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The cell surface heparan sulfate proteoglycan syndecan-1 is induced in stromal fibroblasts of breast carcinomas and participates in a reciprocal feedback loop, which stimulates carcinoma cell growth in vitro and in vivo. To define the molecular mechanism of carcinoma growth stimulation, a three-dimensional co-culture model was developed that combines T47D breast carcinoma cells with immortalized human mammary fibroblasts in collagen gels. By silencing endogenous syndecan-1 induction with short interfering RNA and expressing mutant murine syndecan-1 constructs, it was determined that carcinoma cell mitogenesis required proteolytic shedding of syndecan-1 from the fibroblast surface. The paracrine growth signal was mediated by the syndecan-1 heparan lfate chains rather than the ectodomain of the core protein and required fibroblast growth factor 2 and stroma-derived factor 1. This paracrine pathway may provide an opportunity for the therapeutic disruption of stromaepithelial signaling. The cell surface heparan sulfate proteoglycan syndecan-1 is induced in stromal fibroblasts of breast carcinomas and participates in a reciprocal feedback loop, which stimulates carcinoma cell growth in vitro and in vivo. To define the molecular mechanism of carcinoma growth stimulation, a three-dimensional co-culture model was developed that combines T47D breast carcinoma cells with immortalized human mammary fibroblasts in collagen gels. By silencing endogenous syndecan-1 induction with short interfering RNA and expressing mutant murine syndecan-1 constructs, it was determined that carcinoma cell mitogenesis required proteolytic shedding of syndecan-1 from the fibroblast surface. The paracrine growth signal was mediated by the syndecan-1 heparan lfate chains rather than the ectodomain of the core protein and required fibroblast growth factor 2 and stroma-derived factor 1. This paracrine pathway may provide an opportunity for the therapeutic disruption of stromaepithelial signaling. The mammary epithelium and stromal elements co-evolve during cancer development. As the carcinoma progresses, stromal fibroblasts are recruited, and their phenotype is altered through the action of growth factors and cytokines. The resulting tumor-associated stroma is recognized by pathologists as desmoplasia and forms a permissive and supportive environment for tumor growth (1Liotta L.A. Kohn E.C. Nature. 2001; 411: 375-379Crossref PubMed Scopus (2050) Google Scholar). Compared with normal stromal fibroblasts, breast carcinoma-associated fibroblasts display distinct gene expression and phenotypic changes (2Hornby A.E. Cullen K.J. Exs (Basel). 1995; 74: 249-271PubMed Google Scholar, 3Hu M. Yao J. Cai L. Bachman K.E. van den Brule F. Velculescu V. Polyak K. Nat. Genet. 2005; 37: 899-905Crossref PubMed Scopus (439) Google Scholar, 4Allinen M. Beroukhim R. Cai L. Brennan C. Lahti-Domenici J. Huang H. Porter D. Hu M. Chin L. Richardson A. Schnitt S. Sellers W.R. Polyak K. Cancer Cell. 2004; 6: 17-32Abstract Full Text Full Text PDF PubMed Scopus (1051) Google Scholar). In turn, carcinoma-associated fibroblasts modify the growth, differentiation, and invasive behavior of carcinoma cells (5Bissell M.J. Radisky D. Nat. Rev. Cancer. 2001; 1: 46-54Crossref PubMed Scopus (1745) Google Scholar, 6Tlsty T.D. Semin. Cancer Biol. 2001; 11: 97-104Crossref PubMed Scopus (243) Google Scholar). Breast stromal fibroblasts can modulate carcinoma cell proliferation both in vitro and in vivo (7Sadlonova A. Novak Z. Johnson M.R. Bowe D.B. Gault S.R. Page G.P. Thottassery J.V. Welch D.R. Frost A.R. Breast Cancer Res. 2005; 7: R46-R59Crossref PubMed Google Scholar, 8Brouty-Boye D. Raux H. Anticancer Res. 1993; 13: 1087-1090PubMed Google Scholar). The emerging picture implicates soluble paracrine growth factors and extracellular matrix components in stroma-to-carcinoma cell signaling, but our understanding of these reciprocal pathways is presently incomplete. We and others have recently observed a dramatic overexpression of the cell surface heparan sulfate proteoglycan (HSPG) 2The abbreviations used are: HSPG, heparan sulfate proteoglycan; HMF, human mammary fibroblasts; G6PDH, glyceraldehyde-6-phosphate dehydrogenase; RT, reverse transcription; GFP, green fluorescent protein; siRNA, short interfering RNA; PBS, phosphate-buffered saline; m.o.i., multiplicity of infection; CSGAG, chondroitin sulfate glycosaminoglycan; FACS, fluorescence-activated cell sorter; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; GAG, glycosaminoglycan; FGF, fibroblast growth factor; FGFR, FGF receptor; RPE, (R)-phycoerythrin; MMP, matrix metalloprotease; m, murine; WT, wild type. syndecan-1 (Sdc1) in stromal fibroblasts of invasive breast carcinomas (9Stanley M.J. Stanley M.W. Sanderson R.D. Zera R. Am. J. Clin. Pathol. 