Bone-stromal cells up-regulate tumourigenic markers in a tumour-stromal 3D model of prostate cancer.
BACKGROUND
The cellular and molecular mechanisms that mediate interactions between tumour cells and the surrounding bone stroma are to date largely undetermined in prostate cancer (PCa) progression. The purpose of this study was to evaluate the role of alpha 6 and beta 1 integrin subunits in mediating tumour-stromal interactions.


METHODS
Utilising 3D in vitro assays we evaluated and compared 1. Monocultures of prostate metastatic PC3, bone stromal derived HS5 and prostate epithelial RWPE-1 cells and 2. Tumour-stromal co-cultures (PC3 + HS5) to ascertain changes in cellular phenotype, function and expression of metastatic markers.


RESULTS
In comparison to 3D monocultures of PC3 or HS5 cells, when cultured together, these cells displayed up-regulated invasive and proliferative qualities, along with altered expression of epithelial-to-mesenchymal and chemokine protein constituents implicated in metastatic dissemination. When co-cultured, HS5 cells were found to re-express N-Cadherin and chemokine receptor CXCR7. Alterations in N-Cadherin expression were found to be mediated by soluble factors secreted by PC3 tumour cells, while chemokine receptor re-expression was dependent on direct cell-cell interactions. We have also shown that integrins beta 1 and alpha 6 play an integral role in maintaining cell homeostasis and mediating expression of E-Cadherin, N-Cadherin and vimentin, in addition to chemokine receptor CXCR7.


CONCLUSIONS
Collectively our results suggest that both PC3 and HS5 cells provide a "protective" and reciprocal milieu that promotes tumour growth. As such 3D co-cultures may serve as a more complex and valid biological model in the drug discovery pipeline.
Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University, Nathan, 4111 Brisbane, QLD, Canada. v.avery@griffith.edu.au.
Louisa C E
LC
Windus
Tristan T
TT
Glover
Vicky M
VM
Avery
D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001859:Bone Neoplasms / Q000378:metabolism* / Q000556:secondary; D001842:Bone and Bones / Q000473:pathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048430:Cell Shape; D018920:Coculture Techniques; D058750:Epithelial-Mesenchymal Transition; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039121:Integrin alpha6beta1 / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D008297:Male; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D054387:Receptors, CXCR / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism*; D015854:Up-Regulation; D014746:Vimentin / Q000235:genetics / Q000378:metabolism
C501896:ACKR3 protein, human; D015703:Antigens, CD; D014408:Biomarkers, Tumor; C513384:CDH1 protein, human; C050361:CDH2 protein, human; D015820:Cadherins; D039121:Integrin alpha6beta1; D007797:Laminin; D054387:Receptors, CXCR; D014746:Vimentin