Tchafa Alimatou M, Ta Mi, Reginato Mauricio J, Shieh Adrian C
School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, Pennsylvania.
Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
Mol Cancer Res. 2015 Apr;13(4):755-64. doi: 10.1158/1541-7786.MCR-14-0471. Epub 2015 Jan 7.
A variety of biophysical forces are altered in the tumor microenvironment (TME) and these forces can influence cancer progression. One such force is interstitial fluid flow (IFF)-the movement of fluid through the tissue matrix. IFF was previously shown to induce invasion of cancer cells, but the activated signaling cascades remain poorly understood. Here, it is demonstrated that IFF induces invasion of ERBB2/HER2-expressing breast cancer cells via activation of phosphoinositide-3-kinase (PI3K). In constitutively activate ERBB2-expressing cells that have undergone epithelial-to-mesenchymal transition (EMT), IFF-mediated invasion requires the chemokine receptor CXCR4, a gradient of its ligand CXCL12, and activity of the PI3K catalytic subunits p110α and β. In wild-type ERBB2-expressing cells, IFF-mediated invasion is chemokine receptor-independent and requires only p110α activation. To test whether cells undergoing EMT alter their signaling response to IFF, TGFβ1 was used to induce EMT in wild-type ERBB2-expressing cells, resulting in IFF-induced invasion dependent on CXCR4 and p110β.
This study identifies a novel signaling mechanism for interstitial flow-induced invasion of ERBB2-expressing breast cancer cells, one that depends on EMT and acts through a CXCR4-PI3K pathway. These findings suggest that the response of cancer cells to interstitial flow depends on EMT status and malignancy.
肿瘤微环境（TME）中的多种生物物理力会发生改变，这些力可影响癌症进展。其中一种力是间质液流动（IFF）——液体通过组织基质的运动。先前已表明IFF可诱导癌细胞侵袭，但对激活的信号级联反应仍了解甚少。在此，证明了IFF通过激活磷酸肌醇-3-激酶（PI3K）诱导表达ERBB2/HER2的乳腺癌细胞侵袭。在经历上皮-间质转化（EMT）的组成型激活ERBB2表达细胞中，IFF介导的侵袭需要趋化因子受体CXCR4、其配体CXCL12的梯度以及PI3K催化亚基p110α和β的活性。在野生型ERBB2表达细胞中，IFF介导的侵袭不依赖趋化因子受体，仅需要p110α激活。为了测试经历EMT的细胞是否改变其对IFF的信号反应，使用TGFβ1在野生型ERBB2表达细胞中诱导EMT，导致IFF诱导的侵袭依赖于CXCR4和p110β。
本研究确定了间质流诱导表达ERBB2的乳腺癌细胞侵袭的一种新信号机制，该机制依赖于EMT并通过CXCR4-PI3K途径起作用。这些发现表明癌细胞对间质流的反应取决于EMT状态和恶性程度。