1999; 112: 377-383Crossref PubMed Scopus (122) Google Scholar, 10Maeda T. Alexander C.M. Friedl A. Cancer Res. 2004; 64: 612-621Crossref PubMed Scopus (117) Google Scholar). Sdc1 consists of an extracellular domain carrying heparan sulfate glycosaminoglycan (HSGAG) and chondroitin sulfate glycosaminoglycan (CSGAG), a transmembrane domain and a cytoplasmic domain. The biological functions of Sdc1 are not fully understood, but co-receptor roles in signaling of HSGAG-dependent growth factors and in cell adhesion events are well documented. Most of these activities are mediated through the HSGAG chains, but core protein-specific functions have also been described (11Bernfield M. Gotte M. Park P.W. Reizes O. Fitzgerald M.L. Lincecum J. Zako M. Annu. Rev. Biochem. 1999; 68: 729-777Crossref PubMed Scopus (2332) Google Scholar, 12Beauvais D.M. Burbach B.J. Rapraeger A.C. J. Cell Biol. 2004; 167: 171-181Crossref PubMed Scopus (203) Google Scholar). The Sdc1 ectodomain can be shed from the cell surface by proteolytic cleavage at a juxtamembrane site (13Fitzgerald M.L. Wang Z. Park P.W. Murphy G. Bernfield M. J. Cell Biol. 2000; 148: 811-824Crossref PubMed Scopus (348) Google Scholar). The shed Sdc1 ectodomain retains its biologically active heparan sulfate chains and has been found to promote growth of myeloma tumors in vivo (14Yang Y. Yaccoby S. Liu W. Langford J.K. Pumphrey C.Y. Theus A. Epstein J. Sanderson R.D. Blood. 2002; 100: 610-617Crossref PubMed Scopus (163) Google Scholar). Syndecan-1 is normally expressed in many types of epithelia and plasma cells. Mesenchymal Sdc1 expression has been observed during the development of various organ systems and pathologically in stromal fibroblasts of several carcinoma types (9Stanley M.J. Stanley M.W. Sanderson R.D. Zera R. Am. J. Clin. Pathol. 1999; 112: 377-383Crossref PubMed Scopus (122) Google Scholar, 15Vainio S. Lehtonen E. Jalkanen M. Bernfield M. Saxen L. Dev. Biol. 1989; 134: 382-391Crossref PubMed Scopus (119) Google Scholar, 16Solursh M. Reiter R.S. Jensen K.L. Kato M. Bernfield M. Dev. Biol. 1990; 140: 83-92Crossref PubMed Scopus (92) Google Scholar, 17Mukunyadzi P. Liu K. Hanna E.Y. Suen J.Y. Fan C.Y. Mod. Pathol. 2003; 16: 796-801Crossref PubMed Scopus (43) Google Scholar, 18Mathe M. Suba Z. Nemeth Z. Tatrai P. Fule T. Borgulya G. Barabas J. Kovalszky I. Oral Oncol. 2006; 42: 493-500Crossref PubMed Scopus (35) Google Scholar). Sdc1 expression in carcinoma-associated fibroblasts is seen in the majority of infiltrating breast carcinomas and resembles Sdc1 induction in fibroblasts surrounding terminal end buds during mouse mammary gland development (9Stanley M.J. Stanley M.W. Sanderson R.D. Zera R. Am. J. Clin. Pathol. 1999; 112: 377-383Crossref PubMed Scopus (122) Google Scholar). This suggests that Sdc1 is involved in the reactivation of an oncofetal signaling pathway in breast carcinomas. Our previous study has demonstrated that highly invasive MDA-MB-231 breast carcinoma cells induce Sdc1 expression in fibroblasts in a two-dimensional co-culture system and that Sdc1 overexpression in fibroblasts promotes cancer cell proliferation (10Maeda T. Alexander C.M. Friedl A. Cancer Res. 2004; 64: 612-621Crossref PubMed Scopus (117) Google Scholar). The stimulating effect of stromal Sdc1 on mammary tumor cell growth has also been confirmed in vivo. Using mixed fibroblast-carcinoma cell xenografts, we have observed that forced expression of Sdc1 in fibroblasts promotes tumor growth and tumor angiogenesis (19Maeda T. Desouky J. Friedl A. Oncogene. 