Growth of tumor emboli within a vessel model reveals dependence on the magnitude of mechanical constraint

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Tumor emboli – aggregates of tumor cell within vessels – pose a clinical challenge as they are associated with increased metastasis and tumor recurrence. When growing within a vessel, tumor emboli are subject to a unique mechanical constraint provided by the tubular geometry of the vessel. Current models of tumor emboli use unconstrained multicellular tumor spheroids, which neglect this mechanical interplay. Here, we modelled a lymphatic vessel as a 200 μm-diameter channel in either a stiff or soft, bioinert agarose matrix, and we modelled colon or breast cancer tumor emboli with aggregates of HCT116 or SUM149PT cells, respectively. The stiff vessel model constrained the tumor emboli to the cylindrical geometry, which led to continuous growth of the emboli, in contrast to the growth plateau that unconstrained spheroids exhibit. Emboli morphology in the soft vessel model, however, was dependent on the magnitude of mechanical mismatch between the vessel matrix and the cell aggregates. In general, when the elastic modulus of the vessel was greater than the emboli (<jats:italic>E<jats:sub>ves</jats:sub></jats:italic> / <jats:italic>E<jats:sub>emb</jats:sub></jats:italic> &gt;1), the emboli were constrained to grow within the vessel geometry, and when the elastic modulus of the vessel was less than the emboli (0 &lt; <jats:italic>E<jats:sub>ves</jats:sub></jats:italic> / <jats:italic>E<jats:sub>emb</jats:sub></jats:italic> &lt; 1), the emboli bulged into the matrix. Inhibitors of myosin-related force generation decreased the elastic modulus and/or increased the stress relaxation of the tumor cell aggregates, effectively increasing the mechanical mismatch. The increased mechanical mismatch after drug treatment was correlated with increased confinement of tumor emboli growth along the vessel, which may translate to increased tumor burden due to the increased tumor volume within the diffusion distance of nutrients and oxygen.</jats:p><jats:sec><jats:title>INSIGHT BOX</jats:title><jats:p>The growth of tumor emboli—aggregates of tumor cells within vessels—is associated with aggressive cancer progression and metastasis. Models of their growth have not taken into account their biomechanical context, where radial expansion is constrained, but lengthwise expansion is free in the vessel. Here, we modelled the vessel geometry with a cylindrical microchannel in a hydrogel. In contrast to unconstrained or fully embedded aggregates, vessel-like constraint promotes growth of emboli in our model. The growth advantage is increased when the matrix is stiffened or actomyosin contractility weakened, both of which effectively increase the magnitude of mechanical constraint. This study sheds light on increased tumor burden in vessel-based growth and indicates a need to study tumor progression in similar environments.</jats:p></jats:sec>