A role for the podosome/invadopodia scaffold protein Tks5 in tumor growth in vivo
A role for the podosome/invadopodia scaffold protein Tks5 in tumor growth in vivo
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DOI：
10.1016/j.ejcb.2008.02.008
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发表时间：
2008-09-01
影响因子：
6.6
通讯作者：
Courtneidge, Sara A.
中科院分区：
文献类型：
--
作者：
Blouw, Barbara;Seals, Darren F.;Courtneidge, Sara A.
足体和侵入足是位于细胞膜腹侧的电子致密、富含肌动蛋白的突起。在各种类型的正常细胞中检测到，但也在人癌细胞和Src转化的成纤维细胞中检测到。以前，我们已经表明，支架蛋白Tks 5（酪氨酸激酶底物5）共定位于不同的人类癌细胞和在Src转化的NIH-3 T3细胞中的podosomes/invadopodia。在Tks 5表达减少时，足体形成减少，这导致各种人癌细胞系中体外明胶降解减少。然而，目前尚不清楚癌细胞是否需要podosomes来进行体内肿瘤生长和转移。为了验证这一想法，我们评估了Src转化的NIH-3 T3细胞在小鼠中形成皮下肿瘤的能力，所述细胞显示稳定的Tks 5表达减少和podosome形成（Tks 5 KD）。我们证明Tks 5的表达减少与该部位肿瘤生长减少相关。此外，我们在高静脉注射后从这些细胞产生肺转移。静脉注射Tks 5 KD的小鼠的肺显示出较小的转移灶，但与对照组相比，病变数量无差异，表明从血流外渗至肺实质可能不需要podosomes。独立于微环境。减少的肿瘤生长与减少的肿瘤血管形成相关。我们的数据潜在地暗示了一种新的作用，即作为肿瘤血管生成的介质的podosomes，并支持进一步探索podosomes形成和Tks 5表达如何促进肿瘤进展。(C)2008年Elsevier GmbH。All rights reserved.
Podosomes and invadopodia are electron-dense, actin-rich protrusions located oil the ventral side of the cellular membrane. The), are detected in various types of normal cells, but also in human cancer cells and in Src-transformed fibroblasts. Previously we have shown that the scaffold protein Tks5 (tyrosine kinase substrate 5) co-localizes to podosomes/invadopodia in different human cancer cells and In Src-transformed NIH-3T3 cells. Upon reduced expression of Tks5 podosome formation is decreased, which leads to diminished gelatin degradation in vitro in various human cancer cell lines. It is unclear, however, whether cancer cells need podosomes for tumor growth and metastasis in vivo. To test this idea, We evaluated the ability of Src-transformed NIH-3T3 cells, showing stable reduced expression of Tks5 and podosome formation (Tks5 KD), to form subcutaneous tumors in mice. We demonstrate that decreased expression of Tks5 correlated with reduced tumor growth at this site. In addition, we generated lung metastases from these cells following tall vein injection. The lungs of mice injected i.v. With the Tks5 KD showed smaller-sized metastases, but there was no difference in the number of lesions compared to the controls, indicating that podosomes may not be required for extravasation from the blood stream into the lung parenchyma. Independent of the microenvironment however. the reduced tumor growth correlated with decreased tumor vascularization. Our data potentially implicate a novel role of podosomes as mediators Of tumor angiogenesis and support further exploration of how podosome formation and Tks5 expression contribute to tumor progression. (C) 2008 Elsevier GmbH. All rights reserved.