2006; 25: 1408-1412Crossref PubMed Scopus (120) Google Scholar). Although these studies have advanced our understanding of the importance of HSPGs in epithelial-stromal interactions, they also pose a series of new questions regarding the requirement of specific Sdc1 molecular domains and the molecular mechanisms involved. To maintain a physiologically relevant milieu, we have developed a three-dimensional co-culture system that combines organ site-specific fibroblasts with breast carcinoma cells in a collagen matrix. We found that the growth-stimulating effect is mediated by the HSGAG chains on Sdc1, requires cleavage of the Sdc1 core protein at the cell surface, and also requires FGF2 activity. Because expression of the FGF2 receptor FGFR1c was up-regulated in T47D breast carcinoma cells, a model is proposed that invokes the paracrine activity of fibroblast Sdc1-derived HSGAG forming a complex with FGF2 and FGFR1c on the carcinoma cell surface, resulting in accelerated growth. Antibodies and Reagents—Mouse anti-delta heparan sulfate (3G10) antibody was purchased from Seikagaku America (Associates of Cape Cod, Falmouth, MA). Goat anti-human FGF2 neutralizing antibody was purchased from R PubMed Scopus Google Scholar). cells be to as human mammary fibroblasts T47D cells in with fetal bovine 2 and cells in with 2 and at in a and Cell collagen co-culture was on a described by and Biol. 2005; 7: PubMed Scopus Google Scholar). T47D cells and cells mixed at a of in collagen at a collagen of co-culture was in at in a cells with T47D cells in collagen for an To the cell growth in collagen the collagen was in in phosphate-buffered at for for with PBS, and in in collagen with the a system on an Cell was To and T47D cells in the co-culture both and green fluorescent and cells from T47D cells by of their and In the T47D cell growth a was during the cell Because cells a and a than T47D cells in the they be during the by a T47D we the and the T47D cell We with the described T47D cell from the collagen by and cell and with cells for on with of mouse anti-human syndecan-1 to the on a Cell and used to events for on a with the was to FGF and from collagen by and cell and T47D cells by The RNA was cell of RNA from T47D cells was the are in A. M. M. Kato Y. Y. J. Res. 1999; PubMed Scopus Google Scholar). of the reverse was used in the with on an was used as an for in in for at and for in with in at to with for with in for and with in for 2 at with anti-human Sdc1 antibody at with PBS, the was for at The with In the collagen with the was with a was as described D.M. Burbach B.J. Rapraeger A.C. J. Cell Biol. 2004; 167: 171-181Crossref PubMed Scopus (203) Google Scholar). to human syndecan-1 purchased from was to cells and cells with the cells in and with T47D cells in collagen for A. C. of G. of and from R. of at the Systems 2 to the and of of recombinant to cells to expression was confirmed by cell HSPGs as described C. K. S. Friedl A. Am. J. Pathol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). In cells on with and with of for and a of with to the and at HSPGs with To and with with a of of with The of the was the as of as by J. Biol. 2004; Full Text Full Text PDF PubMed Scopus Google with cells with The and by of of The was with at for in the by and the was by of The was and on a as an The by and of was by the of S. Biochem. PubMed Scopus Google that the was at and HSPGs with and for 2 to glycosaminoglycan and molecular in and to for on a and to a The with anti-delta (3G10) antibody which with by Sdc1 was used for The signal was with T47D Breast Cell an co-culture T47D human breast carcinoma cells with and in three-dimensional collagen gels. cells been immortalized by with human and by expression of C. T. M. G. L. Richardson A. S. A. 2004; PubMed Scopus Google Scholar). was it resembles the extracellular matrix of invasive breast carcinoma than which the extracellular matrix surrounding normal breast epithelium Biol. 2005; 7: PubMed Scopus Google Scholar, T. L. R. F. M.J. J. Cell 2002; PubMed Google Scholar). T47D carcinoma cells in which not in a In the of fibroblasts induced carcinoma cell growth, resulting in and cell of cell that the of fibroblasts a highly growth of the T47D cells from The growth of the fibroblasts was and their growth was by the of T47D cells. T47D Breast Sdc1 in in a we observed that the MDA-MB-231 breast carcinoma cells induced expression of Sdc1 in mouse fibroblasts, carcinoma