Leukocyte, Rather than Tumor-produced SPARC, Determines Stroma and Collagen Type IV Deposition in Mammary Carcinoma

Secreted protein, acidic and rich in cysteine (SPARC), also known as osteonectin or BM-40, is a Ca2+-binding matricellular glycoprotein involved in development, wound healing, and neoplasia. However, the role of SPARC in tumors is ill defined mostly because it is expressed by both tumor and stromal cells, especially inflammatory cells. We analyzed the respective roles of host- and tumor-derived SPARC in wild-type and congenic SPARC knockout (SPARC−/−) mice on a BALB/c genetic background injected into the mammary fat pad with SPARC-producing mammary carcinoma cells derived from c-erB2 transgenic BALB/c mice. Reduced tumor growth but massive parenchyma infiltration, with large areas of necrosis and impaired vascularization were observed in SPARC−/− mice. Immunohistochemical analysis showed a defect in collagen type IV deposition in the stroma of lobular tumors from SPARC−/− mice. Chimeric mice expressing SPARC only in bone marrow–derived cells were able to organize peritumoral and perilobular stroma, whereas reciprocal chimeras transplanted with bone marrow from SPARC−/− mice developed tumors with less defined lobular structures, lacking assembled collagen type IV and with a parenchyma heavily infiltrated by leukocytes. Together, the data indicate that SPARC produced by host leukocytes, rather than the tumor, determines the assembly and function of tumor-associated stroma through the organization of collagen type IV.

[1]  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.

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

[3]  R. Hynes,et al.  Physiological levels of tumstatin, a fragment of collagen IV alpha3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via alphaV beta3 integrin. , 2003, Cancer cell.

[4]  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.

[5]  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.

[6]  M. Nishimura,et al.  Increasing tumor antigen expression overcomes "ignorance" to solid tumors via crosspresentation by bone marrow-derived stromal cells. , 2002, Immunity.

[7]  G. Fleuren,et al.  Transforming growth factor-beta1 induces tumor stroma and reduces tumor infiltrate in cervical cancer. , 2002, Human pathology.

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

[9]  I. Fidler,et al.  Contributions of stromal metalloproteinase-9 to angiogenesis and growth of human ovarian carcinoma in mice. , 2002, Journal of the National Cancer Institute.

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

[11]  Zena Werb,et al.  Stromal Effects on Mammary Gland Development and Breast Cancer , 2002, Science.

[12]  G. Schuler,et al.  Matrix Metalloproteinases 9 and 2 Are Necessary for the Migration of Langerhans Cells and Dermal Dendritic Cells from Human and Murine Skin1 , 2002, The Journal of Immunology.

[13]  M. Ringuette,et al.  Evolutionary conservation and association of SPARC with the basal lamina in Drosophila , 2002, Development Genes and Evolution.

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

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

[16]  Andrew V. Nguyen,et al.  Colony-Stimulating Factor 1 Promotes Progression of Mammary Tumors to Malignancy , 2001, The Journal of experimental medicine.

[17]  Alberto Mantovani,et al.  Inflammation and cancer: back to Virchow? , 2001, The Lancet.

[18]  P. Musiani,et al.  The intriguing role of polymorphonuclear neutrophils in antitumor reactions. , 2001, Blood.

[19]  L. Coussens,et al.  Inflammatory Cells and Cancer: Think Different! , 2001 .

[20]  K. Miyazaki,et al.  Abnormal distribution of collagen type IV in extrahepatic bile duct carcinoma , 2000, Pathology international.

[21]  D. Hanahan,et al.  MMP-9 Supplied by Bone Marrow–Derived Cells Contributes to Skin Carcinogenesis , 2000, Cell.

[22]  L. Camardella,et al.  Trimer Carboxyl Propeptide of Collagen I Produced by Mature Osteoblasts Is Chemotactic for Endothelial Cells* , 2000, The Journal of Biological Chemistry.

[23]  J. Tonn,et al.  Targeting angiogenesis inhibits tumor infiltration and expression of the pro‐invasive protein SPARC , 2000, International journal of cancer.

[24]  M. Amling,et al.  Osteopenia and decreased bone formation in osteonectin-deficient mice , 2000, The Journal of clinical investigation.

[25]  M. Castellazzi,et al.  Down-regulation of the extracellular matrix protein SPARC in vSrc- and vJun-transformed chick embryo fibroblasts contributes to tumor formation in vivo , 2000, Oncogene.

[26]  G. Fantuzzi,et al.  IL-18 regulates IL-1beta-dependent hepatic melanoma metastasis via vascular cell adhesion molecule-1. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[27]  E. Sage,et al.  SPARC, a Matricellular Glycoprotein with Important Biological Functions , 1999, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[28]  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.

[29]  P. Musiani,et al.  Analysis of mammary carcinoma onset and progression in HER-2/neu oncogene transgenic mice reveals a lobular origin. , 1999, Laboratory investigation; a journal of technical methods and pathology.

