAC
SPARC is primarily considered as a tumor suppressor gene [21]. Low level expression is reported in colorectal, ovarian, prostate cancers, and acute myelogenous leukemia [13, 46], while in other cancers, it is overexpressed, including breast cancer, melanoma, and glioblastoma [13, 46]. The hallmark effects of SPARC in cancers are summarized in Fig. 2 and Table 1 [47–93].
3.1 SPARC expression and prognostic value in PDAC
Interest over the role of SPARC in PDAC was raised following molecular profiling studies of PDAC tumor samples in which this protein was noted to be overexpressed compared to normal tissue [94]. Guweidhi et al. reported a 31-fold increase in PDAC and a 16-fold increase in chronic pancreatitis (precancerous condition) relative to normal pancreatic tissues [95]. High-SPARC mRNA expression was also associated with disease progression and poor prognosis in resected PDAC [46, 95–97]. Normal pancreas is characterized by faint SPARC staining with immunohistochemistry (IHC) in acinar cells, islets, and ECM, but not in ductal cells [95]. In contrast, PDAC tumors often overexpress SPARC [95]. Infante et al. examined SPARC expression by IHC in 299 resected PDAC and reported that only 16 % were negative for SPARC [98]. The most frequent pattern of expression was cancer cell negative/stromal fibroblast positive (52 %). Cancer cell staining was found in less than one third of cases; the cancer cell positive/stromal fibroblast negative and cancer cell positive/stromal fibroblast positive patterns representing 17 and 15 % of tumors, respectively. SPARC stromal expression (67 % of tumors) was associated with a significantly shorter median OS (15 months versus 30 months, p > 0.001) and was an independent prognostic factor after adjustment for tumor size, grade, margin status, lymph nodes, and patient age (hazard ratio (HR) = 1.89, 95 % confidence interval (CI) = 1.31–2.74). In contrast, SPARC expression in pancreatic cancer cells was not associated with prognosis. In locally advanced PDAC patients receiving chemoradiation, Mantoni et al. [99] consistently showed that SPARC was expressed predominantly in the stromal PSCs, and SPARC expression in distal stroma was inversely correlated with OS (7.6 versus 10.2 months, HR = 2.23, 95 %CI = 1.05–4.72). In metastatic PDAC, strong stromal fibroblast immunostaining and an absence of signal in tumor cells were also observed in most cases [95]. However, no data are available regarding SPARC expression in metastases from PDAC origin and its correlation with SPARC expression in the primary tumor.
In summary, high-SPARC expression is common in PDAC, with low expression in cancer cells contrasting with high expression in stromal fibroblastic cells, and is associated with poor prognosis.
3.2 Molecular mechanisms and biological consequences
Consistent with IHC data, gene expression profiling revealed that in contrast to normal pancreatic ductal epithelial cells which express SPARC mRNA, expression was absent in the majority of PDAC cell lines (15/17) [100]. Loss of SPARC expression was due to hypermethylation of the promoter CpG islands. Gao et al. also observed a gradual increase in SPARC promoter CpG methylation in normal, chronic pancreatitis, and adjacent normal tissues to cancerous tissues [101]. This loss of SPARC function in cancer cells is thought to confer a proliferative and survival advantage [102]. In particular, although no correlation was observed between SPARC expression and basal growth of a panel of PDAC cell lines, treatment of PDAC cells with exogenous SPARC resulted in growth suppression [95, 99, 100, 103, 104]. In addition, antisense or shRNA inhibition of endogenous SPARC in PDAC cell lines increased cell growth, confirming that SPARC can act as a tumor suppressor gene in PDAC cells [103, 104].
Conversely, SPARC was found to be overexpressed in the stromal compartment of PDAC tumors. More precisely, stromal fibroblasts/PSCs adjacent to infiltrating PDAC frequently display high-SPARC expression levels [95, 98–100]. This expression is hypothesized to be responsible for the dense desmoplastic reaction and low vascularization of PDAC stroma, possibly via VEGF inhibition [95]. Moreover, SPARC expression at the tumor border may promote PDAC cell invasion, in part through MMP-2 induction [95, 99]. In vitro, SPARC expression in fibroblasts/PSCs derived from normal pancreas can be either increased or decreased by co-culture with PDAC cells, suggesting that SPARC expression in fibroblasts adjacent to PDAC cells is regulated through tumor–stromal paracrine loops [100, 103].
Studies from Brekken et al., based on the Pan02 orthotopic model of murine PDAC (SPARC positive) injected into SPARC-deficient mice, have provided precious data for our understanding of the role of SPARC in PDAC tumor biology, notably regarding angiogenesis and TGFβ signaling [105–109]. They showed that lack of host SPARC resulted in: (1) enhanced growth of implanted pancreatic tumor, due to reduced rates of PDAC cell apoptosis; (2) alteration in the deposition of ECM components within the tumor; (3) lower microvessel density, but enhanced vascular permeability and perfusion due to reduced pericyte coverage and vascular basement membrane alterations, with decreased tumor hypoxia; (4) altered distribution of macrophages within the tumor and polarization of immune response toward an immunosuppressive, pro-metastatic profile through promotion of M2 macrophage and regulatory T cells; and (5) increased invasion and metastasis, resulting in shorter survival. These data may appear contradictory with the often suggested pro-oncogenic role of SPARC stromal expression. The authors proposed that SPARC expression should rather be considered as an indicator of how responsive the stroma is to the tumor and may even be a protective mechanism by which the stroma attempts to control aggressive tumor growth.
In addition, they demonstrated that SPARC promotes pericyte recruitment by indirectly interfering with TGFβ signaling [108]. TGFβ is involved in many aspects of PDAC carcinogenesis, including EMT, metastasis, endothelial cell permeability, inflammation, and fibrosis; all of which are deregulated in SPARC-deficient mice. SPARC is normally expressed by pericytes in vivo. Primary SPARC-deficient pericytes exhibited increased basal TGFβ1 activity and decreased cell migration, an effect that can be blocked by inhibiting TGFβ1. SPARC does not directly bind TGFβ or its receptor, but can modulate TGFβ1 activity in pericytes through binding to the TGFβ accessory receptor endoglin, blocking its association with αV integrin, thereby promoting pericyte migration. Furthermore, treatment with losartan (an angiotensin II receptor inhibitor with anti-TGFβ activity properties) reduced local invasion, metastasis, and vascular permeability and modified the immune profile of tumors grown in SPARC-deficient mice, yielding longer survival [109]. These data should be interpreted with caution since murine host SPARC may not interact in the same way as human SPARC. Moreover, development of the immune system in SPARC-deficient mice is impaired [110]. However, this model provides critical information when interpreting the effects of stroma-targeted therapies: SPARC depletion is expected to result in enhanced tumor perfusion and drug delivery, but may also increase the risk of tumor cell invasion and metastasis. Consequently, such strategies need to be associated with other agent(s) with effective antitumor activity.
