Metastatic prostate cancer spreads preferentially to the bone, causing skeletal complications associated with significant morbidity and a poor prognosis, despite current therapeutic approaches. Hence, it is imperative to understand the complex metastatic cascade to develop therapeutic interventions for treating metastatic prostate cancer. 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 at the bone microenvironment remains poorly understood. To this end, we have developed a three-dimensional (3D) in vitro dynamic model of prostate cancer bone metastasis using perfusion bioreactor and compared our results with static conditions to delineate the role of flow-induced shear stress on prostate cancer progression at metastases. We observed an increase in human mesenchymal stem cell (hMSCs) proliferation and differentiation rate under the dynamic culture. The hMSCs form cell agglutinates under static culture, whereas the hMSCs exhibited a directional alignment with broad and flattened morphology under dynamic culture. Further, the expression of mesenchymal to epithelial transition biomarkers is increased in bone metastasized prostate cancer models, and large changes are observed in the cellular and tumoroid morphologies 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 phosphorylated focal adhesion kinase proteins under shear stress. Overall, we report a successful 3D in vitro dynamic model to recapitulate bone metastatic prostate cancer behavior under dynamic conditions.
Breast cancer shows a high affinity toward bone, causing
bone-related
complications, leading to a poor clinical prognosis. The Wnt/β-catenin
signaling pathway has been well-documented for the bone regenerative
process; however, the regulation of the Wnt/β-catenin pathway
in breast cancer bone metastasis is poorly explored. Here, we report
that the Wnt/β-catenin signaling pathway has a significant effect
on osteogenesis during breast cancer bone metastasis. In this study,
we have created a 3D in vitro breast cancer bone
metastatic microenvironment using nanoclay-based scaffolds along with
osteogenically differentiated human mesenchymal stem cells (MSCs)
and human breast cancer cells (MCF-7 and MDA-MB-231). The results
showed upregulation in expressions of Wnt-related factors (Wnt-5a,
β-catenin, AXIN2, and LRP5) in sequential cultures of MSCs with
MCF-7 as compared to sequential cultures of MSCs with MDA-MB-231.
Sequential cultures of MSCs with MCF-7 also showed higher β-catenin
expression on the protein levels than sequential cultures of MSCs
with MDA-MB-231. Stimulation of Wnt/β-catenin signaling in sequential
cultures of MSCs with MCF-7 by ET-1 resulted in increased bone formation,
whereas inactivation of Wnt/β-catenin signaling by DKK-1 displayed
a significant decrease in bone formation, mimicking bone lesions in
breast cancer patients. These data collectively demonstrate that Wnt/β-catenin
signaling governs osteogenesis within the tumor-harboring bone microenvironment,
leading to bone metastasis. The nanoclay scaffold provides a unique
testbed approach for analysis of the pathways of cancer metastasis.
JAK2 and JAK3 are non-receptor protein tyrosine kinases implicated in B-cell- and T-cell-mediated diseases. Both enzymes work via different pathways but are involved in the pathogenesis of common lymphoid-derived diseases. Hence, targeting both Janus kinases together can be a potential strategy for the treatment of these diseases. In the present study, two separate pharmacophore-based 3D-QSAR models ADRR.92 (Q(2)(test)0.663, R(2)(train) 0.849, F value 219.3) for JAK2 and ADDRR.142 (Q(2)(test)0.655, R(2)(train) 0.869, F value 206.9) for JAK3 were developed. These models were employed for the screening of a PHASE database of approximately 1.5 million compounds; subsequently, the retrieved hits were screened employing docking simulations with JAK2 and JAK3 proteins. Finally, ADME properties of screened dual inhibitors displaying essential interactions with both proteins were calculated to filter candidates with poor pharmacokinetic profiles. These candidates could serve as novel therapeutic agents in the treatment of lymphoid-related diseases.
Clays have been used as early as 2500 BC in the human civilization for numerous biomedical applications. Ease of availability, biocompatibility and versatility of these unique charged 2D structures abundantly...
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