SPARC: a matricellular regulator of tumorigenesis

Although many clinical studies have found a correlation of SPARC expression with malignant progression and patient survival, the mechanisms for SPARC function in tumorigenesis and metastasis remain elusive. The activity of SPARC is context- and cell-type-dependent, which is highlighted by the fact that SPARC has shown seemingly contradictory effects on tumor progression in both clinical correlative studies and in animal models. The capacity of SPARC to dictate tumorigenic phenotype has been attributed to its effects on the bioavailability and signaling of integrins and growth factors/chemokines. These molecular pathways contribute to many physiological events affecting malignant progression, including extracellular matrix remodeling, angiogenesis, immune modulation and metastasis. Given that SPARC is credited with such varied activities, this review presents a comprehensive account of the divergent effects of SPARC in human cancers and mouse models, as well as a description of the potential mechanisms by which SPARC mediates these effects. We aim to provide insight into how a matricellular protein such as SPARC might generate paradoxical, yet relevant, tumor outcomes in order to unify an apparently incongruent collection of scientific literature.

[1]  Jean-Michel,et al.  SPARC/osteonectin induces matrix metalloproteinase 2 activation in human breast cancer cell lines. , 1998, Cancer research.

[2]  B. Gardiner,et al.  Osteonectin downregulates E‐cadherin, induces Osteopontin and Focal adhesion kinase activity stimulating an invasive melanoma phenotype , 2007, International journal of cancer.

[3]  S. Fan,et al.  SPARC and Hevin expression correlate with tumour angiogenesis in hepatocellular carcinoma , 2006, The Journal of pathology.

[4]  Li Li,et al.  Mapping and Genome Sequence Analysis of Chromosome 5 Regions Involved in Bladder Cancer Progression , 2001, Laboratory Investigation.

[5]  Hoguen Kim,et al.  Frequent inactivation of SPARC by promoter hypermethylation in colon cancers , 2007, International journal of cancer.

[6]  R. Brekken,et al.  SPARC regulates TGF‐beta1‐dependent signaling in primary glomerular mesangial cells , 2004, Journal of cellular biochemistry.

[7]  E. Sage,et al.  A prototypic matricellular protein in the tumor microenvironment—Where there's SPARC, there's fire , 2008, Journal of cellular biochemistry.

[8]  M. Tang,et al.  Synergism between vitamin D and secreted protein acidic and rich in cysteine–induced apoptosis and growth inhibition results in increased susceptibility of therapy-resistant colorectal cancer cells to chemotherapy , 2007, Molecular Cancer Therapeutics.

[9]  M. Kurrer,et al.  Gene expression profiling of low-grade diffuse astrocytomas by cDNA arrays. , 2000, Cancer research.

[10]  P. Marjoram,et al.  The Molecular Signature of Normal Squamous Esophageal Epithelium Identifies the Presence of a Field Effect and Can Discriminate between Patients with Barrett's Esophagus and Patients with Barrett's-Associated Adenocarcinoma , 2005, Cancer Epidemiology Biomarkers & Prevention.

[11]  J. Foidart,et al.  Induction of SPARC by VEGF in human vascular endothelial cells. , 2001, Biochemical and biophysical research communications.

[12]  E. Sage,et al.  SPARC and tumor growth: Where the seed meets the soil? , 2004, Journal of cellular biochemistry.

[13]  R. Moll,et al.  CD34+ fibrocytes in chronic cystitis and noninvasive and invasive urothelial carcinomas of the urinary bladder , 2007, Virchows Archiv.

[14]  B. Sikic,et al.  Low or absent SPARC expression in acute myeloid leukemia with MLL rearrangements is associated with sensitivity to growth inhibition by exogenous SPARC protein , 2006, Leukemia.

[15]  O. Podhajcer,et al.  Proteomic analysis identified N‐cadherin, clusterin, and HSP27 as mediators of SPARC (secreted protein, acidic and rich in cysteines) activity in melanoma cells , 2007, Proteomics.

[16]  G. Davis,et al.  This Review Is Part of a Thematic Series on Vascular Cell Diversity, Which Includes the following Articles: Heart Valve Development: Endothelial Cell Signaling and Differentiation Molecular Determinants of Vascular Smooth Muscle Cell Diversity Endothelial/pericyte Interactions Endothelial Extracellu , 2022 .

[17]  C. Brodie,et al.  SPARC-induced increase in glioma matrix and decrease in vascularity are associated with reduced VEGF expression and secretion , 2008, International journal of cancer.

[18]  J. Sanes,et al.  Mice deficient for the secreted glycoprotein SPARC/osteonectin/BM40 develop normally but show severe age‐onset cataract formation and disruption of the lens , 1998, The EMBO journal.

[19]  G. Bratthauer,et al.  Osteocalcin and osteonectin immunoreactivity in extraskeletal osteosarcoma: a study of 28 cases. , 1999, Human pathology.