4 Exploiting SPARC as a target in PDAC: the proof-of-concept using nab-paclitaxel
Nab-paclitaxel data shall be regarded as proof-of-concept information to support the important role of SPARC in PDAC. Nab-paclitaxel (ABI-007, Abraxane®) is a solvent-free, albumin-coupled form of paclitaxel. Paclitaxel is an anti-microtubule agent for which efforts have been channeled into developing solvent-free paclitaxel formulations [111, 112]. Albumin is a natural circulatory transporter of hydrophobic molecules with reversible, non-covalent binding characteristics. Furthermore, albumin is not immunogenic and has a long lifetime (3 weeks on average), representing an attractive candidate for drug delivery. Nab-paclitaxel is obtained by mixing paclitaxel with human albumin at high pressure to form 130-nm albumin–drug stable nanoparticles [112]. Upon injection, these “big” lyophilized nanoparticles rapidly dissolve into smaller complexes (10 nm on average) consisting of individual albumin–paclitaxel dimers, avoiding the risk of capillary blockade. This technology allows parenteral administration of paclitaxel without solvent-related risks, avoids premedication and long infusion times, and has a more predictable pharmacokinetic profile.
4.1 Mechanisms of delivery
Intratumor delivery of nab-paclitaxel is a multistep process taking advantage of the biological properties of albumin (Fig. 3) [111, 113]. In the first step, albumin binds to the cell surface receptor glycoprotein gp60 (albondin), activating the intracellular protein caveolin-1, resulting in invagination of the endothelial cell membrane and formation of vesicular structures called caveolae [114]. These vesicles allow transcytotic transport of albumin-bound and albumin-unbound plasma constituents across the endothelial cell into the interstitial space. This mechanism is particularly active in tissues with a high perfusion and metabolic demand, such as tumor and inflammatory tissues. The second step involves the preferential concentration of albumin and bound paclitaxel in specific areas of the tumor. SPARC plays a crucial role in this step as a high-affinity receptor for albumin, leading to albumin–drug complex accumulation in SPARC-positive areas. Nab-paclitaxel uptake is indeed increased in SPARC-expressing tumors, and SPARC expression correlated with tumor response in preclinical and clinical models of breast and head and neck cancers [115, 116].
4.2 Rationale for the role of taxanes in PDAC
Nab-paclitaxel was first developed in breast and head and neck cancers, tumors characterized by their sensitivity to taxane-based chemotherapy [111, 112]. Development of nab-paclitaxel in PDAC was secondary, following the demonstration of high-SPARC expression in PDAC tumor samples. Taxanes were clinically evaluated in PDAC based on their promising activity in PDAC preclinical models. Docetaxel and paclitaxel were tested as single agents or in combination in locally advanced and metastatic PDAC patients, as first- or second-line treatment [117]. As single agents, taxanes showed poor efficacy with median progression-free survival (PFS) of about 3 months and median OS ranging from 6 to 8 months and were frequently associated with limiting toxicities (thrombocytopenia, asthenia, nausea/vomiting, neuropathy). Several phase II studies have evaluated docetaxel- or paclitaxel-based combination regimens. Among them, the GTX regimen (gemcitabine, docetaxel, and capecitabine), PDXG (cisplatin, docetaxel, capecitabine, and gemcitabine), and PEXG (cisplatin, epirubicin, capecitabine, and gemcitabine) showed promising results with median PFS and OS exceeding 6 and 10 months, respectively [118, 119].
4.3 SPARC as a target for nab-paclitaxel in PDAC
The rationale for using nab-paclitaxel in PDAC was primarily based on SPARC overexpression in the stroma. SPARC interaction with albumin of nab-paclitaxel was expected to enhance the intratumoral delivery of nab-paclitaxel and cause “stromal collapse,” a phenomenon of stromal depletion bringing tumor cells closer to each other and to blood vessels, thus increasing delivery and efficacy of administered drugs [10].
To evaluate the potential and safety of SPARC as a target in PAC, a phase I/II study [120] was designed to evaluate gemcitabine plus nab-paclitaxel (NCT00398086). The maximal tolerated dose (MTD) was 1,000 mg/m2 gemcitabine plus 125 mg/m2 nab-paclitaxel on days 1, 8, and 15 of a 28-day cycle. Dose-limiting toxicities were sepsis and neutropenia. At the MTD, the response rate was 48 % with a median OS of 12.2 months. Of note, OS correlated with complete metabolic response on 18fluorodeoxyglucose-PET and decrease in CA19-9 levels. Moreover, SPARC expression in the stroma, but not in the cancer cell compartment, was correlated with improved OS, indicating that stromal SPARC expression may be a useful predictive biomarker for response to nab-paclitaxel-based regimens. These data were consistent with preclinical studies in mice with human PDAC xenografts in which nab-paclitaxel yielded depletion of desmoplastic stroma. In addition, the intratumoral concentration of gemcitabine was increased 2.8-fold in mice receiving nab-paclitaxel with gemcitabine over mice treated with gemcitabine alone. These data confirmed the hypothesis of stromal depletion, i.e., the relevance of stroma-targeted therapy to enhance drug delivery and antitumor effects of nab-paclitaxel.
Single agent nab-paclitaxel was also evaluated in a phase II trial in 19 patients with advanced PDAC after progression under gemcitabine-based therapy (100 mg/m2 at days 1, 8, and 15 of a 28-day cycle) (NCT00691054) [121]. Median PFS and OS were 1.7 and 7.3 months, respectively. Non-hematological toxicities were generally mild with grade 1–2 nausea, anorexia, hypocalcemia, and vomiting occurring in 63, 47, 37, and 26 % of patients, respectively. Grade 3–4 neutropenia, neutropenic fever, and anemia occurred in 32, 11, and 11 % of patients, respectively. Of note, only 2 of 15 available tumors stained positive for SPARC by IHC, and neither patient benefited from the therapy. Inconsistency in the predictive value of SPARC is confounded by a high level of missing data regarding the tumor biopsy origin (primary tumor versus metastases) and staining localization (stroma versus tumor cells). Metastatic lesions are expected to be more frequently SPARC negative since they are classically poorer in stroma and PDAC cells are SPARC negative. Moreover, intratumor heterogeneity is a crucial factor to consider when SPARC status is evaluated from a tumor biopsy versus a surgical specimen. Finally, first-line treatment may also influence SPARC expression.
