Biological role of matrix stiffness in tumor growth and treatment

Abstract

In recent years, the biological role of changes in physical factors in carcinogenesis and progression has attracted increasing attention. Matrix stiffness, also known as ECM stress, is a critical physical factor of tumor microenvironment and remains alternating during carcinogenesis as a result of ECM remodeling through activation of cancer-associated fibroblasts and extracellular collagen accumulation, crosslinking and fibrosis. Different content and density of extracellular collagen in ECM endows matrix with varying stiffness. Physical signals induced by matrix stiffness are transmitted to tumor cells primarily by the integrins receptor family and trigger a series of mechanotransduction that result in changes in tumor cell morphology, proliferative capacity, and invasive ability. Importantly, accumulating evidence revealed that changes in matrix stiffness in tumor tissues greatly control the sensitivity of tumor cells in response to chemotherapy, radiotherapy, and immunotherapy through integrin signaling, YAP signaling, and related signaling pathways. Here, the present review analyzes the current research advances on matrix stiffness and tumor cell behavior with a view to contributing to tumor cell growth and treatment, with the hope of improving the understanding of the biological role of matrix stiffness in tumors.

Keywords: Apoptosis; Cancer therapy; Cell proliferation; Matrix stiffness.

Fig. 1

Remodeling of the ECM by crosslinking and deposit of collagen and other ECM proteins. External solid stress and internal stiffness have been continuously interacting during tumor progression. Tumor cells remodel the ECM through CAFs-mediated deposition, cross-linking and degradation of ECM proteins (mainly collagen). Tumor cells sense changes in ECM stiffness through the integrin receptor signaling and MSCs (Piezo 1) to regulate the cytoskeleton, following which undergo a series of adaptive changes that present different cell behavior characteristics

Fig. 2

Measurement methods of matrix stiffness. a Principle of AFM. When the AFM is working, the laser emitted by the laser to hits the cantilever beam and then reflected back to the spot detector. When the probe is not in contact with the sample, the AFM probe cantilever does not deflect and the spot is not deflected because there is no force acting, so the deflection remains at a fixed value; when the AFM probe cantilever is in contact with the cell (or other samples), the cantilever is subjected to the sensor force acting on the longitudinal deflection, causing the laser light path to change, which leads to the corresponding longitudinal deflection of the laser spot in the four quadrants of the spot detector. The Young's modulus of the object is calculated and analyzed. AFM has a micro cantilever which is usually made of a silicon wafer or silicon nitride wafer that is generally 100–500 um long and 500–5 um thick, and one end of micro cantilever is fixed, and the other end has a tip in contact with the sample. b Principle of SWE. The working principle of SWE can be understood in three points. The first is to generate shear waves through focused acoustic radiation force from a linear ultrasound array. The fast plane wave excitation is then used to track displacement and velocity as the shear waves propagate. Third, calculating the tissue displacement to calculate shear wave velocity and shear modulus