[20]  J. Wrana,et al.  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. , 1991, European journal of biochemistry.

[21]  E. Sage,et al.  SPARC, a matricellular protein that functions in cellular differentiation and tissue response to injury. , 2001, The Journal of clinical investigation.

[22]  Zhihua Liu,et al.  Discovery of Ca2+-relevant and differentiation-associated genes downregulated in esophageal squamous cell carcinoma using cDNA microarray , 2004, Oncogene.

[23]  N. Lemke,et al.  Secreted protein acidic and rich in cysteine promotes glioma invasion and delays tumor growth in vivo. , 2002, Cancer research.

[24]  S. Kohno,et al.  Downregulation of SPARC expression inhibits cell migration and invasion in malignant gliomas. , 2009, International journal of oncology.

[25]  C. Iacobuzio-Donahue,et al.  The desmoplastic response to infiltrating breast carcinoma: gene expression at the site of primary invasion and implications for comparisons between tumor types. , 2002, Cancer research.

[26]  R. Berkowitz,et al.  SPARC (secreted protein acidic and rich in cysteine) induces apoptosis in ovarian cancer cells. , 2001, The American journal of pathology.

[27]  Michael McClelland,et al.  Survey of differentially methylated promoters in prostate cancer cell lines. , 2005, Neoplasia.

[28]  A. Gown,et al.  Distribution of SPARC in normal and neoplastic human tissue. , 1995, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[29]  F. Verrecchia,et al.  Transforming growth factor-β and fibrosis , 2007 .

[30]  J. Davidson,et al.  SPARC-null mice display abnormalities in the dermis characterized by decreased collagen fibril diameter and reduced tensile strength. , 2003, The Journal of investigative dermatology.

[31]  Orit Pappo,et al.  Analysis of differentially expressed genes in hepatocellular carcinoma using cDNA arrays , 2002, Molecular carcinogenesis.

[32]  T. Byzova,et al.  Integrin and Growth Factor Receptor Alliance in Angiogenesis , 2008, Cell Biochemistry and Biophysics.

[33]  Kenneth M. Yamada,et al.  Cell–matrix adhesion , 2007, Journal of cellular physiology.

[34]  M. Yao,et al.  SPARC expression in primary human renal cell carcinoma: upregulation of SPARC in sarcomatoid renal carcinoma. , 2001, Human pathology.

[35]  R. Fässler,et al.  The Tail of Integrins, Talin, and Kindlins , 2009, Science.

[36]  G. Lorusso,et al.  The tumor microenvironment and its contribution to tumor evolution toward metastasis , 2008, Histochemistry and Cell Biology.

[37]  E. Sage,et al.  SPARC-null mice exhibit increased adiposity without significant differences in overall body weight , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[38]  J. Downing,et al.  Gene Expression Profiling of Pediatric Acute Myelogenous Leukemia Materials and Methods , 2022 .

[39]  E. Sage,et al.  SPARC antagonizes the effect of basic fibroblast growth factor on the igration of bovine aortic endothelial cells , 1992, Journal of cellular biochemistry.

[40]  A. Sánchez-Aguilera,et al.  A high-throughput study in melanoma identifies epithelial-mesenchymal transition as a major determinant of metastasis. , 2007, Cancer research.

[41]  R. Ross,et al.  Inhibition of PDGF‐stimulated and matrix‐mediated proliferation of human vascular smooth muscle cells by SPARC is independent of changes in cell shape or cyclin‐dependent kinase inhibitors , 2002, Journal of cellular biochemistry.

[42]  J. Squire,et al.  Effects of THBS3, SPARC and SPP1 expression on biological behavior and survival in patients with osteosarcoma , 2006, BMC Cancer.

[43]  M. Mori,et al.  Clinical significance of secreted protein acidic and rich in cystein in esophageal carcinoma and its relation to carcinoma progression , 2003, Cancer.

[44]  Nerea Martínez,et al.  The molecular signature of mantle cell lymphoma reveals multiple signals favoring cell survival. , 2003, Cancer research.

[45]  R. Timpl,et al.  Crystal structure and mapping by site‐directed mutagenesis of the collagen‐binding epitope of an activated form of BM‐40/SPARC/osteonectin , 1998, The EMBO journal.

[46]  M. Reed,et al.  Compromised production of extracellular matrix in mice lacking secreted protein, acidic and rich in cysteine (SPARC) leads to a reduced foreign body reaction to implanted biomaterials. , 2003, The American journal of pathology.

[47]  A. Zalatnai.  Molecular aspects of stromal-parenchymal interactions in malignant neoplasms. , 2006, Current molecular medicine.

[48]  I. Kalajzic,et al.  Osteonectin-null mutation compromises osteoblast formation, maturation, and survival. , 2003, Endocrinology.

[49]  William P Schiemann,et al.  SPARC inhibits epithelial cell proliferation in part through stimulation of the transforming growth factor-beta-signaling system. , 2003, Molecular biology of the cell.