These results provided the basis for the launch of a phase III study in which 861 metastatic PDAC patients were randomized to receive nab-paclitaxel 125 mg/m2 plus gemcitabine 1,000 mg/m2 on days 1, 8, and 15 every 4 weeks, or gemcitabine alone 1,000 mg/m2 weekly for 7 weeks (cycle 1), then on days 1, 8, and 15 every 4 weeks (≥cycle 2) (NCT00844649) [11]. The results, recently disclosed, demonstrated the superiority of the combination for the primary endpoint, with a median OS of 8.5 versus 6.7 months (HR = 0.72, p = 0.000015). PFS (5.5 versus 3.7 months, HR = 0.69, p = 0.000024), time to treatment failure (5.1 versus 3.6 months, HR = 0.60, p < 0.0001), and overall response rate (23 versus 7 %, HR = 3.19, p = 1.1 × 10−10) were also significantly improved in the nab-paclitaxel plus gemcitabine arm. The most common grade ≥3 toxicities were neutropenia (38 versus 27 %), fatigue (17 versus 7 %), and neuropathy (17 versus 1 %) with nab-paclitaxel plus gemcitabine versus gemcitabine alone. Febrile neutropenia was reported in 3 % (nab-paclitaxel plus gemcitabine arm) versus 1 % (gemcitabine alone arm) of patients. In the combination arm, grade ≥3 neuropathy improved to grade ≤1 in a median of 29 days.
The next step will be to determine the best agent or combination of agents to associate with nab-paclitaxel. Preclinical models suggest that a specific synergistic effect may exist between nab-paclitaxel and gemcitabine, with nab-paclitaxel reducing levels of the primary gemcitabine-metabolizing enzyme, cytidine deaminase [122, 123]. Given the interesting results with the FOLFIRINOX regimen and previous results with taxane-based regimens, the question of combining nab-paclitaxel with fluorouracil and/or platinum salts should also be addressed. Moreover, other drugs targeting the stroma such as the hedgehog inhibitor GDC-0449 have been developed and are currently under clinical evaluation in advanced PDAC.
Current clinical trials evaluating stroma-targeted agents are summarized in Table 2 and a list of abstracts is provided in Table 3.
5 Conclusions
A better understanding of PDAC tumor biology has transformed SPARC from a nonstructural matricellular protein with potential tumor suppressor functions, to a prognostic marker based on its expression pattern of stromal expression being associated with poor survival, to ultimately become a therapeutic target and predictive biomarker of response to nab-paclitaxel on the basis of its role as an albumin “sticker” (Tables 4 and 5). The evolution of SPARC is highly illustrative of the close interaction between molecular biology and the development of novel targeted therapies. Moreover, it provides proof-of-concept that not only targeting the tumor cells but also the stromal compartment can fight PDAC. SPARC is thus a pioneer of a promising new generation of therapeutic targets, which are hoped to lead to substantial improvement in survival in PDAC patients.
References
Siegel, R., Naishadham, D., & Jemal, A. (2013). Cancer statistics, 2013. CA: A Cancer Journal for Clinicians, 63(1), 11–30. doi:10.3322/caac.21166.
Ferlay, J., Shin, H. R., Bray, F., Forman, D., Mathers, C., & Parkin, D. M. (2010). Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. International journal of cancer, 127(12), 2893–2917. doi:10.1002/ijc.25516.
Hidalgo, M. (2010). Pancreatic cancer. The New England Journal of Medicine, 362(17), 1605–1617. doi:10.1056/NEJMra0901557.
Vincent, A., Herman, J., Schulick, R., Hruban, R. H., & Goggins, M. (2011). Pancreatic cancer. Lancet, 378(9791), 607–620. doi:10.1016/S0140-6736(10)62307-0.
Burris, H. A., 3rd, Moore, M. J., Andersen, J., Green, M. R., Rothenberg, M. L., Modiano, M. R., et al. (1997). Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. Journal of Clinical Oncology, 15(6), 2403–2413.
Moore, M. J., Goldstein, D., Hamm, J., Figer, A., Hecht, J. R., Gallinger, S., et al. (2007). Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. Journal of Clinical Oncology, 25(15), 1960–1966. doi:10.1200/JCO.2006.07.9525.
Di Marco, M., Di Cicilia, R., Macchini, M., Nobili, E., Vecchiarelli, S., Brandi, G., et al. (2010). Metastatic pancreatic cancer: is gemcitabine still the best standard treatment? (Review). Oncology Reports, 23(5), 1183–1192.
Conroy, T., Desseigne, F., Ychou, M., Bouche, O., Guimbaud, R., Becouarn, Y., et al. (2011). FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. The New England Journal of Medicine, 364(19), 1817–1825. doi:10.1056/NEJMoa1011923.
Duner, S., Lopatko Lindman, J., Ansari, D., Gundewar, C., & Andersson, R. (2010). Pancreatic cancer: the role of pancreatic stellate cells in tumor progression. Pancreatology, 10(6), 673–681. doi:10.1159/000320711.
Garber, K. (2010). Stromal depletion goes on trial in pancreatic cancer. Journal of the National Cancer Institute, 102(7), 448–450. doi:10.1093/jnci/djq113.
Von Hoff, D. D., Ervin, T. J., Arena, F. P., Chiorean, E. G., Infante, J. R., Moore, M. J., et al. (2012). Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). Journal of Clinical Oncology, 30(suppl 34), abstr LBA148.
Chiodoni, C., Colombo, M. P., & Sangaletti, S. (2010). Matricellular proteins: from homeostasis to inflammation, cancer, and metastasis. Cancer and Metastasis Reviews, 29(2), 295–307. doi:10.1007/s10555-010-9221-8.
Tai, I., Tai, I. T., & Tang, M. J. (2008). SPARC in cancer biology: its role in cancer progression and potential for therapy. Drug Resistance Updates, 11(6), 231–246. doi:10.1016/j.drup.2008.08.005 S1368-7646(08)00048-4.
Bradshaw, A. D., & Sage, E. H. (2001). SPARC, a matricellular protein that functions in cellular differentiation and tissue response to injury. The Journal of Clinical Investigation, 107(9), 1049–1054. doi:10.1172/JCI12939.
Bradshaw, A. D. (2012). Diverse biological functions of the SPARC family of proteins. The International Journal of Biochemistry & Cell Biology, 44(3), 480–488. doi:10.1016/j.biocel.2011.12.021 S1357-2725(12)00004-0.
Swaroop, A., Hogan, B. L., & Francke, U. (1988). Molecular analysis of the cDNA for human SPARC/osteonectin/BM-40: sequence, expression, and localization of the gene to chromosome 5q31-q33. Genomics, 2(1), 37–47.
Nagaraju, G. P., & El-Rayes, B. F. (2013). SPARC and DNA methylation: possible diagnostic and therapeutic implications in gastrointestinal cancers. Cancer Letters, 328(1), 10–17. doi:10.1016/j.canlet.2012.08.028.
