Abstract
Metastasis is a multistep process in which tumor extracellular matrix (ECM) and cancer cell cytoskeleton interactions are pivotal. ECM is connected, through integrins, to the cell’s adhesome at cell–ECM adhesion sites and through them to the actin cytoskeleton and various downstream signaling pathways that enable the cell to respond to external stimuli in a coordinated manner. Cues from cell-adhesion proteins are fundamental for defining the invasive potential of cancer cells, and many of these proteins have been proposed as potent targets for inhibiting cancer cell invasion and thus, metastasis. In addition, ECM accumulation is quite frequent within the tumor microenvironment leading in many cases to an intense fibrotic response, known as desmoplasia, and tumor stiffening. Stiffening is not only required for the tumor to be able to displace the host tissue and grow in size but also contributes to cell–ECM interactions and can promote cancer cell invasion to surrounding tissues. Here, we review the role of cell adhesion and matrix stiffness in cancer cell invasion and metastasis.
Highlights
Reviewed by: Santos Mañes, Consejo Superior de Investigaciones Científicas (CSIC), Spain Leonardo Freire-de-Lima, Universidade Federal do Rio de Janeiro, Brazil
Matrix stiffening can induce epithelial to mesenchymal transition (EMT), leading to the acquisition of a more aggressive phenotype that promotes cancer cell invasion owing to a loss of intercellular adhesions [83], and it is hypothesized to contribute to the transformation of cancer cells to stem cell-like cancer cells that can survive under the harsh hypoxic conditions of the tumor microenvironment, are more resistant to cytotoxic drugs, and can migrate and invade through surrounding tissues [84]
Cell–extracellular matrix (ECM) adhesion proteins, actin cytoskeleton, and ECM stiffness play a major role in driving cancer cell invasion and metastasis being involved in virtually all steps of the metastatic process from cell dissociation from the original tumor, to invasion through surrounding ECM until the final step of cancer cell homing in the new metastasis site
Summary
Cancer cells are able to invade the surrounding ECM in the form of single cells or as collective groups of cells moving together, depending on whether cell–cell adhesion proteins, such as E-cadherin, are completely or partially lost in the original tumor, respectively [11]. Integrin-independent migration has been described [12], both modes of invasion are considered to be heavily dependent on integrin-mediated adhesion to the ECM, whereas collective invasion requires dynamic cell–cell adhesions so that loosening of cell junctions becomes sufficient for invasion. The actual outcome in terms of invasion is dependent upon the balance between E-cadherin-mediated adhesions and integrin cell–ECM adhesions [11]. Activation protein tyrosine kinases Src and focal adhesion kinase (FAK) are activated promoting further cytoskeletal changes as well as activation of downstream signaling pathways vital for cell adhesion, proliferation, survival, migration, DISRUPTION OF CELL–CELL ADHESION
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