Department of Chemistry and Biochemistry & Nanocenter, University of South Carolina, Columbia, SC 29208, USA.
Integr Biol (Camb). 2012 Aug;4(8):897-904. doi: 10.1039/c2ib20034a. Epub 2012 Jun 22.
Cancer stem cells, also known as tumour-initiating cells (TICs), are identified as highly tumorigenic population within tumours and hypothesized to be main regulators in tumour growth, metastasis and relapse. Evidence also suggests that a tumour microenvironment plays a critical role in the development and progression of cancer, by constantly modulating cell-matrix interactions. Scientists have tried to characterize and identify the TIC population but the actual combination of extracellular components in deciphering the fate of TICs has not been explored. The basic unanswered question is the phenotypic stability of this TIC population in a tissue extracellular matrix setting. The in vivo complexity makes it difficult to identify parameters in a diverse milieu that affect TICs behaviour. Herein we studied how the TIC population would respond when subjected to a unique microenvironment composed of different extracellular proteins. The TIC-enriched population isolated from a Her2/neu-induced mouse mammary tumour was cultured on collagen, fibronectin and laminin coated substrates for one to two weeks. Our observations indicate that a laminin substrate can maintain the majority of the self-renewing and tumorigenic TIC population, whereas collagen induced a more differentiated phenotype of the cells. Also interestingly, fibronectin substrates dictated an invasive phenotype of TICs as evidenced from the EMT-related gene expression pattern. The results of this study signify that the microenvironmental cues play a considerable role in tumour relapse and progression by altering the cancer stem cell behaviour and thus this knowledge could be used to design novel cancer therapeutics.
癌症干细胞，也被称为肿瘤起始细胞（TICs），被鉴定为肿瘤内具有高度致瘤性的群体，并被假设为肿瘤生长、转移和复发的主要调节因子。有证据表明，肿瘤微环境通过不断调节细胞-基质相互作用，在癌症的发展和进展中起着关键作用。科学家们试图对 TIC 群体进行特征描述和鉴定，但在解析 TIC 命运时，细胞外成分的实际组合尚未得到探索。基本的未解决问题是，在组织细胞外基质环境中，这种 TIC 群体的表型稳定性如何。体内的复杂性使得难以确定在多样化的环境中影响 TIC 行为的参数。在这里，我们研究了当 TIC 群体受到由不同细胞外蛋白组成的独特微环境的影响时，它们会如何反应。从 Her2/neu 诱导的小鼠乳腺肿瘤中分离出的富含 TIC 的群体，在涂有胶原蛋白、纤维连接蛋白和层粘连蛋白的基质上培养一到两周。我们的观察表明，层粘连蛋白基质可以维持大多数具有自我更新和致瘤性的 TIC 群体，而胶原蛋白则诱导细胞呈现出更分化的表型。此外，有趣的是，纤维连接蛋白基质决定了 TICs 的侵袭表型，这可以从 EMT 相关基因表达模式中得到证明。这项研究的结果表明，微环境线索通过改变癌症干细胞的行为，在肿瘤复发和进展中起着重要作用，因此这方面的知识可以用于设计新的癌症治疗方法。
