Department of Surgery/Urology, and Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, USA.
Int Rev Cell Mol Biol. 2011;289:117-47. doi: 10.1016/B978-0-12-386039-2.00004-3.
Upon detachment from the extracellular matrix, tumor epithelial cells and tumor-associated endothelial cells are capable of overcoming anoikis, gain survival benefits, and hence contribute to the process of metastasis. The focal-adhesion complex formation recruits the association of key adaptor proteins such as FAK (focal-adhesion kinase). Vimentin, paxillin, and talin are responsible for mediating the interaction between the actin cytoskeleton and integrins. Talin is an early-recruited focal-adhesion player that is of structural and functional significance in mediating interactions with integrin cytoplasmic tails leading to destabilization of the transmembrane complex and resulting in rearrangements in the extracellular integrin compartments that mediate integrin activation. Talin-mediated integrin activation plays a definitive role in integrin-mediated signaling and induction of downstream survival pathways leading to protection from anoikis and consequently resulting in cancer progression to metastasis. We recently reported that talin expression is significantly increased in prostate cancer compared with benign and normal prostate tissue and that this overexpression correlates with progression to metastatic disease implicating a prognostic value for talin during tumor progression. At the molecular level, talin is functionally associated with enhanced survival and proliferation pathways and confers anoikis resistance and metastatic spread of primary tumor cells via activation of the Akt survival pathway. In this review, we discuss the growing evidence surrounding the value of talin as a prognostic marker of cancer progression to metastasis and as therapeutic target in advanced prostate cancer, as well as the current understanding of mechanisms regulating its signaling activity in cancer.
当肿瘤上皮细胞和肿瘤相关内皮细胞从细胞外基质上脱离时，它们能够克服失巢凋亡，获得生存优势，从而促进转移过程。黏着斑复合物的形成招募了关键衔接蛋白的关联，如 FAK（黏着斑激酶）。波形蛋白、桩蛋白和塔林负责介导细胞骨架肌动蛋白和整合素之间的相互作用。塔林是一个早期招募的黏着斑参与者，在介导与整合素胞质尾部的相互作用方面具有结构和功能意义，导致跨膜复合物的不稳定，并导致细胞外整合素隔室的重新排列，从而介导整合素的激活。塔林介导的整合素激活在整合素介导的信号转导和诱导下游存活途径中起着决定性作用，导致对失巢凋亡的保护，从而导致癌症进展为转移。我们最近报道，与良性和正常前列腺组织相比，前列腺癌中塔林的表达显著增加，并且这种过表达与进展为转移性疾病相关，表明塔林在肿瘤进展过程中有预后价值。在分子水平上，塔林与增强的存活和增殖途径功能相关，并通过激活 Akt 存活途径赋予原代肿瘤细胞抗失巢凋亡和转移扩散的能力。在这篇综述中，我们讨论了围绕塔林作为癌症进展为转移的预后标志物以及作为晚期前列腺癌治疗靶点的价值的越来越多的证据，以及调节其在癌症中信号活性的机制的当前理解。
