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Nature:膀胱癌耐化疗的分子机理

摘要 : 近日,科学家发现一种类似于正常组织干细胞响应伤口的新机制,新机制或许可以解释在化疗药物治疗的多个周期后,为什么膀胱癌干细胞出现化疗耐药性。针对这个类似“伤口响应”的机制,有可能提供一种新的方法来治疗癌症。研究结果发表在Nature杂志上。

 近日,科学家发现一种类似于正常组织干细胞响应伤口的新机制,新机制或许可以解释在化疗药物治疗的多个周期后,为什么膀胱癌干细胞出现化疗耐药性。针对这个类似“伤口响应”的机制,有可能提供一种新的方法来治疗癌症。研究结果发表在Nature杂志上。治疗晚期膀胱癌仅限于手术和化疗,目前还没有可用的有针对性的治疗方法,通讯作者Keith Syson Chan说:化疗反应很不理想,所以临床上的目标是开发一个更具针对性的疗法。

团队找到了已侵入肌肉的膀胱癌化疗耐药潜在性的发展机制。他们发现在药物治疗周期之间,癌症干细胞的再生积极促进耐化疗治疗。 “癌症干细胞积极重新生长,并响应不同化疗治疗周期所引起的损伤或细胞凋亡(细胞死亡),类似于组织干细胞如何正常响应伤口损伤。

濒死的细胞释放的代谢物(或因子)称为前列腺素E2或PGE 2刺激增殖被从,这将导致癌症干细胞重新填充化疗缩小的肿瘤,他们发现。在正常细胞中,干细胞重生是伤口修复过程的一部分,即PGE 2诱导组织干细胞重新生长。在癌症化疗周期之间,PGE2却诱导多种癌症干细胞的再生。

化疗有周期性,化疗一段时间后就停治疗,让你的骨髓与正常干细胞从损伤中恢复,然后另一个治疗周期重新开始。癌症干细胞也在这段空档期恢复, 濒死癌症细胞释放PGE2。在老鼠身上进行的研究中,研究小组发现阻断前列腺素E2能抑制癌症干细胞再生。

重要的是,我们能够使用已经获得FDA的药物,Kurtova说。 这将有助于我们快速启动人体临床试验。该药物是塞来昔布或Celebrex®,药物最常用作用于关节炎的治疗。

Cytotoxic chemotherapy induces CK14+ cancer cell proliferation despite reducing tumour size.

原文标题:Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance

原文摘要:Cytotoxic chemotherapy is effective in debulking tumour masses initially; however, in some patients tumours become progressively unresponsive after multiple treatment cycles. Previous studies have demonstrated that cancer stem cells (CSCs) are selecively enriched after chemotherapy through enhanced survival1, 2, 3. Here we reveal a new mechanism by which bladder CSCs actively contribute to therapeutic resistance via an unexpected proliferative response to repopulate residual tumours between chemotherapy cycles, using human bladder cancer xenografts. Further analyses demonstrate the recruitment of a quiescent label-retaining pool of CSCs into cell division in response to chemotherapy-induced damages, similar to mobilization of normal stem cells during wound repair4, 5, 6, 7. While chemotherapy effectively induces apoptosis, associated prostaglandin E2 (PGE2) release paradoxically promotes neighbouring CSC repopulation. This repopulation can be abrogated by a PGE2-neutralizing antibody and celecoxib drug-mediated blockade of PGE2 signalling. In vivo administration of the cyclooxygenase-2 (COX2) inhibitor celecoxib effectively abolishes a PGE2- and COX2-mediated wound response gene signature, and attenuates progressive manifestation of chemoresistance in xenograft tumours, including primary xenografts derived from a patient who was resistant to chemotherapy. Collectively, these findings uncover a new underlying mechanism that models the progressive development of clinical chemoresistance, and implicate an adjunctive therapy to enhance chemotherapeutic response of bladder urothelial carcinomas by abrogating early tumour repopulation.

来源: Nature 浏览次数:49

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