Kaufmann, B., Muller, S., Hanisch, F. G., Hartmann, U., Paulsson, M., Maurer, P., et al. (2004). Structural variability of BM-40/SPARC/osteonectin glycosylation: implications for collagen affinity. Glycobiology, 14(7), 609–619. doi:10.1093/glycob/cwh063 cwh063.
Motamed, K. (1999). SPARC (osteonectin/BM-40). The International Journal of Biochemistry & Cell Biology, 31(12), 1363–1366.
Chlenski, A., & Cohn, S. L. (2010). Modulation of matrix remodeling by SPARC in neoplastic progression. Seminars in Cell & Developmental Biology, 21(1), 55–65. doi:10.1016/j.semcdb.2009.11.018 S1084-9521(09)00243-2.
Nagaraju, G. P., & Sharma, D. (2011). Anti-cancer role of SPARC, an inhibitor of adipogenesis. Cancer Treatment Reviews, 37(7), 559–566. doi:10.1016/j.ctrv.2010.12.001 S0305-7372(10)00212-4.
Rahman, M., Chan, A. P., & Tai, I. T. (2011). A peptide of SPARC interferes with the interaction between caspase8 and Bcl2 to resensitize chemoresistant tumors and enhance their regression in vivo. PLoS One, 6(11), e26390. doi:10.1371/journal.pone.0026390 PONE-D-11-11572.
Gilmour, D. T., Lyon, G. J., Carlton, M. B., Sanes, J. R., Cunningham, J. M., Anderson, J. R., et al. (1998). Mice deficient for the secreted glycoprotein SPARC/osteonectin/BM40 develop normally but show severe age-onset cataract formation and disruption of the lens. EMBO Journal, 17(7), 1860–1870. doi:10.1093/emboj/17.7.1860.
Delany, A. M., Amling, M., Priemel, M., Howe, C., Baron, R., & Canalis, E. (2000). Osteopenia and decreased bone formation in osteonectin-deficient mice. The Journal of Clinical Investigation, 105(7), 915–923. doi:10.1172/JCI7039.
Bradshaw, A. D., Puolakkainen, P., Dasgupta, J., Davidson, J. M., Wight, T. N., & Helene Sage, E. (2003). SPARC-null mice display abnormalities in the dermis characterized by decreased collagen fibril diameter and reduced tensile strength. Journal of Investigative Dermatology, 120(6), 949–955. doi:10.1046/j.1523-1747.2003.12241.x.
Schellings, M. W., Vanhoutte, D., Swinnen, M., Cleutjens, J. P., Debets, J., van Leeuwen, R. E., et al. (2009). Absence of SPARC results in increased cardiac rupture and dysfunction after acute myocardial infarction. The Journal of Experimental Medicine, 206(1), 113–123. doi:10.1084/jem.20081244 jem.20081244.
Bradshaw, A. D., Graves, D. C., Motamed, K., & Sage, E. H. (2003). SPARC-null mice exhibit increased adiposity without significant differences in overall body weight. Proceedings of the National Academy of Sciences of the United States of America, 100(10), 6045–6050. doi:10.1073/pnas.1030790100 1030790100.
Shankavaram, U. T., DeWitt, D. L., Funk, S. E., Sage, E. H., & Wahl, L. M. (1997). Regulation of human monocyte matrix metalloproteinases by SPARC. Journal of Cellular Physiology, 173(3), 327–334. doi:10.1002/(SICI)1097-4652(199712)173:3<327::AID-JCP4>3.0.CO;2-P.
Tremble, P. M., Lane, T. F., Sage, E. H., & Werb, Z. (1993). SPARC, a secreted protein associated with morphogenesis and tissue remodeling, induces expression of metalloproteinases in fibroblasts through a novel extracellular matrix-dependent pathway. The Journal of Cell Biology, 121(6), 1433–1444.
Rivera, L. B., Bradshaw, A. D., & Brekken, R. A. (2011). The regulatory function of SPARC in vascular biology. Cellular and Molecular Life Sciences, 68(19), 3165–3173. doi:10.1007/s00018-011-0781-8.
Kupprion, C., Motamed, K., & Sage, E. H. (1998). SPARC (BM-40, osteonectin) inhibits the mitogenic effect of vascular endothelial growth factor on microvascular endothelial cells. Journal of Biological Chemistry, 273(45), 29635–29640.
Raines, E. W., Lane, T. F., Iruela-Arispe, M. L., Ross, R., & Sage, E. H. (1992). The extracellular glycoprotein SPARC interacts with platelet-derived growth factor (PDGF)-AB and -BB and inhibits the binding of PDGF to its receptors. Proceedings of the National Academy of Sciences of the United States of America, 89(4), 1281–1285.
Motamed, K., Blake, D. J., Angello, J. C., Allen, B. L., Rapraeger, A. C., Hauschka, S. D., et al. (2003). Fibroblast growth factor receptor-1 mediates the inhibition of endothelial cell proliferation and the promotion of skeletal myoblast differentiation by SPARC: a role for protein kinase A. Journal of Cellular Biochemistry, 90(2), 408–423. doi:10.1002/jcb.10645.
Hasselaar, P., & Sage, E. H. (1992). SPARC antagonizes the effect of basic fibroblast growth factor on the migration of bovine aortic endothelial cells. Journal of Cellular Biochemistry, 49(3), 272–283. doi:10.1002/jcb.240490310.
Chlenski, A., Liu, S., Guerrero, L. J., Yang, Q., Tian, Y., Salwen, H. R., et al. (2006). SPARC expression is associated with impaired tumor growth, inhibited angiogenesis and changes in the extracellular matrix. International Journal of Cancer, 118(2), 310–316. doi:10.1002/ijc.21357.
Wrana, J. L., Overall, C. M., & Sodek, J. (1991). Regulation of the expression of a secreted acidic protein rich in cysteine (SPARC) in human fibroblasts by transforming growth factor beta. Comparison of transcriptional and post-transcriptional control with fibronectin and type I collagen. European Journal of Biochemistry, 197(2), 519–528.
Francki, A., Bradshaw, A. D., Bassuk, J. A., Howe, C. C., Couser, W. G., & Sage, E. H. (1999). SPARC regulates the expression of collagen type I and transforming growth factor-beta1 in mesangial cells. Journal of Biological Chemistry, 274(45), 32145–32152.
Francki, A., McClure, T. D., Brekken, R. A., Motamed, K., Murri, C., Wang, T., et al. (2004). SPARC regulates TGF-beta1-dependent signaling in primary glomerular mesangial cells. Journal of Cellular Biochemistry, 91(5), 915–925. doi:10.1002/jcb.20008.
