Genomics Institute of the Novartis Research Foundation, San Diego, California, United States of America.
PLoS One. 2013;8(1):e51671. doi: 10.1371/journal.pone.0051671. Epub 2013 Jan 2.
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.
新出现的证据表明，一些癌症中存在一群具有干细胞样特性的肿瘤起始细胞（TICs），而消除 TICs 可能为开发成功的抗癌疗法提供新策略。由于维持 TIC 池的分子机制尚未被充分理解，因此开发 TIC 特异性治疗方法仍然是一个主要挑战。我们首先从一个小鼠乳腺癌模型中鉴定并表征了 TICs 和非 TICs。TICs 表现出增强的肿瘤发生潜能、自我更新、异质性分化和双能性。对 TICs 和非 TICs 的基因表达分析和免疫染色表明，FGFR2 优先在 TICs 中表达。FGFR2 的缺失会损害 TIC 的自我更新能力，从而导致 TIC 群体和肿瘤发生潜能显著下降。FGFR2 的恢复挽救了由 FGFR2 敲低引起的 TIC 池维持、双能性和乳腺肿瘤生长缺陷。此外，FGFR2 激酶活性的药理学抑制导致 TIC 群体减少，从而抑制乳腺肿瘤生长。此外，从患者肿瘤样本中分离出的人乳腺 TICs 被发现富含 FGFR2+群体，该群体足以启动肿瘤生长。我们的数据表明，FGFR2 通过促进自我更新和维持双潜能 TICs 来维持乳腺 TIC 池，这提示了抑制 FGFR2 作为消除乳腺 TIC 的抗癌治疗策略的可能性。
