The role of the tissue microenvironment in the regulation of cancer cell motility and invasion
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The role of the tissue microenvironment in the regulation of cancer cell motility and invasion Jan Brábek1*, Claudia T Mierke2, Daniel Rösel1, Pavel Veselý3, Ben Fabry2
Abstract During malignant neoplastic progression the cells undergo genetic and epigenetic cancer-specific alterations that finally lead to a loss of tissue homeostasis and restructuring of the microenvironment. The invasion of cancer cells through connective tissue is a crucial prerequisite for metastasis formation. Although cell invasion is foremost a mechanical process, cancer research has focused largely on gene regulation and signaling that underlie uncontrolled cell growth. More recently, the genes and signals involved in the invasion and transendothelial migration of cancer cells, such as the role of adhesion molecules and matrix degrading enzymes, have become the focus of research. In this review we discuss how the structural and biomechanical properties of extracellular matrix and surrounding cells such as endothelial cells influence cancer cell motility and invasion. We conclude that the microenvironment is a critical determinant of the migration strategy and the efficiency of cancer cell invasion. Introduction The malignancy of cancer is rooted in the ability of tumor cells to spread to distant locations in the body and to form metastases. The formation of metastases is a complex process involving multiple steps: first, tumor cells must break away from the primary tumor and invade through the surrounding tissue and its extracellular matrix (ECM). Matrix invasion is one of the earliest steps in the metastatic process and a key determinant of the metastatic potential of tumor cells. Next, the tumor cells enter the bloodstream or the lymph vessel system which enables them to quickly and efficiently spread to distant sites; therefore, the metastasizing tumor cells must be capable of intravasation, survival in the bloodstream or lymphatic system, and extravasation (reviewed in [1]). Regardless of whether extravasation takes place, however, the migration through connective tissue (subsequently called invasion) is a prerequisite for metastasis formation. Although cell invasion is foremost a mechanical process, cancer research has focused largely on gene regulation and signaling that lead to uncontrolled cell growth. More recently, the genes and signals involved in the invasion and transendothelial migration of cancer cells, * Correspondence: [email protected] 1 Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic Full list of author information is available at the end of the article
such as the role of adhesion molecules and matrix degrading enzymes, have become the focus of research [2-4]. However, the mechanical processes themselves that control cancer cell invasion, such as cell adhesion, changes of cell shape, cell movements and motility, and the generation of forces, are currently not well understood [5-8]. We argue that the invasion process can only be understood in the context
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