Schiemann, B. J., Neil, J. R., & Schiemann, W. P. (2003). SPARC inhibits epithelial cell proliferation in part through stimulation of the transforming growth factor-beta-signaling system. Molecular Biology of the Cell, 14(10), 3977–3988. doi:10.1091/mbc.E03-01-0001 E03-01-0001.
Chlenski, A., Guerrero, L. J., Yang, Q., Tian, Y., Peddinti, R., Salwen, H. R., et al. (2007). SPARC enhances tumor stroma formation and prevents fibroblast activation. Oncogene, 26(31), 4513–4522. doi:10.1038/sj.onc.1210247.
Weaver, M. S., & Workman, G. (2008). The copper binding domain of SPARC mediates cell survival in vitro via interaction with integrin beta1 and activation of integrin-linked kinase. Journal of Biological Chemistry, 283(33), 22826–22837. doi:10.1074/jbc.M706563200 M706563200.
Kelly, K. A., Allport, J. R., Yu, A. M., Sinh, S., Sage, E. H., Gerszten, R. E., et al. (2007). SPARC is a VCAM-1 counter-ligand that mediates leukocyte transmigration. Journal of Leukocyte Biology, 81(3), 748–756. doi:10.1189/jlb.1105664.
Llera, A. S., Girotti, M. R., Benedetti, L. G., & Podhajcer, O. L. (2010). Matricellular proteins and inflammatory cells: a task force to promote or defeat cancer? Cytokine & Growth Factor Reviews, 21(1), 67–76. doi:10.1016/j.cytogfr.2009.11.010 S1359-6101(09)00117-8.
Chong, H. C., Tan, C. K., Huang, R. L., & Tan, N. S. (2012). Matricellular proteins: a sticky affair with cancers. Journal of Oncology, 2012, 351089. doi:10.1155/2012/351089.
Barker, T. H., Baneyx, G., Cardo-Vila, M., Workman, G. A., Weaver, M., Menon, P. M., et al. (2005). SPARC regulates extracellular matrix organization through its modulation of integrin-linked kinase activity. Journal of Biological Chemistry, 280(43), 36483–36493. doi:10.1074/jbc.M504663200.
Podhajcer, O. L., Benedetti, L., Girotti, M. R., Prada, F., Salvatierra, E., & Llera, A. S. (2008). The role of the matricellular protein SPARC in the dynamic interaction between the tumor and the host. Cancer and Metastasis Reviews, 27(3), 523–537. doi:10.1007/s10555-008-9135-x.
Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144(5), 646–674. doi:10.1016/j.cell.2011.02.013 S0092-8674(11)00127-9.
Yang, E., Kang, H. J., Koh, K. H., Rhee, H., Kim, N. K., & Kim, H. (2007). Frequent inactivation of SPARC by promoter hypermethylation in colon cancers. International Journal of Cancer, 121(3), 567–575. doi:10.1002/ijc.22706.
Lussier, C., Sodek, J., & Beaulieu, J. F. (2001). Expression of SPARC/osteonectin/BM4O in the human gut: predominance in the stroma of the remodeling distal intestine. Journal of Cellular Biochemistry, 81(3), 463–476.
Tai, I. T., Dai, M., Owen, D. A., & Chen, L. B. (2005). Genome-wide expression analysis of therapy-resistant tumors reveals SPARC as a novel target for cancer therapy. The Journal of Clinical Investigation, 115(6), 1492–1502. doi:10.1172/JCI23002.
Cheetham, S., Tang, M. J., Mesak, F., Kennecke, H., Owen, D., & Tai, I. T. (2008). SPARC promoter hypermethylation in colorectal cancers can be reversed by 5-Aza-2'deoxycytidine to increase SPARC expression and improve therapy response. British Journal of Cancer, 98(11), 1810–1819. doi:10.1038/sj.bjc.6604377.
Tang, M. J., & Tai, I. T. (2007). A novel interaction between procaspase 8 and SPARC enhances apoptosis and potentiates chemotherapy sensitivity in colorectal cancers. Journal of Biological Chemistry, 282(47), 34457–34467. doi:10.1074/jbc.M704459200.
Chan, S. K., Griffith, O. L., Tai, I. T., & Jones, S. J. (2008). Meta-analysis of colorectal cancer gene expression profiling studies identifies consistently reported candidate biomarkers. Cancer Epidemiology, Biomarkers & Prevention, 17(3), 543–552. doi:10.1158/1055-9965.EPI-07-2615.
Socha, M. J., Said, N., Dai, Y., Kwong, J., Ramalingam, P., Trieu, V., et al. (2009). Aberrant promoter methylation of SPARC in ovarian cancer. Neoplasia, 11(2), 126–135.
Mok, S. C., Chan, W. Y., Wong, K. K., Muto, M. G., & Berkowitz, R. S. (1996). SPARC, an extracellular matrix protein with tumor-suppressing activity in human ovarian epithelial cells. Oncogene, 12(9), 1895–1901.
Yiu, G. K., Chan, W. Y., Ng, S. W., Chan, P. S., Cheung, K. K., Berkowitz, R. S., et al. (2001). SPARC (secreted protein acidic and rich in cysteine) induces apoptosis in ovarian cancer cells. American Journal of Pathology, 159(2), 609–622. doi:10.1016/S0002-9440(10)61732-4.
Said, N., & Motamed, K. (2005). Absence of host-secreted protein acidic and rich in cysteine (SPARC) augments peritoneal ovarian carcinomatosis. American Journal of Pathology, 167(6), 1739–1752. doi:10.1016/S0002-9440(10)61255-2.
Said, N., Najwer, I., & Motamed, K. (2007). Secreted protein acidic and rich in cysteine (SPARC) inhibits integrin-mediated adhesion and growth factor-dependent survival signaling in ovarian cancer. American Journal of Pathology, 170(3), 1054–1063. doi:10.2353/ajpath.2007.060903.
Said, N. A., Elmarakby, A. A., Imig, J. D., Fulton, D. J., & Motamed, K. (2008). SPARC ameliorates ovarian cancer-associated inflammation. Neoplasia, 10(10), 1092–1104.
Said, N., Socha, M. J., Olearczyk, J. J., Elmarakby, A. A., Imig, J. D., & Motamed, K. (2007). Normalization of the ovarian cancer microenvironment by SPARC. Molecular Cancer Research, 5(10), 1015–1030. doi:10.1158/1541-7786.MCR-07-0001.
Brown, T. J., Shaw, P. A., Karp, X., Huynh, M. H., Begley, H., & Ringuette, M. J. (1999). Activation of SPARC expression in reactive stroma associated with human epithelial ovarian cancer. Gynecologic Oncology, 75(1), 25–33. doi:10.1006/gyno.1999.5552.
Thomas, R., True, L. D., Bassuk, J. A., Lange, P. H., & Vessella, R. L. (2000). Differential expression of osteonectin/SPARC during human prostate cancer progression. Clinical Cancer Research, 6(3), 1140–1149.
