Fibroblast and prostate tumor cell cross-talk: fibroblast differentiation, TGF-β, and extracellular matrix down-regulation.
Growth and survival of tumors at a site of metastasis involve interactions with stromal cells in the surrounding environment. Stromal cells aid tumor cell growth by producing cytokines as well as by modifying the environment surrounding the tumor through modulation of the extracellular matrix (ECM). Small leucine-rich proteoglycans (SLRPs) are biologically active components of the ECM which can be altered in the stroma surrounding tumors. The influence tumor cells have on stromal cells has been well elucidated. However, little is understood about the effect metastatic cancer cells have on the cell biology and behavior of the local stromal cells. Our data reveal a significant down-regulation in the expression of ECM components such as collagens I, II, III, and IV, and the SLRPs, decorin, biglycan, lumican, and fibromodulin in stromal cells when grown in the presence of two metastatic prostate cancer cell lines PC3 and DU145. Interestingly, TGF-β down-regulation was observed in stromal cells, as well as actin depolymerization and increased vimentin and α5β1 integrin expression. MT1-MMP expression was upregulated and localized in stromal cell protrusions which extended into the ECM. Moreover, enhanced stromal cell migration was observed after cross-talk with metastatic prostate tumor cells. Xenografting metastatic prostate cancer cells together with "activated" stromal cells led to increased tumorigenicity of the prostate cancer cells. Our findings suggest that metastatic prostate cancer cells create a metastatic niche by altering the phenotype of local stromal cells, leading to changes in the ECM.
Coulson-Thomas
Vivien J
VJ
Departamento de Bioquímica, Universidade Federal de São Paulo, São Paulo, SP, Brazil. vcoulsonthomas@gmail.com
Gesteira
Tarsis F
TF
Coulson-Thomas
Yvette M
YM
Vicente
Carolina M
CM
Tersariol
Ivarne L S
IL
Nader
Helena B
HB
Toma
Leny
L
D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D002450:Cell Communication / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002465:Cell Movement / Q000187:drug effects; D018920:Coculture Techniques; D003599:Cytoskeleton / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D005109:Extracellular Matrix / Q000187:drug effects / Q000235:genetics*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D021381:Protein Transport / Q000187:drug effects; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D057134:Antibodies, Neutralizing; D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; D019030:Receptors, Vitronectin; D016212:Transforming Growth Factor beta; C094340:integrin alphavbeta1; C071736:betaglycan; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1