Could growth factor-mediated extracellular matrix deposition and degradation offer the ground for directed pharmacological targeting in fibrosarcoma?
Could growth factor-mediated extracellular matrix deposition and degradation offer the ground for directed pharmacological targeting in fibrosarcoma?
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生长因子介导的细胞外基质沉积和降解能否为纤维肉瘤的定向药理靶向奠定基础？
DOI：
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发表时间：
2013
影响因子：
4.1
通讯作者：
G. Tzanakakis
中科院分区：
文献类型：
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作者：
D. Nikitovic;A. Berdiaki;A. Banos;A. Tsatsakis;Nikos Karamanos;G. Tzanakakis
肿瘤细胞外基质（ECM）的特定组织是肿瘤发生的复杂途径中固有的基本步骤。纤维肉瘤是一种罕见的致命性恶性肿瘤，起源于成纤维细胞，其特征是形成丰富的 ECM。经历恶性转化的成纤维细胞会特异性改变其 ECM 的组成和组织，以促进生长、存活和侵袭。纤维肉瘤细胞具有高含量和高周转的 ECM 成分，包括透明质酸、蛋白聚糖、胶原蛋白、纤连蛋白和层粘连蛋白。内源性生长因子（例如 TGFβ、EGF、FGF2、VEGF 和 IFG-I）的细胞信号传导与 ECM 重塑、基质形成和纤维肉瘤进展直接相关。在这方面，生长因子影响基质大分子的表达，例如分泌的和细胞相关的蛋白聚糖、透明质酸及其受体CD44和RHAMM，以及基质降解金属蛋白酶的表达和活性，这些在组织重塑和纤维肉瘤进展中至关重要。因此，考虑人类癌症中生长因子及其受体以及下游信号传导的治疗方法很可能是目前正在探索的药理学目标。在本文中，我们重点关注生长因子信号在ECM大分子沉积和降解水平上调节纤维肉瘤细胞ECM组织、ECM重塑与纤维肉瘤细胞恶性行为的关系以及其治疗干预的假定策略。
The specific organization of the tumor extracellular matrix (ECM) is an intrinsic and basic step in the convoluted pathways of tumorigenesis. Fibrosarcoma is a rare, lethal, malignant tumor originating from fibroblasts, characterized by the formation of an abundant ECM. Fibroblastoid cells undergoing malignant transformation specifically alter composition and organization of their ECM to facilitate growth, survival and invasion. Fibrosarcoma cells were shown to have a high content and turnover of ECM components including hyaluronan, proteoglycans, collagens, fibronectin and laminin. Cell signaling by endogenous growth factors, such as TGFβ, EGF, FGF2, VEGF and IFG-I, is directly correlated to ECM remodeling, stroma formation and fibrosarcoma progression. In this regard, growth factors affect the expression of matrix macromolecules, such as secreted and cell-associated proteoglycans, hyaluronan and its receptors CD44 and RHAMM, as well as the expression and activity of matrix- degrading metalloproteinases, which are of critical importance in tissue remodeling and fibrosarcoma progression. Therefore, therapeutic approaches considering growth factors and their receptors as well as downstream signaling in human cancers may well be pharmacological targets being currently explored. In this article, we focus on growth factor signaling regulating fibrosarcoma cell ECM organization at the level of deposition and degradation of ECM macromolecules, the relation of ECM remodeling with fibrosarcoma cell malignant behaviour as well as the putative strategies for its therapeutic intervention.