[30]  G. Yancopoulos,et al.  New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF , 1999, Oncogene.

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

[32]  G. Kollias,et al.  Mice deficient in tumor necrosis factor-α are resistant to skin carcinogenesis , 1999, Nature Medicine.

[33]  C C Howe,et al.  Disruption of the Sparc locus in mice alters the differentiation of lenticular epithelial cells and leads to cataract formation. , 1999, Experimental eye research.

[34]  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.

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

[36]  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.

[37]  D. Hanahan,et al.  Tumor microenvironment can restrict the effectiveness of activated antitumor lymphocytes. , 1998, Cancer research.

[38]  Piero Musiani,et al.  Interleukin 12–mediated Prevention of Spontaneous Mammary Adenocarcinomas in Two Lines of Her-2/neu Transgenic Mice , 1998, The Journal of experimental medicine.

[39]  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.

[40]  Gomes Mc Population aging and forms of residence in Mexico , 1997 .

[41]  R. Timpl,et al.  Differential modulation of cell adhesion by interaction between adhesive and counter-adhesive proteins: characterization of the binding of vitronectin to osteonectin (BM40, SPARC). , 1997, The Biochemical journal.

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

[43]  E. Sage Terms of attachment: SPARC and tumorigenesis , 1997, Nature Medicine.

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

[45]  W. Wiktor-Jedrzejczak,et al.  Impaired tumor growth in colony‐stimulating factor 1 (CSF‐1)‐deficient, macrophage‐deficient op/op mouse: Evidence for a role of CSF‐1‐dependent macrophages in formation of tumor stroma , 1996, International journal of cancer.

[46]  S. Hauser,et al.  Stimulus specificity of matrix metalloproteinase dependence of human T cell migration through a model basement membrane. , 1996, Journal of immunology.

[47]  E. Waubant,et al.  T cell gelatinases mediate basement membrane transmigration in vitro. , 1995, Journal of immunology.

[48]  P. Vernier,et al.  SPARC and thrombospondin genes are repressed by the c‐jun oncogene in rat embryo fibroblasts. , 1994, The EMBO journal.

[49]  R. Berkowitz,et al.  Molecular cloning of differentially expressed genes in human epithelial ovarian cancer. , 1994, Gynecologic oncology.

[50]  M. Colombo,et al.  Regression of an established tumor genetically modified to release granulocyte colony-stimulating factor requires granulocyte-T cell cooperation and T cell-produced interferon gamma , 1993, The Journal of experimental medicine.

[51]  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.

[52]  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.

[53]  R. Timpl,et al.  Calcium-dependent binding of basement membrane protein BM-40 (osteonectin, SPARC) to basement membrane collagen type IV. , 1991, European journal of biochemistry.

[54]  M. Iruela-Arispe,et al.  Differential expression of extracellular proteins is correlated with angiogenesis in vitro. , 1991, Laboratory investigation; a journal of technical methods and pathology.

[55]  M. Colombo,et al.  Down-regulation of SPARC/osteonectin/BM-40 expression in methylcholanthrene-induced fibrosarcomas and in Kirsten-MSV transformed fibroblasts. , 1991, European journal of cancer.

[56]  W. Wiktor-Jedrzejczak,et al.  Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[57]  S. Nishikawa,et al.  The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene , 1990, Nature.

[58]  P. Delmas,et al.  Complex formation of human thrombospondin with osteonectin. , 1988, European journal of biochemistry.

[59]  B. Hogan,et al.  Molecular analysis of the cDNA for human SPARC/osteonectin/BM-40: sequence, expression, and localization of the gene to chromosome 5q31-q33. , 1988, Genomics.

[60]  S. Segal,et al.  An immune response against the alloantigens of the 3LL Lewis lung carcinoma prevents the growth of lung metastases, but not of local allografts. , 1982, Invasion and Metastasis.

[61]  I. Gresser,et al.  Inhibition by interferon preparations of a solid malignant tumour and pulmonary metastasis in mice. , 1972, Nature: New biology.

[62]  A. Zuckerman,et al.  Australia Antigen as a Marker of Propagation of the Serum Hepatitis Virus in Liver Cultures , 1972, Nature.

[63]  G. Sheline,et al.  THE ELIMINATION OF ADMINISTERED ZINC IN PANCREATIC JUICE, DUODENAL JUICE, AND BILE OF THE DOG AS MEASURED BY ITS RADIOACTIVE ISOTOPE (Zn65) , 1943, Journal of Experimental Medicine.

[64]  James Gane CASE OF CHOLERA SPASMODICA, TENDING TO PROVE THE EXISTENCE OF AN EPIDEMIC DISEASE IN ENGLAND,: SIMILAR TO THE INDIAN CHOLERA, BUT ENTIRELY UNCONNECTED WITH THAT PESTILENCE , 1832 .