A key aspect of cancer metastases is the tendency for specific cancer cells to home to defined subsets of secondary organs. Despite these known tendencies, the underlying mechanisms remain poorly understood. Here we develop a microfluidic 3D in vitro model to analyze organ-specific human breast cancer cell extravasation into bone- and muscle-mimicking microenvironments through a microvascular network concentrically wrapped with mural cells. Extravasation rates and microvasculature permeabilities were significantly different in the bone-mimicking microenvironment compared with unconditioned or myoblast containing matrices. Blocking breast cancer cell A₃ adenosine receptors resulted in higher extravasation rates of cancer cells into the myoblast-containing matrices compared with untreated cells, suggesting a role for adenosine in reducing extravasation. These results demonstrate the efficacy of our model as a drug screening platform and a promising tool to investigate specific molecular pathways involved in cancer biology, with potential applications to personalized medicine.

Cancer metastases arise following extravasation of circulating tumor cells with certain tumors exhibiting high organ specificity. Here, we developed a 3D microfluidic model to analyze the specificity of human breast cancer metastases to bone, recreating a vascularized osteo-cell conditioned microenvironment with human osteo-differentiated bone marrow-derived mesenchymal stem cells and endothelial cells. The tri-culture system allowed us to study the transendothelial migration of highly metastatic breast cancer cells and to monitor their behavior within the bone-like matrix. Extravasation, quantified 24 h after cancer cell injection, was significantly higher in the osteo-cell conditioned microenvironment compared to collagen gel-only matrices (77.5 ± 3.7% vs. 37.6 ± 7.3%), and the migration distance was also significantly greater (50.8 ± 6.2 μm vs. 31.8 ± 5.0 μm). Extravasated cells proliferated to form micrometastases of various sizes containing 4 to more than 60 cells by day 5. We demonstrated that the breast cancer cell receptor CXCR2 and the bone-secreted chemokine CXCL5 play a major role in the extravasation process, influencing extravasation rate and traveled distance. Our study provides novel 3D in vitro quantitative data on extravasation and micrometastasis generation of breast cancer cells within a bone-like microenvironment and demonstrates the potential value of microfluidic systems to better understand cancer biology and screen for new therapeutics.

The generation of functional microvascular networks is critical for the development of advanced in vitro models to replicate pathophysiological conditions.

Purpose Osteoarthritis (OA) represents a relevant social and economic burden worldwide. “Mesenchymal stem cells” or, as recently proposed, “medicinal signaling cells” (MSCs) have been recently introduced as injective treatments for OA with the aim of restoring joint homeostasis. The aim of this review is to provide the reader with the tools necessary to interpret the currently available clinical data, focusing on the MSC mechanisms of action which might help to clarify what we should expect from this treatment. Methods Clinical studies reporting MSC injections for the treatment of knee OA, either freshly isolated or culture-expanded cells, have been included and commented in relation to the supposed therapeutic effect that MSCs might exert giving their supposed mode of actions. Results The majority of the studies reports significant improvements in terms of pain and knee function compared to baseline values, up to 24 months of follow-up. Although these data support the expected therapeutic effect of this therapy giving the features of these cells, only 14% of the studies present a control group and more than one-third of them report the results on less than ten patients. Conclusions Despite the constant presence of positive and satisfactory results in the studies analyzed, the complexity of MSC metabolism and related therapeutic effects as well as the weakness of most of the studies do not allow withdrawing definitive conclusions about the superiority of one tissue source over another, as well as about the best cell dose and the long-term durability of the effects of these procedures. Given the high potential value of these therapies in the treatment of OA, further studies accurately designed, carefully defining the type of patients to be included and pursuing minimal standard requirements in terms of follow-up, number of patients, and types of measurements should be conducted to finally assess the efficacy of MSC-based injective treatments.