Dhanasekaran, S. M., Barrette, T. R., Ghosh, D., Shah, R., Varambally, S., Kurachi, K., et al. (2001). Delineation of prognostic biomarkers in prostate cancer. Nature, 412(6849), 822–826. doi:10.1038/35090585.
Wong, S. Y., Crowley, D., Bronson, R. T., & Hynes, R. O. (2008). Analyses of the role of endogenous SPARC in mouse models of prostate and breast cancer. Clinical & Experimental Metastasis, 25(2), 109–118. doi:10.1007/s10585-007-9126-2.
Said, N., Frierson, H. F., Jr., Chernauskas, D., Conaway, M., Motamed, K., & Theodorescu, D. (2009). The role of SPARC in the TRAMP model of prostate carcinogenesis and progression. Oncogene, 28(39), 3487–3498. doi:10.1038/onc.2009.205.
Chlenski, A., Liu, S., Crawford, S. E., Volpert, O. V., DeVries, G. H., Evangelista, A., et al. (2002). SPARC is a key Schwannian-derived inhibitor controlling neuroblastoma tumor angiogenesis. Cancer Research, 62(24), 7357–7363.
Chlenski, A., Liu, S., Baker, L. J., Yang, Q., Tian, Y., Salwen, H. R., et al. (2004). Neuroblastoma angiogenesis is inhibited with a folded synthetic molecule corresponding to the epidermal growth factor-like module of the follistatin domain of SPARC. Cancer Research, 64(20), 7420–7425. doi:10.1158/0008-5472.CAN-04-2141.
Smid, M., Dorssers, L. C., & Jenster, G. (2003). Venn Mapping: clustering of heterologous microarray data based on the number of co-occurring differentially expressed genes. Bioinformatics, 19(16), 2065–2071.
Bergamaschi, A., Tagliabue, E., Sorlie, T., Naume, B., Triulzi, T., Orlandi, R., et al. (2008). Extracellular matrix signature identifies breast cancer subgroups with different clinical outcome. The Journal of Pathology, 214(3), 357–367. doi:10.1002/path.2278.
Teschendorff, A. E., Miremadi, A., Pinder, S. E., Ellis, I. O., & Caldas, C. (2007). An immune response gene expression module identifies a good prognosis subtype in estrogen receptor negative breast cancer. Genome Biology, 8(8), R157. doi:10.1186/gb-2007-8-8-r157.
Dhanesuan, N., Sharp, J. A., Blick, T., Price, J. T., & Thompson, E. W. (2002). Doxycycline-inducible expression of SPARC/Osteonectin/BM40 in MDA-MB-231 human breast cancer cells results in growth inhibition. Breast Cancer Research and Treatment, 75(1), 73–85.
Koblinski, J. E., Kaplan-Singer, B. R., VanOsdol, S. J., Wu, M., Engbring, J. A., Wang, S., et al. (2005). Endogenous osteonectin/SPARC/BM-40 expression inhibits MDA-MB-231 breast cancer cell metastasis. Cancer Research, 65(16), 7370–7377. doi:10.1158/0008-5472.CAN-05-0807.
Sangaletti, S., Stoppacciaro, A., Guiducci, C., Torrisi, M. R., & Colombo, M. P. (2003). Leukocyte, rather than tumor-produced SPARC, determines stroma and collagen type IV deposition in mammary carcinoma. The Journal of Experimental Medicine, 198(10), 1475–1485. doi:10.1084/jem.20030202.
Bellahcene, A., & Castronovo, V. (1995). Increased expression of osteonectin and osteopontin, two bone matrix proteins, in human breast cancer. American Journal of Pathology, 146(1), 95–100.
Barth, P. J., Moll, R., & Ramaswamy, A. (2005). Stromal remodeling and SPARC (secreted protein acid rich in cysteine) expression in invasive ductal carcinomas of the breast. Virchows Archiv, 446(5), 532–536. doi:10.1007/s00428-005-1256-9.
Jones, C., Mackay, A., Grigoriadis, A., Cossu, A., Reis-Filho, J. S., Fulford, L., et al. (2004). Expression profiling of purified normal human luminal and myoepithelial breast cells: identification of novel prognostic markers for breast cancer. Cancer Research, 64(9), 3037–3045.
Campo McKnight, D. A., Sosnoski, D. M., Koblinski, J. E., & Gay, C. V. (2006). Roles of osteonectin in the migration of breast cancer cells into bone. Journal of Cellular Biochemistry, 97(2), 288–302. doi:10.1002/jcb.20644.
Briggs, J., Chamboredon, S., Castellazzi, M., Kerry, J. A., & Bos, T. J. (2002). Transcriptional upregulation of SPARC, in response to c-Jun overexpression, contributes to increased motility and invasion of MCF7 breast cancer cells. Oncogene, 21(46), 7077–7091. doi:10.1038/sj.onc.1205857.
Schultz, C., Lemke, N., Ge, S., Golembieski, W. A., & Rempel, S. A. (2002). Secreted protein acidic and rich in cysteine promotes glioma invasion and delays tumor growth in vivo. Cancer Research, 62(21), 6270–6277.
Yunker, C. K., Golembieski, W., Lemke, N., Schultz, C. R., Cazacu, S., Brodie, C., et al. (2008). SPARC-induced increase in glioma matrix and decrease in vascularity are associated with reduced VEGF expression and secretion. International Journal of Cancer, 122(12), 2735–2743. doi:10.1002/ijc.23450.
Rempel, S. A., Golembieski, W. A., Ge, S., Lemke, N., Elisevich, K., Mikkelsen, T., et al. (1998). SPARC: a signal of astrocytic neoplastic transformation and reactive response in human primary and xenograft gliomas. Journal of Neuropathology and Experimental Neurology, 57(12), 1112–1121.
Shi, Q., Bao, S., Maxwell, J. A., Reese, E. D., Friedman, H. S., Bigner, D. D., et al. (2004). Secreted protein acidic, rich in cysteine (SPARC), mediates cellular survival of gliomas through AKT activation. Journal of Biological Chemistry, 279(50), 52200–52209. doi:10.1074/jbc.M409630200.
Shi, Q., Bao, S., Song, L., Wu, Q., Bigner, D. D., Hjelmeland, A. B., et al. (2007). Targeting SPARC expression decreases glioma cellular survival and invasion associated with reduced activities of FAK and ILK kinases. Oncogene, 26(28), 4084–4094. doi:10.1038/sj.onc.1210181.
McClung, H. M., Thomas, S. L., Osenkowski, P., Toth, M., Menon, P., Raz, A., et al. (2007). SPARC upregulates MT1-MMP expression, MMP-2 activation, and the secretion and cleavage of galectin-3 in U87MG glioma cells. Neuroscience Letters, 419(2), 172–177. doi:10.1016/j.neulet.2007.04.037.