cells, to (10Maeda T. Alexander C.M. Friedl A. Cancer Res. 2004; 64: 612-621Crossref PubMed Scopus (117) Google Scholar). Using the three-dimensional co-culture system described T47D cells induced the fibroblast expression of Sdc1 In expression of the and The induction of Sdc1 was confirmed at the protein by and by and and stromal Sdc1 induction in human and mouse mammary tumors in vivo. T47D Breast Cell by Sdc1 in have recently described that Sdc1 induction in mouse fibroblasts stimulates breast carcinoma cell growth in vitro and in which to stromal Sdc1 induction in human fibroblasts was also for breast carcinoma cell growth in three-dimensional (10Maeda T. Alexander C.M. Friedl A. Cancer Res. 2004; 64: 612-621Crossref PubMed Scopus (117) Google Scholar, T. Desouky J. Friedl A. Oncogene. 2006; 25: 1408-1412Crossref PubMed Scopus (120) Google Scholar). fibroblasts with Sdc1 to co-culture Sdc1 induction with the with an which HSPGs a of Sdc1 effect on the of HSPGs fibroblasts with be to as cells the of the The of Sdc1 induction in cells was confirmed by which also demonstrated that Sdc1 expression in the carcinoma cells was of Sdc1 induction in fibroblasts the T47D carcinoma cell growth by the of fibroblasts but effect on fibroblast growth forced expression of murine Sdc1 which is not by the in the cells by the T47D growth that Sdc1 induction in the fibroblasts is required for their effect on the carcinoma cells. of in cells was confirmed by to was by antibody and expression not the of HSPGs The Sdc1 for the on T47D Breast Sdc1 is of a core protein and HSGAG and which Sdc1 activities to its core protein domains D.M. Burbach B.J. Rapraeger A.C. J. Cell Biol. 2004; 167: 171-181Crossref PubMed Scopus (203) Google Scholar, K.J. D.M. Burbach B.J. Rapraeger A.C. J. Cell 2006; PubMed Scopus Google Scholar, J.K. Y. T. Sanderson R.D. J. Biol. 2005; Full Text Full Text PDF PubMed Scopus Google to the core protein was required for carcinoma cell growth by cells to murine as a which is expressed by mammary fibroblasts at but is not induced in breast carcinoma was Sdc1, the to the cell surface but to Sdc1 from the overexpression in the fibroblasts carcinoma cell growth to that the Sdc1 core protein is not required The in mammary fibroblasts in and co-culture are to maintain carcinoma cell but forced overexpression for Sdc1 HSGAG on Sdc1 but for T47D Cell suggests that carcinoma cell growth may be to HSGAG To we cells with the In which the HSGAG have been to the J.K. Stanley M.J. D. Sanderson R.D. J. Biol. Full Text Full Text PDF PubMed Scopus Google with and that was expressed and that its was with expression in cells growth of T47D carcinoma cells, that of is required for its activity The activity seen with mutant may be to the the transmembrane domain and which are with chains but can also J.K. Stanley M.J. D. Sanderson R.D. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). The of the effect on Sdc1 was by to of and T47D cells. to the at to during Sdc1 induction in the fibroblasts, but activity was to HSGAG chains not promote T47D cell growth in that factors are of Sdc1 from the for T47D Cell that mammary fibroblasts and T47D cells in the three-dimensional collagen the that Sdc1 may at a from its cell surface cleavage of Sdc1 with of the ectodomain from the cell surface has been described in vitro and in a myeloma shed Sdc1 ectodomain tumor growth in vivo in an (14Yang Y. Yaccoby S. Liu W. Langford J.K. Pumphrey C.Y. Theus A. Epstein J. Sanderson R.D. Blood. 2002; 100: 610-617Crossref PubMed Scopus (163) Google Scholar). which can for Sdc1 in our is also from the cell surface by cleavage of its This to the that Sdc1 shedding may also a in paracrine breast carcinoma growth an Sdc1 which a transmembrane and cytoplasmic domain and is was expressed in cells, the effect on T47D cells was that the soluble Sdc1 ectodomain is fully active in with and that soluble is expressed at to and is with HSGAG chains To the shedding is required for Sdc1 we expressed an Sdc1 mutant in which the juxtamembrane proteolytic cleavage site from to been with the domain of human (13Fitzgerald M.L. Wang Z. Park P.W. Murphy G. Bernfield M. J. Cell Biol. 2000; 148: 811-824Crossref PubMed Scopus (348) Google This Sdc1 mutant was expressed at to