FGFR2 promotes breast tumorigenicity through maintenance of breast tumor-initiating cells.
FGFR2 promotes breast tumorigenicity through maintenance of breast tumor-initiating cells.
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DOI：
10.1371/journal.pone.0051671
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Reddy VA
中科院分区：
文献类型：
--
作者：
Kim S;Dubrovska A;Salamone RJ;Walker JR;Grandinetti KB;Bonamy GM;Orth AP;Elliott J;Porta DG;Garcia-Echeverria C;Reddy VA
新的证据表明，一些癌症含有干细胞样抽搐(肿瘤启动细胞)，消除抽搐可能为开发成功的抗癌疗法提供一种新的策略。由于维持TIC池的分子机制尚不清楚，TIC特异性治疗的发展仍然是一个主要的挑战。我们首先从小鼠乳腺癌模型中分离出痉挛和非痉挛，并对其进行了鉴定。TICS表现出更强的致瘤潜能、自我更新、异质分化和双潜能。抽动症和非抽动症的基因表达分析和免疫组织化学染色显示，FGFR2在抽动症中优先表达。FGFR2的缺失损害了TIC的自我更新，从而导致TIC数量和致瘤潜力的显著下降。FGFR2的修复挽救了由FGFR2基因敲除导致的TIC池维护、双能和乳腺肿瘤生长方面的缺陷。此外，药物抑制FGFR2激酶活性导致TIC数量减少，从而抑制乳腺肿瘤的生长。此外，从患者肿瘤样本中分离出的人类乳房抽搐被发现富含FGFR2+人群，足以启动肿瘤生长。我们的数据表明，FGFR2在通过促进自我更新和维持生物潜能抽搐来维持乳房TIC池中是必不可少的，并提高了抑制FGFR2作为通过根除乳房抽搐而作为抗癌治疗策略的可能性。
Emerging evidence suggests that some cancers contain a population of stem-like TICs (tumor-initiating cells) and eliminating TICs may offer a new strategy to develop successful anti-cancer therapies. As molecular mechanisms underlying the maintenance of the TIC pool are poorly understood, the development of TIC-specific therapeutics remains a major challenge. We first identified and characterized TICs and non-TICs isolated from a mouse breast cancer model. TICs displayed increased tumorigenic potential, self-renewal, heterogeneous differentiation, and bipotency. Gene expression analysis and immunostaining of TICs and non-TICs revealed that FGFR2 was preferentially expressed in TICs. Loss of FGFR2 impaired self-renewal of TICs, thus resulting in marked decreases in the TIC population and tumorigenic potential. Restoration of FGFR2 rescued the defects in TIC pool maintenance, bipotency, and breast tumor growth driven by FGFR2 knockdown. In addition, pharmacological inhibition of FGFR2 kinase activity led to a decrease in the TIC population which resulted in suppression of breast tumor growth. Moreover, human breast TICs isolated from patient tumor samples were found enriched in a FGFR2+ population that was sufficient to initiate tumor growth. Our data suggest that FGFR2 is essential in sustaining the breast TIC pool through promotion of self-renewal and maintenance of bipotent TICs, and raise the possibility of FGFR2 inhibition as a strategy for anti-cancer therapy by eradicating breast TICs.
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影响因子：
10.5
作者：
Dontu, G;Abdallah, WM;Wicha, MS
通讯作者：
Wicha, MS
DOI：
10.1073/pnas.95.9.5082
发表时间：
1998-04-28
影响因子：
11.1
作者：
Arman, E;Haffner-Krausz, R;Lonai, P
通讯作者：
Lonai, P
影响因子：
50.3
作者：
Kouros-Mehr, Hosein;Bechis, Seth K.;Werb, Zena
通讯作者：
Werb, Zena
影响因子：
2.2
作者：
Bonnefoix, T;Bonnefoix, P;Sotto, JJ
通讯作者：
Sotto, JJ
影响因子：
11.2
作者：
Li, Chenwei;Heidt, David G.;Simeone, Diane M.
通讯作者：
Simeone, Diane M.