[50]  N. Said,et al.  Secreted protein acidic and rich in cysteine (SPARC) inhibits integrin-mediated adhesion and growth factor-dependent survival signaling in ovarian cancer. , 2007, The American journal of pathology.

[51]  R L Juliano,et al.  Signal transduction by cell adhesion receptors and the cytoskeleton: functions of integrins, cadherins, selectins, and immunoglobulin-superfamily members. , 2002, Annual review of pharmacology and toxicology.

[52]  W. Frankel,et al.  Stromal Osteonectin Overexpression Is Associated with Poor Outcome in Patients with Ampullary Cancer , 2006, Annals of Surgical Oncology.

[53]  O. Podhajcer,et al.  Suppression of SPARC expression by antisense RNA abrogates the tumorigenicity of human melanoma cells , 1997, Nature Medicine.

[54]  R H Hruban,et al.  Invasion-specific genes in malignancy: serial analysis of gene expression comparisons of primary and passaged cancers. , 2001, Cancer research.

[55]  T. Fujita,et al.  SPARC stimulates the synthesis of OPG/OCIF, MMP-2 and DNA in human periodontal ligament cells. , 2002, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[56]  E. Sage,et al.  Targeted Deletion of the SPARC Gene Accelerates Disc Degeneration in the Aging Mouse , 2005, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[57]  E. Sage,et al.  SPARC deficiency leads to early-onset cataractogenesis. , 1998, Investigative ophthalmology & visual science.

[58]  H. Kleinman,et al.  Endogenous osteonectin/SPARC/BM-40 expression inhibits MDA-MB-231 breast cancer cell metastasis. , 2005, Cancer research.

[59]  Y. Miyagi,et al.  Stimulation of Motility of Human Renal Cell Carcinoma by SPARC/Osteonectin/BM-40 Associated with Type IV Collagen , 1999, Invasion and Metastasis.

[60]  M. Benito,et al.  Overexpression of SPARC protein contrasts with its transcriptional silencing by aberrant hypermethylation of SPARC CpG-rich region in endometrial carcinoma. , 2007, Oncology reports.

[61]  P. Abbe,et al.  SPARC represses E-cadherin and induces mesenchymal transition during melanoma development. , 2006, Cancer research.

[62]  S. Dedhar,et al.  SPARC Regulates Extracellular Matrix Organization through Its Modulation of Integrin-linked Kinase Activity* , 2005, Journal of Biological Chemistry.

[63]  R. Brekken,et al.  Enhanced growth of tumors in SPARC null mice is associated with changes in the ECM. , 2003, The Journal of clinical investigation.

[64]  E. Thompson,et al.  Doxycycline-Inducible Expression of SPARC/ Osteonectin/ BM40 in MDA-MB-231 Human Breast Cancer Cells Results in Growth Inhibition , 2002, Breast Cancer Research and Treatment.

[65]  P. Bornstein,et al.  Matricellular proteins: extracellular modulators of cell function. , 2002, Current opinion in cell biology.

[66]  T. Barker,et al.  HSP27 mediates SPARC‐induced changes in glioma morphology, migration, and invasion , 2008, Glia.

[67]  R. Hruban,et al.  Multiple genes are hypermethylated in intraductal papillary mucinous neoplasms of the pancreas , 2008, Modern Pathology.

[68]  G. Watkins,et al.  Increased levels of SPARC (osteonectin) in human breast cancer tissues and its association with clinical outcomes. , 2005, Prostaglandins, leukotrienes, and essential fatty acids.

[69]  S. Yachida,et al.  Genetic and Epigenetic Alterations of Familial Pancreatic Cancers , 2008, Cancer Epidemiology Biomarkers & Prevention.

[70]  Mariano J. Alvarez,et al.  SPARC endogenous level, rather than fibroblast-produced SPARC or stroma reorganization induced by SPARC, is responsible for melanoma cell growth. , 2007, The Journal of investigative dermatology.

[71]  N. Said,et al.  Absence of host-secreted protein acidic and rich in cysteine (SPARC) augments peritoneal ovarian carcinomatosis. , 2005, The American journal of pathology.

[72]  E. Sage,et al.  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 , 2003, Journal of cellular biochemistry.

[73]  K. Kinzler,et al.  Genes expressed in human tumor endothelium. , 2000, Science.

[74]  E. Sage,et al.  Development of UV-induced squamous cell carcinomas is suppressed in the absence of SPARC. , 2004, The Journal of investigative dermatology.

[75]  B. le Bail,et al.  Osteonectin/SPARC is overexpressed in human hepatocellular carcinoma , 1999, The Journal of pathology.

[76]  D. Massi,et al.  Osteonectin expression correlates with clinical outcome in thin cutaneous malignant melanomas. , 1999, Human pathology.

[77]  C. Gondi,et al.  SPARC-induced migration of glioblastoma cell lines via uPA-uPAR signaling and activation of small GTPase RhoA. , 2006, International journal of oncology.