and was fully but not T47D cell growth In these that Sdc1 is shed co-culture that Sdc1 ectodomain is and that shedding is required for T47D cell growth T47D Cell by FGF2 and that modulate the activity of a of growth This is for the FGF are to in a complex with the FGF and the signaling receptor This to expression in T47D cells during and co-culture are and are to to and the are expressed in cells and are by and the are expressed in cells and are by and in the of fibroblasts, the expression of the FGFR1c and in T47D cells was up-regulated in to This is of the overexpression of FGFR1c during of cells G. Y. G. S. Cell. Biol. 1993; 13: PubMed Scopus Google Scholar). 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The an antibody the effect of cells on T47D cells not and that the is a of our to the on both FGF2 and SDF1 is a of the signaling To SDF1 of FGF2 with recombinant FGF2 T47D carcinoma cell growth in with antibody In SDF1 to T47D growth in with antibody This suggests that FGF2 signaling of the SDF1 The a model in which T47D breast carcinoma cells induce expression of Sdc1 in mammary fibroblasts and that the fibroblasts T47D cell growth by a mechanism that Sdc1 shedding from the fibroblast surface. The on both SDF1 and FGF2 signaling is of SDF1 of the Sdc1 ectodomain by proteolytic which is for has been well both in vitro and in vivo Z. Gotte M. Bernfield M. Reizes O. 2005; PubMed Scopus Google Scholar, V. Wang H. C. Bernfield M. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, V. Gotte M. Reizes O. K. Bernfield M. J. 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Full Text PDF PubMed Google Scholar). expression of a soluble of Sdc1 in myeloma cells accelerated tumor growth in with our (14Yang Y. Yaccoby S. Liu W. Langford J.K. Pumphrey C.Y. Theus A. Epstein J. Sanderson R.D. Blood. 2002; 100: 610-617Crossref PubMed Scopus (163) Google Scholar). for a of shed Sdc1 is by the that the Sdc1 ectodomain is an factor in myeloma and with in cancer R. G. T. G. J. 2005; PubMed Scopus Google Scholar, H. A. M. R. H. V. S. Cancer Res. 2002; Google Scholar). The of Sdc1 ectodomain on tumor cells are not to and (14Yang Y. Yaccoby S. Liu W. Langford J.K. Pumphrey C.Y. Theus A. Epstein J. Sanderson R.D. Blood. 2002; 100: 610-617Crossref PubMed Scopus (163) Google observed of myeloma cells in to Sdc1 In our fibroblasts induced carcinoma cells to which infiltrating carcinoma Our a model in which FGF2 stimulates breast carcinoma growth and requires HSGAG as a This is FGF2 is not a growth of breast carcinoma cells. T47D cells are not and Sdc1 B.J. Friedl A. C. 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Our and others have that in of human with breast Sdc1 with an highly cancer phenotype and F. K. van R. J. Y. W. Friedl A. Breast Cancer Res. 2006; PubMed Scopus Google Scholar, M. P. D. L. S. O. A. E. C. Cancer. 2003; PubMed Scopus Google Scholar). Compared with normal breast breast carcinoma cell have an to a complex with FGF2 and FGFR1c in an activity that with Sdc1 expression C. K. S. Friedl A. Am. J. Pathol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). from of the carcinomas activity as FGF2 that in a of carcinomas HSPGs not FGF2 signaling. Because T47D cells to FGF2 are it can be that T47D are as FGF2 The of the factor in FGF signaling in breast carcinoma is by from M. E. H. Cell Res. PubMed Scopus Google that MDA-MB-231 breast carcinoma cells that FGF2 signaling. the of was by the cells may which for carcinoma cell HSPGs with activity with carcinoma cell HSPGs with activity in FGF2 signaling. Sdc1 ectodomain can be modified in the Sdc1 ectodomain from mouse mammary cells from FGF2 signaling FGFR1c but is to a of domains by M. Wang H. V. Fitzgerald M.L. S. D.M. Bernfield M. Nat. PubMed Scopus Google Scholar). are required for Sdc1 ectodomain in our model is In we define a reciprocal signaling pathway mammary fibroblasts and breast carcinoma cells that requires the proteolytic cleavage of Sdc1 from the fibroblast surface, the activity of Sdc1 HSGAG chains, and This model several for therapeutic The specific disruption of proteolytic Sdc1 shedding as a We are to Sanderson for several mutant as We for with with
Su et al. (Thu,) studied this question.
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