| dc.description.abstract | Metastatic prostate cancer spreads preferentially to the bone, causing skeletal complications associated with significant morbidity and a poor prognosis, despite current therapeutic approaches. Increasing evidence suggests the synergistic role of biochemical and biophysical cues in cancer progression at metastases. However, the mechanism underlying the crosstalk between interstitial flow-induced mechanical stimuli and prostate cancer progression in the bone microenvironment remains poorly understood. To this end, we have developed 3D in vitro dynamic models of prostate cancer bone metastasis using perfusion bioreactor and horizontal flow bioreactor to delineate the role of flow-induced shear stress on prostate cancer progression and migration, respectively at metastases. Using a perfusion bioreactor, we observed changes in the expressions of MET biomarkers and the tumoroid morphologies of prostate cancer cells under dynamic culture. Evaluation of cell adhesion proteins indicated that the altered cancer cell morphologies resulted from the constant force pulling due to increased E-cadherin and FAK proteins under shear stress.
Using a horizontal flow bioreactor, we demonstrated that the percent cell migration rate of prostate cancer cells was increased in the presence of bone under dynamic conditions. The results showed that interstitial fluid flow did not alter the CXCR4 level, but bone upregulated CXCR4 levels, leading to increased MMP-9 levels. In addition, both αvβ3 integrins and MMP-9 levels were upregulated by fluid flow conditions, contributing to an increased migration rate under dynamic conditions.
Breast cancer cells also tend to preferentially disseminate to bone and colonize within the remodeling bone site to cause bone metastases. We have previously developed a 3D in vitro breast cancer bone metastasis model using hMSCs and commercial breast cancer cells (MCF-7 and MDAMB231), recapitulating late-stage breast cancer metastasis to bone. In the present study, we have validated our model using patient-derived breast cancer cell lines- NT013 and NT023, exhibiting hormone-positive and triple-negative characteristics, respectively that showed MET and formed tumors in the presence of bone. In addition, the results showed ET-1 (NT013) and DKK-1 (NT023) mediated stimulation and abrogation of the osteogenesis via Wnt/β catenin pathway, in line with our previous results with MCF-7 and MDAMB231 cell lines. | en_US |
