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

Abstract

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.

Chemotherapy-Induced Changes in the Lung Microenvironment: The Role of MMP-2 in Facilitating Intravascular Arrest of Breast Cancer Cells

“…Both mechanical entrapment and adhesion of cancer cells to the vascular wall have been reported to play a role in intravascular arrest [ 18 , 19 , 20 , 21 , 22 ]. However, discrepancy remains and the molecular details are not well-established (reviews, [ 23 , 24 , 25 ]). We suspected that entrapment is not the major reason for CTX to increase cancer burden at 3 h in our model, because a single dose of CTX—at four days prior—is unlikely to change the biomechanics of the blood vessel to entrap more cancer cells.…”

3D Cancer Models: The Need for a Complex Stroma, Compartmentalization and Stiffness

“…This aids the cellular cross-talk between cancer and stromal cells generating gradients of angiogenic and fibrotic factors. Studying vascular network formation, remodeling and disruption in relation to a growing tumor mass is important in order to understand the cancer's ability for nutrient acquisition and metastasis (Perea Paizal et al, 2021) in addition to identify future drug targets (Farnsworth et al, 2014). In terms of studying the reactive cancer environment, the biggest gap in modeling the cancer stroma consists of not including the appropriate immune cell population.…”

Similarities and perspectives on the two C’s—Cancer and COVID‐19

“…35 The tendency for cancers to disseminate means that cancer particulate matter may escape into the venous circulation and may get lodged in the narrow-lumen pulmonary microcirculation. 36 These tumor emboli are not thrombotic in nature and thus reporting them as thrombo-emboli may not be correct. CT reports should ideally term them pulmonary filling defects rather than PE.…”

“…It can play one of the crucial non‐respiratory roles by filtering out thrombus material, fibrin clumps, and possibly other exogenous materials from the venous circulation 35 . The tendency for cancers to disseminate means that cancer particulate matter may escape into the venous circulation and may get lodged in the narrow‐lumen pulmonary microcirculation 36 . These tumor emboli are not thrombotic in nature and thus reporting them as thrombo‐emboli may not be correct.…”