Alternative NF-kB activation in post-chemotherapy setting to elucidate novel mechanisms of ovarian cancer relapse

《科学文摘》 卵巢癌是美国最致命的妇科恶性肿瘤，尽管患者最初 对细胞毒性化疗有反应，大多数在24个月内复发并伴有化疗耐药疾病。确实有 我们在支持疾病复发的机制方面的知识存在几个关键差距，但对 过去十年，肿瘤起始细胞(TIC)是耐药肿瘤细胞的一个亚群，这一观点得到了支持 负责促进复发，针对这些难以捉摸的细胞进行联合治疗可能会导致更长的时间 缓解甚至治愈。尽管许多基因和信号通路被认为与维持 抽搐，在我们对这些细胞在细胞毒作用下存活的过程的理解上有几个关键的空白 化疗并成功重建肿瘤。例如，目前还不清楚抽搐中活跃的通路 是否构成或是否可以由肿瘤微环境(TME)中的因素诱导。我们之前的研究 揭示了替代的核因子-kB信号在维持卵巢痉挛和抵抗细胞毒作用中的重要作用 化疗。核因子-kB是一个转录因子家族，能响应TME中的信号而促进 癌细胞的增殖、抗药性和存活率。新出现的证据表明TME发生了变化 细胞毒性化疗后可导致信号因子的释放，从而激活癌症中的核因子-kB 细胞。我们最近的数据显示，TWEEP是一种由巨噬细胞和间质分泌的多功能细胞因子 化疗后TME中的细胞活性升高，并可诱导替代的核因子-kB和 干细胞基因在多种卵巢癌细胞中的表达。接受手术的患者的临床资料 新辅助化疗表明，编码TWINE和替代的NF-kB家族成员的基因是 与治疗前水平相比，细胞毒化疗后切除的肿瘤显著升高。这些 数据引导我们得出我们的核心假设，即化疗提供了有利于TIC发展的环境 通过激活替代的核因子-kB。为了研究这一假设，我们将1)确定 化疗诱导卵巢TME中的TWINE信号激活卵巢癌细胞中的替代核因子-kB 2)建立替代的核因子-kB激酶，NIK，在卵巢癌化疗耐药和复发中的作用 3)探讨核因子-kB介导的Notch激活在支持卵巢TICS中的作用。 化疗。与大多数已发表的研究不同，我们关注的是这些细胞中的途径和活动 化疗，以产生评估复发机制的新范例。考虑到最初的强烈反应 对于化疗来说，确定一个早期的治疗后事件是非常有意义的，可以在 与细胞毒性药物相结合以抑制维持抽搐的通路。厘清新机制(S) 这种支持化疗耐药的未被研究的途径将指导更好的治疗方法的设计以延长 缓解或有可能治愈卵巢癌患者。

Scientific Abstract Ovarian cancer is the most lethal gynecological malignancy in the United States and although patients initially respond to cytotoxic chemotherapy, most relapse with chemoresistant disease within 24 months. There are several critical gaps in our knowledge of the mechanisms that support disease recurrence but research over the last decade support the notion tumor-initiating cells (TICs), a subpopulation of drug resistant tumor cells, are responsible for facilitating relapse and combination therapies targeting these elusive cells may lead to longer remission or even cures. Although numerous genes and signaling pathways have been implicated in maintaining TICs, there are several critical gaps in our understanding of the processes these cells use to survive cytotoxic chemotherapy and successfully re-establish tumors. For example, it is unclear whether pathways active in TICs are constitutive or if they can be induced by factors in the tumor microenvironment (TME). Our previous studies revealed an important role for alternative NF-kB signaling in maintaining ovarian TICs and resistance to cytotoxic chemotherapy. NF-kB is a family of transcription factors that respond to signals in the TME to promote proliferation, chemoresistance, and survival of cancer cells. Emerging evidence suggest alterations of the TME following cytotoxic chemotherapy can result in the release of signaling factors that can activate NF-kB in cancer cells. Our recent data show that TWEAK, a multifunctional cytokine secreted from macrophages and stromal cells, is elevated in the TME following chemotherapy and can induce activation of alternative NF-kB and expression of stemness genes in a variety of ovarian cancer cells. Clinical data from patients undergoing neoadjuvant chemotherapy show that genes encoding TWEAK and alternative NF-kB family members are significantly elevated in tumors resected following cytotoxic chemotherapy relative to pre-treatment levels. These data lead us to our central hypothesis that chemotherapy provides an environment that favors TIC development through activation of alternative NF-kB. To investigate this hypothesis, we will 1) determine whether chemotherapy-induced TWEAK signaling in the ovarian TME activates alternative NF-kB in ovarian cancer cells 2) establish the function of the alternative NF-kB kinase, NIK, in ovarian cancer chemoresistance and relapse and 3) investigate the role of NF-kB-mediated activation of Notch in supporting ovarian TICs following chemotherapy. Unlike most published studies, we are focusing on the pathways and activities in these cells after chemotherapy, to generate new paradigms for evaluating relapse mechanisms. Given the strong initial response to chemotherapy, it is of great interest to identify an early post-treatment event that could be targeted in combination with cytotoxic drugs to inhibit pathways that maintain TICs. Clarifying novel mechanism(s) by which this under-examined pathway supports chemoresistance will guide the design of better therapies to prolong remission or potentially achieve cures for ovarian cancer patients.