Cell and Tissue Nanomechanics: From Early Development to Carcinogenesis

Abstract

Cell and tissue nanomechanics, being inspired by progress in high-resolution physical mapping, has recently burst into biomedical research, discovering not only new characteristics of normal and diseased tissues, but also unveiling previously unknown mechanisms of pathological processes. Some parallels can be drawn between early development and carcinogenesis. Early embryogenesis, up to the blastocyst stage, requires a soft microenvironment and internal mechanical signals induced by the contractility of the cortical actomyosin cytoskeleton, stimulating quick cell divisions. During further development from the blastocyst implantation to placenta formation, decidua stiffness is increased ten-fold when compared to non-pregnant endometrium. Organogenesis is mediated by mechanosignaling inspired by intercellular junction formation with the involvement of mechanotransduction from the extracellular matrix (ECM). Carcinogenesis dramatically changes the mechanical properties of cells and their microenvironment, generally reproducing the structural properties and molecular organization of embryonic tissues, but with a higher stiffness of the ECM and higher cellular softness and fluidity. These changes are associated with the complete rearrangement of the entire tissue skeleton involving the ECM, cytoskeleton, and the nuclear scaffold, all integrated with each other in a joint network. The important changes occur in the cancer stem-cell niche responsible for tumor promotion and metastatic growth. We expect that the promising concept based on the natural selection of cancer cells fixing the most invasive phenotypes and genotypes by reciprocal regulation through ECM-mediated nanomechanical feedback loop can be exploited to create new therapeutic strategies for cancer treatment.

Keywords: FAC complex; YAP/TAZ; cancer; carcinogenesis; cytoskeleton; extracellular matrix; intermediate filaments; mechanotransduction; microfilaments; microtubules; stem cell niche.

Figure 1

A schematic visualization of main factors influencing and maintaining cell and tissue mechanics. Cell and tissue mechanics are supported by a developed tissue skeleton system. The cytoskeleton is represented by three types of filaments—microfilament, intermediate filaments, and microtubules. These fibrillar structures are intensively interconnected with each other by various crosstalk proteins, and are also anchored to the cell membrane, facilitating intercellular contact. The cell surface system is also responsible for cell interaction with the extracellular matrix, which, by complex processes of mechanoinduction, unites extracellular and intracellular skeletal elements into an ensemble of coordinated structures. Varying force of mechanical load onto the cell surface is compensated by recruitment and reassembly of cortical cytoskeleton. The cytoskeleton also serves as a mediator, helping to sense extracellular mechanical signals and transduce them to initiate genetic response.

Figure 2

A schematic visualization of molecular pathways activated by mechanoreception. A cell possesses a developed system of mechanical receptors, including complexes contacting the ECM (extracellular matrix) and cell junctions. The majority of these receptors induce the ROCK-based signal transduction mechanism, which initiates actomyosin contraction. This mechanochemical response induces activation and transfer of the YAP/TAZ complex to the cell nucleus to influence gene expression. This may lead to synthesis of various components of both cytoskeleton and the ECM, therefore stimulating the ECM remodeling and reconstruction, therefore launching the complex feedback loop of tissue skeleton dynamics. This mechanism can be induced by a direct mechanical impact on any components of the cytoskeleton that are integrated into the membrane-associated complexes, and also interconnected with each other in the cytoplasm.

Figure 3

Possible pathways of mesenchymal stem cell differentiation in response to mechanical properties of extracellular matrix. The softest materials not only support the cellular stemness, but inhibit cell division processes.

Figure 4

Embryonic mechanosensing promoted by mechanical parameters of tissue microenvironment. Early embryogenesis requires soft environment and intercellular mechanosignaling promoted by contraction of actomyosin cortical cytoskeleton. Further development is characterized by increased stiffness of decidua. However, cellular contractility and formation of intercellular junctions are still important for cellular differentiation.

Figure 5

Reaggregation and reassembling of the cell—ECM (extracellular matrix) complex during malignization. The normal cells are regular-shaped and form around themselves a specifically organized structure. The cancer ECM is less organized, and may be partially disrupted due to metalloproteinases, synthesized by cancer cells.