Suppression of cancer relapse and metastasis by inhibiting cancer stemness
Suppression of cancer relapse and metastasis by inhibiting cancer stemness
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DOI：
10.1073/pnas.1424171112
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发表时间：
2015-02-10
影响因子：
11.1
通讯作者：
Li, Chiang J.
中科院分区：
文献类型：
--
作者：
Li, Youzhi;Rogoff, Harry A.;Li, Chiang J.
部分甚至完全的癌症消退可以在一些患者中实现当前的癌症治疗。然而，这种最初的反应几乎总是伴随着复发，复发的癌症对进一步的治疗具有抗性。因此，发现对抗复发的治疗方法对于推进癌症医学至关重要。癌细胞在其恶性潜能、药物敏感性以及其转移和导致复发的潜能方面是极其异质的，即使在每个个体患者中也是如此。事实上，高度致瘤性和转移性的高度恶性癌细胞，称为癌症干细胞或干细胞-高癌细胞，已经从具有多种肿瘤类型的癌症患者中分离出来。此外，这种高干细胞癌细胞对常规化疗和放疗具有抗性。在这里，我们表明，BBI 608，一种通过其抑制由Stat 3驱动的基因转录的能力和癌症干细胞特性鉴定的小分子，可以抑制干细胞基因表达并阻断从各种癌症类型中分离的高干细胞癌细胞的球体形成或杀死干细胞。此外，BBI 608在小鼠中有效地阻断癌症复发和转移。这些数据表明靶向癌症干性是开发下一代癌症治疗剂以抑制癌症复发和转移的新方法。
Partial or even complete cancer regression can be achieved in some patients with current cancer treatments. However, such initial responses are almost always followed by relapse, with the recurrent cancer being resistant to further treatments. The discovery of therapeutic approaches that counteract relapse is, therefore, essential for advancing cancer medicine. Cancer cells are extremely heterogeneous, even in each individual patient, in terms of their malignant potential, drug sensitivity, and their potential to metastasize and cause relapse. Indeed, hypermalignant cancer cells, termed cancer stem cells or stemness-high cancer cells, that are highly tumorigenic and metastatic have been isolated from cancer patients with a variety of tumor types. Moreover, such stemness-high cancer cells are resistant to conventional chemotherapy and radiation. Here we show that BBI608, a small molecule identified by its ability to inhibit gene transcription driven by Stat3 and cancer stemness properties, can inhibit stemness gene expression and block spherogenesis of or kill stemness-high cancer cells isolated from a variety of cancer types. Moreover, cancer relapse and metastasis were effectively blocked by BBI608 in mice. These data demonstrate targeting cancer stemness as a novel approach to develop the next generation of cancer therapeutics to suppress cancer relapse and metastasis.