Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy.
Int J Mol Sci. 2019 Oct 7;20(19):4947. doi: 10.3390/ijms20194947.
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.
细胞外基质（ECM）是细胞外分泌的大分子的复杂网络，例如胶原蛋白、酶和糖蛋白，其主要功能涉及细胞和组织的结构支架和生化支持。ECM 稳态对于器官发育和生理条件下的功能至关重要，而其持续的修饰或失调可导致病理状况。在癌症进展过程中，上皮肿瘤细胞可能经历上皮-间充质转化（EMT），这是一种形态和功能重塑，深刻改变了肿瘤细胞的特征，导致上皮标志物（例如 E-钙黏蛋白）的丧失、细胞极性和细胞间连接的变化以及间质标志物（例如 N-钙黏蛋白、纤连蛋白和波形蛋白）的增加。这个过程增强了肿瘤细胞从原始肿瘤块脱落和侵袭的能力，这是转移发生所必需的，从而允许肿瘤细胞进入血液或淋巴液并在远处定植。导致特定部位转移发展的机制在很大程度上仍然不清楚，但靶组织 ECM 中发生的修饰正在被深入研究。基质金属蛋白酶和几种粘附受体，其中整合素发挥关键作用，参与与转移相关的 ECM 修饰。此外，参与转移灶形成的细胞，如癌症相关成纤维细胞（CAF）和肿瘤相关巨噬细胞（TAM），已被发现在促进肿瘤细胞粘附和生长的 ECM 改变中发挥重要作用。在这篇综述中，我们重点介绍了在癌症进展和远处转移过程中发生的 ECM 修饰的分子机制，特别关注肺、肝和骨。此外，还将根据最新发现，综述形成肿瘤微环境的细胞的功能作用。
