Autocrine CSF1R signaling mediates switching between invasion and proliferation downstream of TGFβ in claudin-low breast tumor cells.
Autocrine CSF1R signaling mediates switching between invasion and proliferation downstream of TGFβ in claudin-low breast tumor cells.
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患者数据表明，集落刺激因子-1(CSF1)及其受体(CSF1R)在乳腺癌进展过程中发挥关键作用。我们先前已经证明，在同时表达CSF1和CSF1R的人乳腺肿瘤中，体内的侵袭既依赖于与肿瘤相关巨噬细胞的旁分泌相互作用，也依赖于肿瘤细胞本身对CSF1R的自分泌调节。虽然肿瘤细胞和巨噬细胞之间的旁分泌相互作用已经被广泛研究，但对自分泌CSF1R信号促进肿瘤进展的机制知之甚少。我们在这里显示，克劳丁低亚型乳腺癌患者CSF1R的表达显著增加。利用一组乳腺癌细胞系，我们证实CSF1R的表达被转化生长因子β特异性地上调并调节在克拉丁低细胞系中。在MDA-MB-231异种移植瘤(一种克拉丁含量低的细胞系)中，自分泌CSF1R信号的缺失导致肿瘤体积增加，促进了增殖，但显著减少了侵袭、扩散和转移。事实上，我们发现，只有在克拉丁低细胞系中，转化生长因子β下游的CSF1R相反地调控着细胞的增殖和侵袭。活体多光子成像显示，抑制肿瘤细胞中的CSF1R会导致体内运动性降低，并使形态更紧密。我们发现，在体外和体内，CSF1R的抑制通过显著上调腔内角蛋白和紧密连接蛋白(如Claudins)，逆转了Claudin低标记的表达。最后，我们证明了在MDA-MB-231细胞中人工过表达Claudins足以将细胞从侵袭状态转变为增殖状态。我们的结果表明，自分泌CSF1R信号是维持Claudin低表达所必需的，它在转化生长因子β下游的Claudin低表达肿瘤细胞中介导了增殖状态和侵袭状态之间的转换。
Patient data suggest that colony stimulating factor-1 (CSF1) and its receptor (CSF1R) play critical roles during breast cancer progression. We have previously shown that in human breast tumors expressing both CSF1 and CSF1R, invasion in vivo is dependent both on a paracrine interaction with tumor-associated macrophages and an autocrine regulation of CSF1R in the tumor cells themselves. Although the role of the paracrine interaction between tumor cells and macrophages has been extensively studied, very little is known about the mechanism by which the autocrine CSF1R signaling contributes to tumor progression. We show here that breast cancer patients of the claudin-low subtype have significantly increased expression of CSF1R. Using a panel of breast cancer cells lines, we confirm that CSF1R expression is elevated and regulated by TGFβ specifically in claudin-low cell lines. Abrogation of autocrine CSF1R signaling in MDA-MB-231 xenografts (a claudin-low cell line) leads to increased tumor size by enhanced proliferation, but significantly reduced invasion, dissemination and metastasis. Indeed, we show that proliferation and invasion are oppositely regulated by CSF1R downstream of TGFβ only in claudin-low cells lines. Intravital multiphoton imaging revealed that inhibition of CSF1R in the tumor cells leads to decreased in vivo motility and a more cohesive morphology. We show that, both in vitro and in vivo, CSF1R inhibition results in a reversal of claudin-low marker expression by significant upregulation of luminal keratins and tight junction proteins such as claudins. Finally, we show that artificial overexpression of claudins in MDA-MB-231 cells is sufficient to tip the cells from an invasive state to a proliferative state. Our results suggest that autocrine CSF1R signaling is essential in maintaining low claudin expression and that it mediates a switch between the proliferative and the invasive state in claudin-low tumor cells downstream of TGFβ.
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影响因子：
3.7
作者：
Agarwal R;Mori Y;Cheng Y;Jin Z;Olaru AV;Hamilton JP;David S;Selaru FM;Yang J;Abraham JM;Montgomery E;Morin PJ;Meltzer SJ
通讯作者：
Meltzer SJ
影响因子：
6.4
作者：
Lanigan, Fiona;McKiernan, Eadaoin;Gallagher, William M.
通讯作者：
Gallagher, William M.
影响因子：
12.3
作者：
Herschkowitz JI;Simin K;Weigman VJ;Mikaelian I;Usary J;Hu Z;Rasmussen KE;Jones LP;Assefnia S;Chandrasekharan S;Backlund MG;Yin Y;Khramtsov AI;Bastein R;Quackenbush J;Glazer RI;Brown PH;Green JE;Kopelovich L;Furth PA;Palazzo JP;Olopade OI;Bernard PS;Churchill GA;Van Dyke T;Perou CM
通讯作者：
Perou CM
影响因子：
11.2
作者：
Aharinejad, S;Paulus, P;Abraham, D
通讯作者：
Abraham, D
影响因子：
8
作者：
Gil-Henn, H.;Patsialou, A.;Wang, Y.;Warren, M. S.;Condeelis, J. S.;Koleske, A. J.
通讯作者：
Koleske, A. J.