Prostate cancer cells specifically reorganize epithelial cell-fibroblast communication through proteoglycan and junction pathways.
Microenvironment and stromal fibroblasts are able to inhibit tumor cell proliferation both through secreted signaling molecules and direct cell-cell interactions but molecular mechanisms of these effects remain unclear. In this study, we investigated a role of cell-cell contact-related molecules (protein ECM components, proteoglycans (PGs) and junction-related molecules) in intercellular communications between the human TERT immortalized fibroblasts (BjTERT fibroblasts) and normal (PNT2) or cancer (LNCaP, PC3, DU145) prostate epithelial cells. It was shown that BjTERT-PNT2 cell coculture resulted in significant decrease of both BjTERT and PNT2 proliferation rates and reorganization of transcriptional activity of cell-cell contact-related genes in both cell types. Immunocytochemical staining revealed redistribution of DCN and LUM in PNT2 cells and significant increase of SDC1 at the intercellular contact zones between BjTERT and PNT2 cells, suggesting active involvement of the PGs in cell-cell contacts and contact inhibition of cell proliferation. Unlike to PNT2 cells, PC3 cells did not respond to BjTERT in terms of PGs expression, moderately increased transcriptional activity of junctions-related genes (especially tight junction) and failed to establish PC3-BjTERT contacts. At the same time, PC3 cells significantly down-regulated junctions-related genes (especially focal adhesions and adherens junctions) in BjTERT fibroblasts resulting in visible preference for homotypic PC3-PC3 over heterotypic PC3-BjTERT contacts and autonomous growth of PC3 clones. Taken together, the results demonstrate that an instructing role of fibroblasts to normal prostate epithelial cells is revoked by cancer cells through deregulation of proteoglycans and junction molecules expression and overall disorganization of fibroblast-cancer cell communication.
a MTC, Karolinska Institute , Stockholm , Sweden.|b Institute of Molecular Biology and Biophysics , Novosibirsk , Russia.
Anastasia V
AV
Suhovskih
a MTC, Karolinska Institute , Stockholm , Sweden.|c Institute of Molecular Biology and Genetics , Kiev , Ukraine.
Vladimir I
VI
Kashuba
a MTC, Karolinska Institute , Stockholm , Sweden.
George
G
Klein
a MTC, Karolinska Institute , Stockholm , Sweden.|b Institute of Molecular Biology and Biophysics , Novosibirsk , Russia.
Elvira V
EV
Grigorieva
D002450:Cell Communication; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008954:Models, Biological; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D011509:Proteoglycans / Q000378:metabolism*; D019098:Telomerase / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism*
D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D019098:Telomerase
extracellular matrix; fibroblast; junction molecules; microenvironment; prostate cancer; proteoglycan