上皮-間質(zhì)轉(zhuǎn)化（epithelial mesenchymal transitions,，EMT）是指上皮細(xì)胞在形態(tài)學(xué)上發(fā)生向成纖維細(xì)胞或間充質(zhì)細(xì)胞表型的轉(zhuǎn)變并獲得遷移的能力,。EMT是胚胎發(fā)育中的一個(gè)基本過(guò)程，它使在特殊部位產(chǎn)生的上皮細(xì)胞從上皮組織分離并遷移到其他位置,，是正常發(fā)育,、傷口愈合以及惡性上皮腫瘤發(fā)生的基礎(chǔ)。
上皮間質(zhì)轉(zhuǎn)化（EMT）對(duì)促進(jìn)乳腺癌侵襲,、全身性的散播是必不可少的,，乳腺癌細(xì)胞發(fā)生上皮間質(zhì)轉(zhuǎn)化后可以引起乳腺癌細(xì)胞微轉(zhuǎn)移，EMT過(guò)程部分依賴(lài)于粘著斑激酶（FAK）發(fā)揮作用,。
研究人員證實(shí)Pyk2的表達(dá)存在以下幾點(diǎn)：（一）人乳腺癌復(fù)發(fā)患者中水平上調(diào),；（二）該蛋白的表達(dá)可以預(yù)測(cè)人源MDA-MB-231乳腺癌癌細(xì)胞的轉(zhuǎn)移性生長(zhǎng)，但不與腫瘤細(xì)胞的侵襲能力相關(guān),；（三）與原發(fā)腫瘤組織細(xì)胞相比,，體外培養(yǎng)轉(zhuǎn)移性病灶乳腺癌細(xì)胞中高表達(dá)。
進(jìn)一步的研究表明,，轉(zhuǎn)移性人源和小鼠來(lái)源的乳腺癌細(xì)胞在EMT過(guò)程中,，接受轉(zhuǎn)化生長(zhǎng)因子-β（TGF-β）刺激情況下會(huì)高表達(dá)Pyk2?；蛩交蚴撬幬锼揭种芇YK2表明,，這種蛋白酪氨酸激酶的活性對(duì)于乳腺癌細(xì)胞接受TGF-β后侵襲能力上調(diào),、小鼠原位乳腺腫瘤的形成是非常重要的。
與之形成鮮明對(duì)比的,，PYK2的缺失會(huì)阻止三維培養(yǎng)過(guò)程中TGF-β刺激的乳腺癌細(xì)胞生長(zhǎng),，而在體內(nèi)研究中PYK2的缺失會(huì)抑制乳腺癌細(xì)胞轉(zhuǎn)移至老鼠肺部。Pyk2表達(dá)與E-鈣粘素的表達(dá)呈負(fù)相關(guān),，PYK2表達(dá)水平的增高穩(wěn)定整合素β1的表達(dá),，而整合素β1的表達(dá)對(duì)啟動(dòng)轉(zhuǎn)移性乳腺癌細(xì)胞的生長(zhǎng)至關(guān)重要。
因此,，該研究闡明了PYK2在EMT過(guò)程中以及TGF-β刺激的腫瘤轉(zhuǎn)移中起關(guān)鍵調(diào)控作用,，該蛋白的表達(dá)會(huì)促進(jìn)新生轉(zhuǎn)移灶腫瘤細(xì)胞的生長(zhǎng)。（生物谷：Bioon.com）
doi:10.1038/onc.2012.230
PMC:
PMID:
TGF-β stimulates Pyk2 expression as part of an epithelial-mesenchymal transition program required for metastatic outgrowth of breast cancer
M K Wendt1, B J Schiemann1, J G Parvani1, Y-H Lee1, Y Kang2 and W P Schiemann1
Epithelial-mesenchymal transition (EMT) programs are essential in promoting breast cancer invasion, systemic dissemination and in arousing proliferative programs in breast cancer micrometastases, a reaction that is partially dependent on focal adhesion kinase (FAK). Many functions of FAK are shared by its homolog, protein tyrosine kinase 2 (Pyk2), raising the question as to whether Pyk2 also participates in driving the metastatic outgrowth of disseminated breast cancer cells. In addressing this question, we observed Pyk2 expression to be (i) significantly upregulated in recurrent human breast cancers; (ii) differentially expressed across clonal isolates of human MDA-MB-231 breast cancer cells in a manner predictive for metastatic outgrowth, but not for invasiveness; and (iii) dramatically elevated in ex vivo cultures of breast cancer cells isolated from metastatic lesions as compared with cells that produced the primary tumor. We further show that metastatic human and murine breast cancer cells robustly upregulate their expression of Pyk2 during EMT programs stimulated by transforming growth factor-β (TGF-β). Genetic and pharmacological inhibition of Pyk2 demonstrated that the activity of this protein tyrosine kinase was dispensable for the ability of breast cancer cells to undergo invasion in response to TGF-β, and to form orthotopic mammary tumors in mice. In stark contrast, Pyk2-deficiency prevented TGF-β from stimulating the growth of breast cancer cells in 3D-organotypic cultures that recapitulated pulmonary microenvironments, as well as inhibited the metastatic outgrowth of disseminated breast cancer cells in the lungs of mice. Mechanistically, Pyk2 expression was inversely related to that of E-cadherin, such that elevated Pyk2 levels stabilized β1 integrin expression necessary to initiate the metastatic outgrowth of breast cancer cells. Thus, we have delineated novel functions for Pyk2 in mediating distinct elements of the EMT program and metastatic cascade regulated by TGF-β, particularly the initiation of secondary tumor outgrowth by disseminated cells.
