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Cancer is a complex and dynamic disease that is aberrant both biologically and physically. There is growing appreciation that physical abnormalities with both cancer cells and their microenvironment that span multiple length scales are important drivers for cancer growth and metastasis. The scope of this review is to highlight the key advancements in micro‐ and nanoscale tools for delineating the cause and consequences of the aberrant physical properties of tumors. Herein, the following three important physical aspects of cancer are focused: 1) solid mechanical properties, 2) fluid mechanical properties, and 3) mechanical alterations to cancer cells. Beyond posing physical barriers to the delivery of cancer therapeutics, these properties are also known to influence numerous biological processes, including cancer cell invasion and migration leading to metastasis, and response and resistance to therapy. There is a comment on how micro‐ and nanoscale tools have transformed the fundamental understanding of the physical dynamics of cancer progression and their potential for bridging toward future applications at the interface of oncology and physical sciences. 

Abstract Angiogenesis is associated with increased vessel sprouting and permeability. Important mediators of these angiogenic responses include local environment of signaling molecules and supporting extracellular matrix (ECM). However, dissecting the interplay of these instructive signals in vivo with multiple cells and extracellular molecules remains a central challenge. Here, microfluidic biomimicry is integrated with 3D ECM hydrogels that are well‐characterized for molecular‐binding and mechanical properties to reconstitute vessel‐like analogues in vitro. This study focuses on three distinct isoforms of the pro‐metastatic chemokine CXCL12. In collagen‐only hydrogel, CXCL12‐α is the most potent isoform in promoting sprouting and permeability, followed by CXCL12‐β and CXCL12‐γ. Strikingly, addition of hyaluronan (HA), a large and negatively charged glycosaminoglycan, with collagen matrices selectively increases vessel sprouting and permeability conferred by CXCL12‐γ. This outcome is supported by the measured binding affinities to collagen/HA ECM, suggesting that negatively charged HA increases the binding of CXCL12‐γ to augment its angiogenic potency. Moreover, it is shown that addition of HA to collagen matrices on its own decreases vessel sprouting and permeability, and these responses are nullified by blocking the HA receptor CD44. Collectively, these results demonstrate that differences in binding to extracellular HA help underlie CXCL12 isoform‐specific responses toward directing angiogenesis.