Abstract
The extracellular matrix (ECM) is a complex network of extracellular-secreted macromolecules, such as collagen, enzymes and glycoproteins, whose main functions deal with structural scaffolding and biochemical support of cells and tissues. ECM homeostasis is essential for organ development and functioning under physiological conditions, while its sustained modification or dysregulation can result in pathological conditions. During cancer progression, epithelial tumor cells may undergo epithelial-to-mesenchymal transition (EMT), a morphological and functional remodeling, that deeply alters tumor cell features, leading to loss of epithelial markers (i.e., E-cadherin), changes in cell polarity and intercellular junctions and increase of mesenchymal markers (i.e., N-cadherin, fibronectin and vimentin). This process enhances cancer cell detachment from the original tumor mass and invasiveness, which are necessary for metastasis onset, thus allowing cancer cells to enter the bloodstream or lymphatic flow and colonize distant sites. The mechanisms that lead to development of metastases in specific sites are still largely obscure but modifications occurring in target tissue ECM are being intensively studied. Matrix metalloproteases and several adhesion receptors, among which integrins play a key role, are involved in metastasis-linked ECM modifications. In addition, cells involved in the metastatic niche formation, like cancer associated fibroblasts (CAF) and tumor associated macrophages (TAM), have been found to play crucial roles in ECM alterations aimed at promoting cancer cells adhesion and growth. In this review we focus on molecular mechanisms of ECM modifications occurring during cancer progression and metastatic dissemination to distant sites, with special attention to lung, liver and bone. Moreover, the functional role of cells forming the tumor niche will also be reviewed in light of the most recent findings.
Highlights
The extracellular matrix (ECM) is a complex network of extracellular-secreted macromolecules, such as collagen, enzymes and glycoproteins, whose main functions deal with structural scaffolding and biochemical support of cells and tissues
In order to prepare the appropriate soil for the colonization of distant sites, metastatic tumor cells set in motion a complex mechanism aimed at promoting the formation of a suitable microenvironment, thereby creating the conditions for attachment, survival and growth of circulating tumor cells (CTC) (Figure 1)
It appears that the most targetable steps in metastasis deal with the formation of premetastatic niche and colonization of distant sites—two mechanisms that deeply imply the involvement of ECM
Summary
The extracellular matrix (ECM), for years considered as a mere support structure for tissue architecture, is a dynamic compartment that modulates and regulates cell functions such as adhesion, migration, proliferation and differentiation [1]. It is an intricate network composed of approximately 300 proteins that vary in a cell/tissue-specific manner. The triple-stranded α helix can, in turn, assemble to form supramolecular structures, such as fibrils and networks Elastin, another abundantly expressed protein in ECM, is secreted as a precursor protein, tropoelastin, that assembles in fibers with a great number of crosslinks due to the presence of lysine residues. It is not surprising that alterations in a specific ECM component or in the interactions with adhesion receptors can have a remarkable impact on the biochemical and physical properties of the ECM and eventually lead to dysregulation of cell adhesion and function
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