[78]  E Helene Sage,et al.  Enhanced growth of pancreatic tumors in SPARC-null mice is associated with decreased deposition of extracellular matrix and reduced tumor cell apoptosis. , 2004, Molecular cancer research : MCR.

[79]  M. Herlyn,et al.  Osteonectin/SPARC induction by ectopic beta(3) integrin in human radial growth phase primary melanoma cells. , 2002, Cancer research.

[80]  M. West,et al.  Gene expression profiling and genetic markers in glioblastoma survival. , 2005, Cancer research.

[81]  A. Charchanti,et al.  Immunohistochemical expression of extracellular matrix components tenascin, fibronectin, collagen type IV and laminin in breast cancer: their prognostic value and role in tumour invasion and progression. , 2002, European journal of cancer.

[82]  C. Iacobuzio-Donahue,et al.  Peritumoral fibroblast SPARC expression and patient outcome with resectable pancreatic adenocarcinoma. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[83]  R. Tibshirani,et al.  Gene expression profiling identifies clinically relevant subtypes of prostate cancer. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[84]  M. Pan,et al.  The Nonsteroidal Anti-Inflammatory Drug NS398 Reactivates SPARC Expression via Promoter Demethylation to Attenuate Invasiveness of Lung Cancer Cells , 2008, Experimental biology and medicine.

[85]  E. A. Everitt,et al.  SPARC, a secreted protein associated with cellular proliferation, inhibits cell spreading in vitro and exhibits Ca+2-dependent binding to the extracellular matrix , 1989, The Journal of cell biology.

[86]  N. Hogg,et al.  Integrins take partners: cross-talk between integrins and other membrane receptors. , 1998, Trends in cell biology.

[87]  David Yang,et al.  Identification of cervical cancer markers by cDNA and tissue microarrays. , 2003, Cancer research.

[88]  P. Bornstein,et al.  Thrombospondins as matricellular modulators of cell function. , 2001, The Journal of clinical investigation.

[89]  C. Streuli,et al.  Signal co-operation between integrins and other receptor systems. , 2009, The Biochemical journal.

[90]  B. Nordlinger,et al.  Overexpression of stromelysin-3, BM-40/SPARC, and MET genes in human esophageal carcinoma: implications for prognosis. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[91]  L. Ellis,et al.  The role of the microenvironment and intercellular cross-talk in tumor angiogenesis. , 2002, Seminars in cancer biology.

[92]  C. Logothetis,et al.  A secreted isoform of ErbB3 promotes osteonectin expression in bone and enhances the invasiveness of prostate cancer cells. , 2007, Cancer research.

[93]  Qiwei Yang,et al.  SPARC expression is associated with impaired tumor growth, inhibited angiogenesis and changes in the extracellular matrix , 2006, International journal of cancer.

[94]  D. Berger,et al.  The role of the tumor microenvironment in the progression of pancreatic cancer. , 2008, The Journal of surgical research.

[95]  Andy J. Minn,et al.  Genes that mediate breast cancer metastasis to lung , 2005, Nature.

[96]  H. Friess,et al.  Osteonectin Influences Growth and Invasion of Pancreatic Cancer Cells , 2005, Annals of surgery.

[97]  J. Lea,et al.  Secreted protein acidic and rich in cysteine as a regulator of murine ovarian cancer growth and chemosensitivity. , 2009, American journal of obstetrics and gynecology.

[98]  J. Koblinski,et al.  Roles of osteonectin in the migration of breast cancer cells into bone , 2006, Journal of cellular biochemistry.

[99]  Andrew H. Beck,et al.  The fibromatosis signature defines a robust stromal response in breast carcinoma , 2008, Laboratory Investigation.

[100]  E. Sage,et al.  The Copper Binding Domain of SPARC Mediates Cell Survival in Vitro via Interaction with Integrin β1 and Activation of Integrin-linked Kinase* , 2008, Journal of Biological Chemistry.

[101]  V. Castronovo,et al.  Increased expression of osteonectin and osteopontin, two bone matrix proteins, in human breast cancer. , 1995, The American journal of pathology.

[102]  D. Stanimirovic,et al.  Molecular markers of extracellular matrix remodeling in glioblastoma vessels: Microarray study of laser‐captured glioblastoma vessels , 2007, Glia.

[103]  S. Mok,et al.  Aberrant promoter methylation of SPARC in ovarian cancer. , 2009, Neoplasia.

[104]  M. Reed,et al.  Differential expression of SPARC and thrombospondin 1 in wound repair: immunolocalization and in situ hybridization. , 1993, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[105]  Keith March,et al.  IFATS Collection: Combinatorial Peptides Identify α5β1 Integrin as a Receptor for the Matricellular Protein SPARC on Adipose Stromal Cells , 2008, Stem cells.

[106]  Chin-Tarng Lin,et al.  Transcription factor SOX‐5 enhances nasopharyngeal carcinoma progression by down‐regulating SPARC gene expression , 2007, The Journal of pathology.

