Impact of the physical microenvironment on tumor progression and metastasis

Abstract

The tumor microenvironment is increasingly understood to contribute to cancer development and progression by affecting the complex interplay of genetic and epigenetic changes within the cells themselves. Moreover, recent research has highlighted that, besides biochemical cues from the microenvironment, physical cues can also greatly alter cellular behavior such as proliferation, cancer stem cell properties, and metastatic potential. Whereas initial assays have focused on basic ECM physical properties, such as stiffness, novel in vitro systems are becoming increasingly sophisticated in differentiating between distinct physical cues-ECM pore size, fiber alignment, and molecular composition-and elucidating the different roles these properties play in driving tumor progression and metastasis. Combined with advances in our understanding of the mechanisms responsible for how cells sense these properties, a new appreciation for the role of mechanics in cancer is emerging.

Figure 1. The tumor microenvironment

The behavior of cancer cells is largely influenced by their environment. Hypoxia can induce epithelial-mesenchymal transition (EMT), stromal cells can release chemotactic growth factors, and cell-induced mechanical strains can realign ECM fibers. Moreover, these factors have been implicated with tumor progression, invasion, and metastasis. Furthermore, cells mediate considerable crosstalk between the environmental factors. For instance, in response to hypoxia, cells can stiffen the matrix through increased LOX expression. Additionally, tumor cells interact with fibroblasts causing the deposition of new ECM molecules, and physical forces from strains are associated with fiber alignment, leading to persistent migration and tissue invasion of cancer cells.

Figure 2. Intracellular signaling pathways integrate cell responses

Cancer cells integrate a multitude of external signals to direct their responses. Besides well-established growth factor stimuli, for instance, LPA, which binds to G-protein coupled receptors (GPCR), physical forces also affect cell behavior. Cell-cell or cell-matrix adhesion molecules such as E-cadherin or integrins have a dual role: On the one hand, they provide structural support by linking the intracellular cytoskeleton with other cells or ECM, respectively. On the other hand, these molecules are also involved in signaling cascades, with a substantial overlap with the cascades mediated by growth factors. They, as well as some molecules binding to them, such as focal adhesion (FA) molecules, are constantly exposed to forces which, for instance, originate from myosin-mediated intracellular tension. Downstream of the cascades, molecules such as YAP integrate those different stimuli and direct transcriptional programs involved in proliferation, stem cell properties or metastasis.