Designer Biomaterials to Model Cancer Cell Invasion In Vitro: Predictive Tools or Just Pretty Pictures?

Metastasis is the leading cause of mortality in cancer patients. Underlying this process is the invasion and colonization of cancer cells into healthy tissues. Engineered hydrogel models of tumor microenvironments present an opportunity to understand the microenvironmental determinants of cellular invasion. The biochemical and mechanical cues, presented in the form of adhesion sites, degradable cues, matrix stiffness, and architecture, have significant effects on the extent of cancer cell migration, and the mechanisms employed by these cells to move through their matrix. Coculture with stromal cells such as cancer associated fibroblasts, endothelial cells, and immune cells that are associated with poor prognosis demonstrate that these cells exacerbate cancer cell invasion. With these models, researchers aim not only to recapitulate known cancer cell behaviors in a dish, but also to uncover new insights into mechanisms underlying these phenomena, paving the way for novel treatment strategies. In this perspective, the design of engineered models that are used to study cancer cell invasion and metastasis in vitro is discussed. To this end, the authors seek to understand and put into perspective: do these models reveal relevant mechanisms of cancer cell migration, or are they simply pretty pictures with little biological translatability?     

HtrA3-Mediated Endothelial Cell–Extracellular Matrix Crosstalk Regulates Tip Cell Specification

Angiogenesis is critical in tissue engineering and regenerative medicine. Once initiated, outgrowing capillaries are spearheaded by specialized endothelial cells (ECs) termed tip cells. Specification of tip cells from ECs during angiogenesis is greatly influenced by the surrounding extracellular matrix (ECM). However, the crosstalk between ECs and the ECM in tip cell specification is poorly understood. Here, this study shows that the high-temperature requirement A3 (HtrA3) protein is deeply involved in this process. Specifically, HtrA3 is upregulated in the frontal area of tissue repair and cancer progression through VEGFR2 activation by VEGF in ECs. Secreted HtrA3 degrades the surrounding Collagen IV, which provides space for tip cell morphogenesis and exposes integrin β1-related ligands. Integrin β1-ligand binding activates PI3K/AKT/mTOR signaling, which subsequently suppresses the Notch signaling pathway, eventually promoting tip cell specification. Moreover, local administration of exogeneous recombinant HtrA3 in rat cranial bone defects significantly increases blood vessel formation. Conversely, injection of HtrA3 siRNA decreases developmental retinal angiogenesis. These data show that HtrA3 mediated crosstalk between ECs and the ECM enhances tip cell specification of ECs. Hence, HtrA3 can act as a therapeutic agent for improving angiogenesis in situations in need, as well as serve as a therapeutic target for pathological angiogenesis.