[107]  J. Beaulieu,et al.  Expression of SPARC/osteonectin/BM4O in the human gut: Predominance in the stroma of the remodeling distal intestine , 2001, Journal of cellular biochemistry.

[108]  Julie A. Wilkins,et al.  Deficiency of SPARC suppresses intestinal tumorigenesis in APCMin/+ mice , 2007, Gut.

[109]  H. Juan,et al.  Molecular signatures of metaplastic carcinoma of the breast by large-scale transcriptional profiling: identification of genes potentially related to epithelial–mesenchymal transition , 2007, Oncogene.

[110]  N. Hu,et al.  Tissue microarray analysis reveals a tight correlation between protein expression pattern and progression of esophageal squamous cell carcinoma , 2006, BMC Cancer.

[111]  D. Bigner,et al.  Secreted Protein Acidic, Rich in Cysteine (SPARC), Mediates Cellular Survival of Gliomas through AKT Activation* , 2004, Journal of Biological Chemistry.

[112]  F. Rödel,et al.  Stromal SPARC expression and patient survival after chemoradiation for non-resectable pancreatic adenocarcinoma , 2008, Cancer biology & therapy.

[113]  Qiwei Yang,et al.  Neuroblastoma Angiogenesis Is Inhibited with a Folded Synthetic Molecule Corresponding to the Epidermal Growth Factor-Like Module of the Follistatin Domain of SPARC , 2004, Cancer Research.

[114]  R. Moll,et al.  Stromal remodeling and SPARC (secreted protein acid rich in cysteine) expression in invasive ductal carcinomas of the breast , 2005, Virchows Archiv.

[115]  W. Couser,et al.  SPARC Regulates the Expression of Collagen Type I and Transforming Growth Factor-β1 in Mesangial Cells* , 1999, The Journal of Biological Chemistry.

[116]  F. Sarkar,et al.  Increased osteonectin expression is associated with malignant transformation and tumor associated fibrosis in the lung. , 2004, Lung cancer.

[117]  E. Sage,et al.  Primary mesenchymal cells isolated from SPARC-null mice exhibit altered morphology and rates of proliferation. , 1999, Molecular biology of the cell.

[118]  F. Verrecchia,et al.  Transforming growth factor-beta and fibrosis. , 2007, World journal of gastroenterology.

[119]  D. Owen,et al.  Genome-wide expression analysis of therapy-resistant tumors reveals SPARC as a novel target for cancer therapy. , 2005, The Journal of clinical investigation.

[120]  Y. Doki,et al.  Integrative approach for differentially overexpressed genes in gastric cancer by combining large-scale gene expression profiling and network analysis , 2008, British Journal of Cancer.

[121]  S. Sleijfer,et al.  Association of an Extracellular Matrix Gene Cluster with Breast Cancer Prognosis and Endocrine Therapy Response , 2008, Clinical Cancer Research.

[122]  H. Kleinman,et al.  The basement membrane matrix in malignancy , 2003, The Journal of pathology.

[123]  P. Parsons,et al.  Novel markers for poor prognosis in head and neck cancer , 2005, International journal of cancer.

[124]  K. Wakamatsu,et al.  Highly Sensitive Detection of Melanoma at an Early Stage Based on the Increased Serum Secreted Protein Acidic and Rich in Cysteine and Glypican-3 Levels , 2005, Clinical Cancer Research.

[125]  D. Stupack.  The biology of integrins. , 2007, Oncology.

[126]  A. Bosserhoff,et al.  Snail-regulated genes in malignant melanoma , 2005, Melanoma research.

[127]  G. Ivy,et al.  SPARC/Osteonectin mRNA Is Induced in Blood Vessels Following Injury to the Adult Rat Cerebral Cortex , 1998, Neurochemical Research.

[128]  Yoshiyuki Sakaki,et al.  Osteonectin-expressing cells in human stomach cancer and their possible clinical significance. , 2002, Cancer letters.

[129]  M. Young,et al.  Osteonectin/SPARC/BM-40 in human decidua and carcinoma, tissues characterized by de novo formation of basement membrane. , 1988, The American journal of pathology.

[130]  I. Kovalszky,et al.  Proteoglycans and tumor progression: Janus-faced molecules with contradictory functions in cancer. , 2002, Seminars in cancer biology.

[131]  R L Vessella,et al.  Differential expression of osteonectin/SPARC during human prostate cancer progression. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[132]  C. Streuli.  Integrins and cell-fate determination , 2009, Journal of Cell Science.

[133]  M. Reed,et al.  Increased fibrovascular invasion of subcutaneous polyvinyl alcohol sponges in SPARC‐null mice , 2001, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[134]  D. Bigner,et al.  Bone-related Genes Expressed in Advanced Malignancies Induce Invasion and Metastasis in a Genetically Defined Human Cancer Model* , 2003, The Journal of Biological Chemistry.

