Arresting metastasis within the microcirculation.

The behaviour of circulating tumour cells in the microcirculation remains poorly understood. Growing evidence suggests that biomechanical adaptations and interactions with blood components, i.e. immune cells and platelets within capillary beds, may add more complexity to CTCs journey towards metastasis. Revisiting how these mediators impact the ability of circulating tumour cells to survive and metastasise, will be vital to understand the role of microcirculation and advance our knowledge on metastasis

Squeezing through the microcirculation: survival adaptations of circulating tumour cells to seed metastasis

During metastasis, tumour cells navigating the vascular circulatory system—circulating tumour cells (CTCs)—encounter capillary beds, where they start the process of extravasation. Biomechanical constriction forces exerted by the microcirculation compromise the survival of tumour cells within capillaries, but a proportion of CTCs manage to successfully extravasate and colonise distant sites. Despite the profound importance of this step in the progression of metastatic cancers, the factors about this deadly minority of cells remain elusive. Growing evidence suggests that mechanical forces exerted by the capillaries might induce adaptive mechanisms in CTCs, enhancing their survival and metastatic potency. Advances in microfluidics have enabled a better understanding of the cell-survival capabilities adopted in capillary-mimicking constrictions. In this review, we will highlight adaptations developed by CTCs to endure mechanical constraints in the microvasculature and outline how these mechanical forces might trigger dynamic changes towards a more invasive phenotype. A better understanding of the dynamic mechanisms adopted by CTCs within the microcirculation that ultimately lead to metastasis could open up novel therapeutic avenues

Vascularized Tissue Blocks Using a Suspension 3D Printed Spheroid Blood Vessel

In order for engineered tissue grafts and eventually organs to successfully integrate in a clinical setting, a functional vascular network is imperative. Without vasculature, the tissue constructs cannot receive nutrients essential for their survival, but also lack the stimuli that determine the tissue’s biophysical properties i.e. cell fate determination, cell to cell junctions, and cell orientation. In order for the vascular network to functionally connect to the patient, a hierarchical organization, resembling the vascular tree, is important. From previous studies it is known that fluid flow is a crucial component in controlling the formation of the vascular tree, and that the organization of the vascular network can be further controlled using gradients of angiogenic growth factors such as VEGF. By utilizing spheroid bioprinting within a microgel suspension, an artificial vessel structure was assembled. The deposited spheroids maintained viability and fused over time into perfusable vessels.The subsequent formation of small-diameter vascular structures and capillaries was regulated by an on-demand flow through the bioprinted vessel, resulting in controllable fluid flow shear stresses. Furthermore, VEGF was spatially patterned in the tissue block by locally doping the suspension with growth factor releasing microparticles. By varying both these stimuli, the location of vascular sprout formation and subsequent growth of the new vascular structures could be influenced. This spheroid 3D bioprinting platform offers a dynamic, customizable and accurate method to trigger and control the process of angiogenesis in vitro. By stimulating an artificial blood vessel with controlled fluid flow and growth factor gradients, a vascular complex vascular network can be produced and modulated. The combination of this approach with a gradual replacement of the microgel suspension with cells, can pave the way for the production of vascularized tissue blocks