Kunigal, S., Gondi, C. S., Gujrati, M., Lakka, S. S., Dinh, D. H., Olivero, W. C., et al. (2006). SPARC-induced migration of glioblastoma cell lines via uPA-uPAR signaling and activation of small GTPase RhoA. International Journal of Oncology, 29(6), 1349–1357.
Golembieski, W. A., Thomas, S. L., Schultz, C. R., Yunker, C. K., McClung, H. M., Lemke, N., et al. (2008). HSP27 mediates SPARC-induced changes in glioma morphology, migration, and invasion. GLIA, 56(10), 1061–1075. doi:10.1002/glia.20679.
Prada, F., Benedetti, L. G., Bravo, A. I., Alvarez, M. J., Carbone, C., & Podhajcer, O. L. (2007). SPARC endogenous level, rather than fibroblast-produced SPARC or stroma reorganization induced by SPARC, is responsible for melanoma cell growth. The Journal of Investigative Dermatology, 127(11), 2618–2628. doi:10.1038/sj.jid.5700962.
Haber, C. L., Gottifredi, V., Llera, A. S., Salvatierra, E., Prada, F., Alonso, L., et al. (2008). SPARC modulates the proliferation of stromal but not melanoma cells unless endogenous SPARC expression is downregulated. International Journal of Cancer, 122(7), 1465–1475. doi:10.1002/ijc.23216.
Ledda, F., Bravo, A. I., Adris, S., Bover, L., Mordoh, J., & Podhajcer, O. L. (1997). The expression of the secreted protein acidic and rich in cysteine (SPARC) is associated with the neoplastic progression of human melanoma. The Journal of Investigative Dermatology, 108(2), 210–214.
Massi, D., Franchi, A., Borgognoni, L., Reali, U. M., & Santucci, M. (1999). Osteonectin expression correlates with clinical outcome in thin cutaneous malignant melanomas. Human Pathology, 30(3), 339–344.
Alonso, S. R., Tracey, L., Ortiz, P., Perez-Gomez, B., Palacios, J., Pollan, M., et al. (2007). A high-throughput study in melanoma identifies epithelial-mesenchymal transition as a major determinant of metastasis. Cancer Research, 67(7), 3450–3460. doi:10.1158/0008-5472.CAN-06-3481.
Ledda, M. F., Adris, S., Bravo, A. I., Kairiyama, C., Bover, L., Chernajovsky, Y., et al. (1997). Suppression of SPARC expression by antisense RNA abrogates the tumorigenicity of human melanoma cells. Nature Medicine, 3(2), 171–176.
Alvarez, M. J., Prada, F., Salvatierra, E., Bravo, A. I., Lutzky, V. P., Carbone, C., et al. (2005). Secreted protein acidic and rich in cysteine produced by human melanoma cells modulates polymorphonuclear leukocyte recruitment and antitumor cytotoxic capacity. Cancer Research, 65(12), 5123–5132. doi:10.1158/0008-5472.CAN-04-1102.
Von Hoff, D. D., Penny, R., Shack, S., Campbell, E., Taverna, D., Borad, M., et al. (2006). Frequency of potential therapeutic targets identified by immunochemistry (IHC) and DNA microarray (DMA) in tumors from patients who have progressed on multiple therapeutic agents. Journal of Clinical Oncology, 24(18S), abstr 3071.
Guweidhi, A., Kleeff, J., Adwan, H., Giese, N. A., Wente, M. N., Giese, T., et al. (2005). Osteonectin influences growth and invasion of pancreatic cancer cells. Annals of Surgery, 242(2), 224–234.
Miyoshi, K., Sato, N., Ohuchida, K., Mizumoto, K., & Tanaka, M. (2010). SPARC mRNA expression as a prognostic marker for pancreatic adenocarcinoma patients. Anticancer Research, 30(3), 867–871.
Prenzel, K. L., Warnecke-Eberz, U., Xi, H., Brabender, J., Baldus, S. E., Bollschweiler, E., et al. (2006). Significant overexpression of SPARC/osteonectin mRNA in pancreatic cancer compared to cancer of the papilla of Vater. Oncology Reports, 15(5), 1397–1401.
Infante, J. R., Matsubayashi, H., Sato, N., Tonascia, J., Klein, A. P., Riall, T. A., et al. (2007). Peritumoral fibroblast SPARC expression and patient outcome with resectable pancreatic adenocarcinoma. Journal of Clinical Oncology, 25(3), 319–325. doi:10.1200/JCO.2006.07.8824.
Mantoni, T. S., Schendel, R. R., Rodel, F., Niedobitek, G., Al-Assar, O., Masamune, A., et al. (2008). Stromal SPARC expression and patient survival after chemoradiation for non-resectable pancreatic adenocarcinoma. Cancer Biology & Therapy, 7(11), 1806–1815.
Sato, N., Fukushima, N., Maehara, N., Matsubayashi, H., Koopmann, J., Su, G. H., et al. (2003). SPARC/osteonectin is a frequent target for aberrant methylation in pancreatic adenocarcinoma and a mediator of tumor-stromal interactions. Oncogene, 22(32), 5021–5030. doi:10.1038/sj.onc.1206807.
Gao, J., Song, J., Huang, H., Li, Z., Du, Y., Cao, J., et al. (2010). Methylation of the SPARC gene promoter and its clinical implication in pancreatic cancer. Journal of Experimental & Clinical Cancer Research, 29, 28. doi:10.1186/1756-9966-29-28.
Nagaraju, G. P., & Ei-Rayes, B. F. (2013). SPARC and DNA methylation: possible diagnostic and therapeutic implications in gastrointestinal cancers. Cancer Letters, 328(1), 10–17. doi:10.1016/j.canlet.2012.08.028S0304-3835(12)00516-2.
Chen, G., Tian, X., Liu, Z., Zhou, S., Schmidt, B., Henne-Bruns, D., et al. (2010). Inhibition of endogenous SPARC enhances pancreatic cancer cell growth: modulation by FGFR1-III isoform expression. British Journal of Cancer, 102(1), 188–195. doi:10.1038/sj.bjc.66054406605440.
Zhivkova-Galunska, M., Adwan, H., Eyol, E., Kleeff, J., Kolb, A., Bergmann, F., et al. (2010). Osteopontin but not osteonectin favors the metastatic growth of pancreatic cancer cell lines. Cancer Biology & Therapy, 10(1), 54–64.
Puolakkainen, P. A., Brekken, R. A., Muneer, S., & Sage, E. H. (2004). Enhanced growth of pancreatic tumors in SPARC-null mice is associated with decreased deposition of extracellular matrix and reduced tumor cell apoptosis. Molecular Cancer Research, 2(4), 215–224.