[135]  G. Geiss,et al.  Discovery of Novel Methylation Biomarkers in Cervical Carcinoma by Global Demethylation and Microarray Analysis , 2006, Cancer Epidemiology Biomarkers & Prevention.

[136]  Ivan Stamenkovic,et al.  Functional structure and composition of the extracellular matrix , 2003, The Journal of pathology.

[137]  J. Foidart,et al.  High production of SPARC/osteonectin/BM-40 in mouse metastatic B16 melanoma cell lines , 2009, Pathology Oncology Research.

[138]  T. Mikkelsen,et al.  SPARC: a signal of astrocytic neoplastic transformation and reactive response in human primary and xenograft gliomas. , 1998, Journal of neuropathology and experimental neurology.

[139]  H. Dvorak.  Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. , 1986, The New England journal of medicine.

[140]  N. Said,et al.  Normalization of the Ovarian Cancer Microenvironment by SPARC , 2007, Molecular Cancer Research.

[141]  Kenneth M. Yamada,et al.  The matrix reorganized: extracellular matrix remodeling and integrin signaling. , 2006, Current opinion in cell biology.

[142]  Elise C. Kohn,et al.  The microenvironment of the tumour–host interface , 2001, Nature.

[143]  H. Auer,et al.  Tissue-Wide Expression Profiling Using cDNA Subtraction and Microarrays to Identify Tumor-Specific Genes , 2004, Cancer Research.

[144]  P. Higgins,et al.  Modulation of SPARC expression during butyrate-induced terminal differentiation of cultured human keratinocytes: regulation via a TGF-beta-dependent pathway. , 1993, Experimental cell research.

[145]  Sanjay Kumar,et al.  Mechanics, malignancy, and metastasis: The force journey of a tumor cell , 2009, Cancer and Metastasis Reviews.

[146]  M. Ringuette,et al.  Activation of SPARC expression in reactive stroma associated with human epithelial ovarian cancer. , 1999, Gynecologic oncology.

[147]  P. Pavasant,et al.  The synergistic effect of TGF-beta and 1,25-dihydroxyvitamin D3 on SPARC synthesis and alkaline phosphatase activity in human pulp fibroblasts. , 2003, Archives of oral biology.

[148]  S. Ethier,et al.  Identification of gene expression profiles that predict the aggressive behavior of breast cancer cells. , 2001, Cancer research.

[149]  R. Brekken,et al.  SPARC, a matricellular protein: at the crossroads of cell-matrix communication. , 2001, Matrix biology : journal of the International Society for Matrix Biology.

[150]  B. Eliceiri.  This Review is part of a thematic series on Integrins, which includes the following articles: Integrins and the Myocardium Functional Consequences of Integrin Gene Mutations in Mice Integrins in Vascular Development Integrin and Growth Factor Receptor Crosstalk , 2001 .

[151]  E. Sage,et al.  SPARC (BM-40, Osteonectin) Inhibits the Mitogenic Effect of Vascular Endothelial Growth Factor on Microvascular Endothelial Cells* , 1998, The Journal of Biological Chemistry.

[152]  R. Ross,et al.  The extracellular glycoprotein SPARC interacts with platelet-derived growth factor (PDGF)-AB and -BB and inhibits the binding of PDGF to its receptors. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[153]  K. Mimori,et al.  Prognostic score of gastric cancer determined by cDNA microarray. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[154]  T. Yeatman,et al.  Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer , 2007, Genome Biology.

[155]  강현주,et al.  Frequent inactivation of SPARC by promoter hypermethylation in colon cancers , 2007 .

[156]  K. Klinger,et al.  Alterations in Vascular Gene Expression in Invasive Breast Carcinoma , 2004, Cancer Research.

[157]  Kornelia Polyak,et al.  Molecular markers in ductal carcinoma in situ of the breast. , 2003, Molecular cancer research : MCR.

[158]  K. Gustafson,et al.  Quantitative methylation‐specific PCR for the detection of aberrant DNA methylation in liquid‐based Pap tests , 2008, Cancer.

[159]  Gema Moreno-Bueno,et al.  Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. , 2008, Cancer research.

[160]  Yoshiyuki Sakaki,et al.  Appearance of Osteonectin‐expressing Fibroblastic Cells in Early Rat Stomach Carcinogenesis and Stomach Tumors Induced with N‐Methyl‐N′‐nitro‐N‐nitrosoguanidine , 2002, Japanese journal of cancer research : Gann.

[161]  M. Webber,et al.  Osteonectin promotes prostate cancer cell migration and invasion: a possible mechanism for metastasis to bone. , 1999, Cancer research.

[162]  H. Kanayama,et al.  Analysis of the gene expression of SPARC and its prognostic value for bladder cancer. , 2001, The Journal of urology.

[163]  E Helene Sage,et al.  Enhanced expression of SPARC/osteonectin in the tumor-associated stroma of non-small cell lung cancer is correlated with markers of hypoxia/acidity and with poor prognosis of patients. , 2003, Cancer research.

