Role of the mechanical microenvironment in cancer development and progression

Abstract

Cross-talk between tumor cells and mechanical stress in the tumor microenvironment has been shown to be involved in carcinogenesis. High mechanical stress in tumors can alter the metabolism and behaviors of cancer cells and cause cancer cells to attain cancer stem-like cell properties, thus driving tumor progression and promoting metastasis. The mechanical signal is converted into a biochemical signal that activates tumorigenic signaling pathways through mechanotransduction. Herein, we describe the physical changes occurring during reprogramming of cancer cell metabolism, which regulate cancer stem cell functions and promote tumor progression and aggression. Furthermore, we highlight emerging therapeutic strategies targeting mechanotransduction signaling pathways.

Keywords: Cancer stem cell; cell metabolism; mechanical force; tumor progression.

Figure 1

Schematic presentation of biomechanical force transmission from the extracellular environment into cancer cells. Changes in the mechanical properties of the TME transmit to cancer cells through 2 distinct pathways: the physical nuclear-cytoskeletal connection and biochemical signaling. Mechanical stress transmission occurs through physical nuclear-cytoskeletal connections involving integrins, F-actin, nesprin, and SUN proteins (red box). Moreover, integrin clustering and focal adhesion assembly, driven by biomechanical forces, activate biochemical signaling pathways such as PI3K-Akt, GDF15/Akt/CREB1, YAP/TAZ, TWIST1-G3BP2, CXCR4/CXCL12, and MEK/ERK (green box).