Arnold, S., Mira, E., Muneer, S., Korpanty, G., Beck, A. W., Holloway, S. E., et al. (2008). Forced expression of MMP9 rescues the loss of angiogenesis and abrogates metastasis of pancreatic tumors triggered by the absence of host SPARC. Experimental Biology and Medicine (Maywood, N.J.), 233(7), 860–873. doi:10.3181/0801-RM-12 0801-RM-12.
Arnold, S. A., Rivera, L. B., Miller, A. F., Carbon, J. G., Dineen, S. P., Xie, Y., et al. (2010). Lack of host SPARC enhances vascular function and tumor spread in an orthotopic murine model of pancreatic carcinoma. Disease Models & Mechanisms, 3(1–2), 57–72. doi:10.1242/dmm.003228 dmm.003228.
Rivera, L. B., & Brekken, R. A. (2011). SPARC promotes pericyte recruitment via inhibition of endoglin-dependent TGF-beta1 activity. The Journal of Cell Biology, 193(7), 1305–1319. doi:10.1083/jcb.201011143.
Arnold, S. A., Rivera, L. B., Carbon, J. G., Toombs, J. E., Chang, C. L., Bradshaw, A. D., et al. (2012). Losartan slows pancreatic tumor progression and extends survival of SPARC-null mice by abrogating aberrant TGFbeta activation. PLoS One, 7(2), e31384. doi:10.1371/journal.pone.0031384 PONE-D-11-19108.
Rempel, S. A., Hawley, R. C., Gutierrez, J. A., Mouzon, E., Bobbitt, K. R., Lemke, N., et al. (2007). Splenic and immune alterations of the Sparc-null mouse accompany a lack of immune response. Genes and Immunity, 8(3), 262–274. doi:10.1038/sj.gene.6364388.
Gradishar, W. J. (2006). Albumin-bound paclitaxel: a next-generation taxane. Expert Opinion on Pharmacotherapy, 7(8), 1041–1053. doi:10.1517/14656566.7.8.1041.
Guarneri, V., Dieci, M. V., & Conte, P. (2012). Enhancing intracellular taxane delivery: current role and perspectives of nanoparticle albumin-bound paclitaxel in the treatment of advanced breast cancer. Expert Opinion on Pharmacotherapy, 13(3), 395–406. doi:10.1517/14656566.2012.651127.
Schilling, U., Friedrich, E. A., Sinn, H., Schrenk, H. H., Clorius, J. H., & Maier-Borst, W. (1992). Design of compounds having enhanced tumour uptake, using serum albumin as a carrier—part II. In vivo studies. International Journal of Radiation Applications and Instrumentation. Part B, 19(6), 685–695.
Minshall, R. D., Tiruppathi, C., Vogel, S. M., & Malik, A. B. (2002). Vesicle formation and trafficking in endothelial cells and regulation of endothelial barrier function. Histochemistry and Cell Biology, 117(2), 105–112. doi:10.1007/s00418-001-0367-x.
Desai, N., Trieu, V., Damascelli, B., & Soon-Shiong, P. (2009). SPARC expression correlates with tumor response to albumin-bound paclitaxel in head and neck cancer patients. Translational Oncology, 2(2), 59–64.
Ibrahim, N. K., Desai, N., Legha, S., Soon-Shiong, P., Theriault, R. L., Rivera, E., et al. (2002). Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel. Clinical Cancer Research, 8(5), 1038–1044.
Belli, C., Cereda, S., & Reni, M. (2012). Role of taxanes in pancreatic cancer. World Journal of Gastroenterology, 18(33), 4457–4465. doi:10.3748/wjg.v18.i33.4457.
Fine, R. L., Fogelman, D. R., Schreibman, S. M., Desai, M., Sherman, W., Strauss, J., et al. (2008). The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemotherapy and Pharmacology, 61(1), 167–175. doi:10.1007/s00280-007-0473-0.
Reni, M., Cereda, S., Rognone, A., Belli, C., Ghidini, M., Longoni, S., et al. (2012). A randomized phase II trial of two different 4-drug combinations in advanced pancreatic adenocarcinoma: cisplatin, capecitabine, gemcitabine plus either epirubicin or docetaxel (PEXG or PDXG regimen). Cancer Chemotherapy and Pharmacology, 69(1), 115–123. doi:10.1007/s00280-011-1680-2.
Von Hoff, D. D., Ramanathan, R. K., Borad, M. J., Laheru, D. A., Smith, L. S., Wood, T. E., et al. (2011). Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. Journal of Clinical Oncology, 29(34), 4548–4554. doi:10.1200/JCO.2011.36.5742JCO.2011.36.5742.
Hosein, P. J., de Lima Lopes, G., Jr., Pastorini, V. H., Gomez, C., Macintyre, J., Zayas, G., et al. (2012). A phase II trial of nab-paclitaxel as second-line therapy in patients with advanced pancreatic cancer. American Journal of Clinical Oncology. doi:10.1097/COC.0b013e3182436e8c.
Awasthi, N., Ostapoff, K., Zhang, C., Schwarz, M. A., & Schwarz, R. E. (2012). Evaluation of combination treatment benefits of nab-paclitaxel in experimental pancreatic cancer. Journal of Clinical Oncology, 30(suppl 4), abstr 170.
Frese, K. K., Neesse, A., Cook, N., Bapiro, T. E., Lolkema, M. P., Jodrell, D. I., et al. (2012). nab-Paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer. Cancer Discovery, 2(3), 260–269. doi:10.1158/2159-8290.CD-11-0242.
Acknowledgments
This work was supported by the Foundation Nelia & Amadeo Barleta and by the Association pour l’Aide à la Recherche & l’Enseignement en Cancérologie. The authors thank Sarah MacKenzie for manuscript editing. The authors also sincerely thank Prof. Philippe Ruszniewski, Dr. Maria Eugenia Riveiro, Dr. Maria Serova, and Dr. Armand de Gramont for thorough review and wise criticisms of the manuscript, which have strongly contributed to the quality of this review.
Conflict of interest
Pascal Hammel is a consultant for Novartis, Pfizer, and Ipsen; Sandrine Faivre is a consultant for Merck, Pfizer, Novartis, Bayer, and Lilly; and Eric Raymond is a consultant for Pfizer, Novartis, Bayer, and Lilly. Other authors have no conflict of interest.
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Neuzillet, C., Tijeras-Raballand, A., Cros, J. et al. Stromal expression of SPARC in pancreatic adenocarcinoma. Cancer Metastasis Rev 32, 585–602 (2013). https://doi.org/10.1007/s10555-013-9439-3
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DOI: https://doi.org/10.1007/s10555-013-9439-3