[164]  Y. Nagashima,et al.  Expression of SPARC in tongue carcinoma of stage II is associated with poor prognosis: an immunohistochemical study of 86 cases. , 2005, International journal of molecular medicine.

[165]  S Hsueh,et al.  Overexpression of SPARC gene in human gastric carcinoma and its clinic–pathologic significance , 2004, British Journal of Cancer.

[166]  John I. Clark,et al.  Alterations in the lens capsule contribute to cataractogenesis in SPARC-null mice. , 2002, Journal of cell science.

[167]  G. Schultz,et al.  Interactions between extracellular matrix and growth factors in wound healing , 2009, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[168]  R. Berkowitz,et al.  SPARC, an extracellular matrix protein with tumor-suppressing activity in human ovarian epithelial cells. , 1996, Oncogene.

[169]  A. Raz,et al.  SPARC upregulates MT1-MMP expression, MMP-2 activation, and the secretion and cleavage of galectin-3 in U87MG glioma cells , 2007, Neuroscience Letters.

[170]  O. Podhajcer,et al.  The expression of the secreted protein acidic and rich in cysteine (SPARC) is associated with the neoplastic progression of human melanoma. , 1997, The Journal of investigative dermatology.

[171]  R. Hruban,et al.  SPARC/osteonectin is a frequent target for aberrant methylation in pancreatic adenocarcinoma and a mediator of tumor–stromal interactions , 2003, Oncogene.

[172]  S. Cohn,et al.  SPARC enhances tumor stroma formation and prevents fibroblast activation , 2007, Oncogene.

[173]  Gong Yang,et al.  The inflammatory network: bridging senescent stroma and epithelial tumorigenesis. , 2009, Frontiers in bioscience.

[174]  S. Rempel,et al.  SPARC: a potential diagnostic marker of invasive meningiomas. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[175]  M. Reed,et al.  SPARC-null Mice Exhibit Accelerated Cutaneous Wound Closure , 2002, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[176]  Jonas S. Almeida,et al.  Accurate Discrimination of Barrett's Esophagus and Esophageal Adenocarcinoma Using a Quantitative Three-Tiered Algorithm and Multimarker Real-time Reverse Transcription-PCR , 2005, Clinical Cancer Research.

[177]  Kai Stühler,et al.  Tumor suppressor Smad4 mediates downregulation of the anti‐adhesive invasion‐promoting matricellular protein SPARC: Landscaping activity of Smad4 as revealed by a “secretome” analysis , 2004, Proteomics.

[178]  D. Owen,et al.  SPARC promoter hypermethylation in colorectal cancers can be reversed by 5-Aza-2′deoxycytidine to increase SPARC expression and improve therapy response , 2008, British Journal of Cancer.

[179]  Maozhen Tian,et al.  The TGF-beta paradox in human cancer: an update. , 2009, Future oncology.

[180]  A. Nakeff,et al.  SPARC Modulates Cell Growth, Attachment and Migration of U87 Glioma Cells on Brain Extracellular Matrix Proteins , 2001, Journal of Neuro-Oncology.

[181]  T. Whiteside.  The tumor microenvironment and its role in promoting tumor growth , 2008, Oncogene.

[182]  Chi-Ying F. Huang,et al.  Combination of microarray profiling and protein-protein interaction databases delineates the minimal discriminators as a metastasis network for esophageal squamous cell carcinoma. , 2009, International journal of oncology.

[183]  M. Colombo,et al.  Macrophage-derived SPARC bridges tumor cell-extracellular matrix interactions toward metastasis. , 2008, Cancer research.

[184]  J. Pollard,et al.  Microenvironmental regulation of metastasis , 2009, Nature Reviews Cancer.

[185]  Mark A. Rubin,et al.  Expression profiling of human renal carcinomas with functional taxonomic analysis , 2002, BMC Bioinformatics.

[186]  A. Gown,et al.  Alterations in SPARC and VEGF immunoreactivity in epithelial ovarian cancer. , 2000, Gynecologic oncology.

[187]  P. Bornstein.  Cell-matrix interactions: the view from the outside. , 2002, Methods in cell biology.

[188]  T. Mikkelsen,et al.  Increased SPARC expression promotes U87 glioblastoma invasion in vitro , 1999, International Journal of Developmental Neuroscience.

[189]  T. Byzova,et al.  Molecular Pathway for Cancer Metastasis to Bone* , 2003, Journal of Biological Chemistry.

[190]  T. Takano,et al.  Quantitative analysis of osteonectin mRNA in thyroid carcinomas. , 2002, Endocrine journal.

[191]  M. Reed,et al.  Induction of TGF-beta1 by the matricellular protein SPARC in a rat model of glomerulonephritis. , 2000, Kidney international.

[192]  P. Chambon,et al.  Neoplastic progression of human colorectal cancer is associated with overexpression of the stromelysin‐3 and BM‐40/SPARC genes , 1995, International journal of cancer.

