Biophysics Role and Biomimetic Culture Systems of ECM Stiffness in Cancer EMT

Abstract

Oncological diseases have become the second leading cause of death from noncommunicable diseases worldwide and a major threat to human health. With the continuous progress in cancer research, the mechanical cues from the tumor microenvironment environment (TME) have been found to play an irreplaceable role in the progression of many cancers. As the main extracellular mechanical signal carrier, extracellular matrix (ECM) stiffness may influence cancer progression through biomechanical transduction to modify downstream gene expression, promote epithelial-mesenchymal transition (EMT), and regulate the stemness of cancer cells. EMT is an important mechanism that induces cancer cell metastasis and is closely influenced by ECM stiffness, either independently or in conjunction with other molecules. In this review, the unique role of ECM stiffness in EMT in different kinds of cancers is first summarized. By continually examining the significance of ECM stiffness in cancer progression, a biomimetic culture system based on 3D manufacturing and novel material technologies is developed to mimic ECM stiffness. The authors then look back on the novel development of the ECM stiffness biomimetic culture systems and finally provide new insights into ECM stiffness in cancer progression which can broaden the fields' horizons with a view toward developing new cancer diagnosis methods and therapies.

Keywords: biomimetic culture system; epithelial‐mesenchymal transition; epithelial‐mesenchymal transition stiffness; mechanotransduction; tumor microenvironment.

Figure 1

With the tumor progression, the ECM stiffness is generally increasing, mainly due to the increased matrix deposition, the crosslinking of collagen, strain stiffening, elevated cell density, and increased interstitial fluid pressure. Besides, the crosstalking‐between cellular consortiums in tumors facilitated this process.

Figure 2

The mechanical transduction pathway network plays a role in stiffness‐mediated EMT by regulating target genes. The TGFβ family activates downstream pathways through the TβR to promote EMT. Through mechanical transduction pathways, ECM stiffness activates different downstream molecules and then regulates the activation of EMT‐TF, which controls the downstream gene transcription such as upregulating mesenchymal markers, elevating cell membrane receptor expression, and downregulating epithelial markers. The dotted line indicates that there is a relationship in upregulation, but the direct action needs further confirmation.

Figure 3

Inducers and intracellular pathways involved in stiffness‐mediated EMT in different types of cancers. The mechanotransduction pathways in different types of cancers are not the same. In most cases, a stiff ECM can promote EMT in cancer cells, while in H‐Ras‐transformed MCF10A cells and metastatic OCCs, it is a soft matrix that promotes EMT.

Figure 4

Diagram of 2D and 3D culture system. Different strategies to construct 3D culture systems for studying physical cues (upper part). The concentric circles represent the strengths, shortages, and strategies of different cultural systems from the inside out. More details are available in Table 2.

Figure 5

Stiffness‐mediated EMT occurs in cancer cells. ECM stiffness can independently act as a force cue or synergistically stimulate EMT in cancer cells with costimulators, including biochemical (such as TGFβ family, LOX family, MMP3) and physical factors (ECM topography, adhesion ligands concentration, hypoxia, etc.). In soft matrix cases, the loss of E‐cadherin in cancer cells impairs the balance between cell–cell adhesions and integrins‐mediated cell‐ECM adhesion, resulting in the occurrence of metastasis and invasion. The thin dotted line means that the effect is minor.

Figure 6

Perspectives for future ECM stiffness studies. Much work needs to be done, including identifying specific mechanisms in diverse cancers, deeply exploring the mechanism of ECM stiffness in tumor progression, and developing culture systems more akin to living tissues.