[193]  M. Castellazzi,et al.  Transcriptional upregulation of SPARC, in response to c-Jun overexpression, contributes to increased motility and invasion of MCF7 breast cancer cells , 2002, Oncogene.

[194]  G. Pagès,et al.  Gene expression profiling of normal human pulmonary fibroblasts following coculture with non-small-cell lung cancer cells reveals alterations related to matrix degradation, angiogenesis, cell growth and survival , 2003, Oncogene.

[195]  Yajun Yi,et al.  Molecular Alterations in Primary Prostate Cancer after Androgen Ablation Therapy , 2005, Clinical Cancer Research.

[196]  N. Futran,et al.  Examination of oral cancer biomarkers by tissue microarray analysis. , 2008, Archives of otolaryngology--head & neck surgery.

[197]  J. Casal,et al.  Proteomics-based Validation of Genomic Data , 2006, Molecular & Cellular Proteomics.

[198]  T. Sørlie,et al.  Extracellular matrix signature identifies breast cancer subgroups with different clinical outcome , 2008, The Journal of pathology.

[199]  R. Tibshirani,et al.  Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. , 2004, The New England journal of medicine.

[200]  D. Bigner,et al.  Targeting SPARC expression decreases glioma cellular survival and invasion associated with reduced activities of FAK and ILK kinases , 2007, Oncogene.

[201]  M. Reed,et al.  TGF‐β1 induces the expression of type I collagen and SPARC, and enhances contraction of collagen gels, by fibroblasts from young and aged donors , 1994 .

[202]  Mariano J. Alvarez,et al.  Secreted protein acidic and rich in cysteine produced by human melanoma cells modulates polymorphonuclear leukocyte recruitment and antitumor cytotoxic capacity. , 2005, Cancer research.

[203]  J. Ambati,et al.  Loss of SPARC-mediated VEGFR-1 suppression after injury reveals a novel antiangiogenic activity of VEGF-A. , 2006, The Journal of clinical investigation.

[204]  J. Nährig,et al.  Identification of gene signatures for invasive colorectal tumor cells. , 2007, Cancer detection and prevention.

[205]  U. Shankavaram,et al.  Regulation of human monocyte matrix metalloproteinases by SPARC , 1997, Journal of cellular physiology.

[206]  O. Volpert,et al.  SPARC is a key Schwannian-derived inhibitor controlling neuroblastoma tumor angiogenesis. , 2002, Cancer research.

[207]  Andrea S. Llera,et al.  The role of the matricellular protein SPARC in the dynamic interaction between the tumor and the host , 2008, Cancer and Metastasis Reviews.

[208]  W. Stolz,et al.  Identification of differentially expressed genes in models of melanoma progression by cDNA array analysis: SPARC, MIF and a novel cathepsin protease characterize aggressive phenotypes , 2003, Experimental dermatology.

[209]  Giulio Gabbiani,et al.  The stroma reaction myofibroblast: a key player in the control of tumor cell behavior. , 2004, The International journal of developmental biology.

[210]  C. Gutschow,et al.  Significant overexpression of SPARC/osteonectin mRNA in pancreatic cancer compared to cancer of the papilla of Vater. , 2006, Oncology reports.

[211]  N. Wernert.  The multiple roles of tumour stroma , 1997, Virchows Archiv.

[212]  M. Colombo,et al.  Leukocyte, Rather than Tumor-produced SPARC, Determines Stroma and Collagen Type IV Deposition in Mammary Carcinoma , 2003, The Journal of experimental medicine.

[213]  Klaus Pantel,et al.  Molecular signature associated with bone marrow micrometastasis in human breast cancer. , 2003, Cancer research.

[214]  Zhihua Liu,et al.  The differential expression of SPARC in esophageal squamous cell carcinoma. , 2006, International journal of molecular medicine.

[215]  Alan Mackay,et al.  Expression profiling of purified normal human luminal and myoepithelial breast cells: identification of novel prognostic markers for breast cancer. , 2004, Cancer research.

[216]  R. Brekken,et al.  Forced Expression of MMP9 Rescues the Loss of Angiogenesis and Abrogates Metastasis of Pancreatic Tumors Triggered by the Absence of Host SPARC , 2008, Experimental biology and medicine.

[217]  John I. Clark,et al.  Expression of the Matricellular Protein SPARC in Murine Lens: SPARC Is Necessary for the Structural Integrity of the Capsular Basement Membrane , 2003, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[218]  A. Olshen,et al.  Insights into extramedullary tumour cell growth revealed by expression profiling of human plasmacytomas and multiple myeloma , 2003, British journal of haematology.

[219]  T. Sasaki,et al.  Immunochemical and tissue analysis of protease generated neoepitopes of BM-40 (osteonectin, SPARC) which are correlated to a higher affinity binding to collagens. , 1999, Matrix biology : journal of the International Society for Matrix Biology.