Survival and Recurrence of Dormant Cancer Cells

复发性乳腺癌是一种典型的不治之症。因此，乳腺癌的趋势 治疗后复发是临床结果的最重要决定因素。复发性肿瘤总是 来自残留肿瘤细胞（RTC）的储存库，这些细胞可以在假定的休眠状态下持续存在于患者体内 在原发肿瘤治疗后的许多年里。因此，微小残留病、肿瘤休眠和 复发构成肿瘤进展的基本表现，其共同负责肿瘤的复发。 绝大多数乳腺癌死亡。尽管乳房的这些方面具有无与伦比的临床重要性， 然而，癌症进展的潜在机制在很大程度上是未知的。因此，委员会认为， 了解RTC的生物学，阐明导致肿瘤休眠的分子途径 和复发是癌症研究中的一个关键优先事项。 我们认为，通过使休眠的RTC在乳腺癌中持续存在的生存机制失效， 治疗后的患者将耗尽这一关键的细胞库，减少肿瘤复发， 提高生存率。使用基因工程小鼠模型，忠实地再现肿瘤休眠， 复发，我们已经确定uPAR及其结合伴侣，α5整合素， 但随后在自发复发肿瘤中上调，沿着FAK活性 随机的潜伏期。当与升高uPAR和 α5整合素表达与乳腺癌复发风险增加密切相关， 我们假设uPAR和α5β1整合素的下调是进入肿瘤细胞所必需的。 治疗后的休眠状态，以及随后的uPAR/α5β1/FAK信号转导的上调促进了 通过诱导休眠的RTC重新进入细胞周期来抑制乳腺肿瘤复发。 本研究的具体目的是：（1）明确uPAR/α5β1/FAK通路在原发性肝癌残留病中的作用; 小鼠和患者。uPAR/α5β1/FAK通路活化将在原发性肿瘤、复发性肿瘤和复发性肿瘤中进行评价。 靶向治疗后GEM模型中的肿瘤、乳腺中的RTC以及BM和肺中的DTC 或化疗。伴随研究将评估BM DTC中的uPAR/α5β1/FAK通路，以及 乳腺癌患者中的原发性和复发性转移性肿瘤细胞;以及（2）确定 uPAR/α5β1/ FAK通路调节对残余病变和复发的影响 通过探索RTC的生物学和导致肿瘤复发的途径， 研究将推进维持肿瘤细胞处于休眠状态的治疗目标， 针对其生存机制，或阻断复发的首选途径。我们预计， 知识将有助于开发更有效的复发治疗方法， 改善数百万乳腺癌幸存者的治疗选择。

Recurrent breast cancer is typically an incurable disease. Consequently, the tendency of breast cancers to recur following treatment is the most important determinant of clinical outcome. Recurrent tumors invariably arise from the reservoir of residual tumor cells (RTCs) that can persist in patients in a presumed dormant state for many years after treatment of their primary tumor. As such, minimal residual disease, tumor dormancy, and recurrence constitute fundamental manifestations of tumor progression that collectively are responsible for the vast majority of breast cancer deaths. Despite the unrivaled clinical importance of these aspects of breast cancer progression, however, the mechanisms underlying them are largely unknown. Consequently, understanding the biology of RTCs and elucidating the molecular pathways that contribute to tumor dormancy and recurrence is a critical priority in cancer research. We propose that disabling the survival mechanisms by which dormant RTCs persist in breast cancer patients following treatment will deplete this critical reservoir of cells, reduce tumor recurrence, and thereby improve survival. Using genetically engineered mouse models that faithfully recapitulate tumor dormancy and recurrence, we have determined that uPAR and its binding partner, α5 integrin, are markedly down-regulated in dormant RTCs, but are subsequently up-regulated, along with FAK activity, in spontaneous recurrent tumors that arise with a stochastic latency period. When taken together with the observations that elevated uPAR and α5 integrin expression are each strongly associated with an increased risk of recurrence in women with breast cancer, we hypothesize that down-regulation of uPAR and α5β1 integrin are required for entrance into the dormant state following therapy, and that subsequent up-regulation of uPAR/α5β1/FAK signaling promotes mammary tumor recurrence by inducing the re-entry of dormant RTCs into the cell cycle. The specific aims of this proposal are to: (1) Define uPAR/α5β1/FAK pathway status in residual disease in mice and in patients. uPAR/α5β1/FAK pathway activation will be evaluated in primary tumors, recurrent tumors, RTC in the mammary gland, and DTC in the BM and lungs in GEM models following targeted therapy or chemotherapy. Companion studies will evaluate the uPAR/α5β1/FAK pathway in BM DTCs, as well as primary and recurrent metastatic tumor cells in breast cancer patients; and (2) Determine the impact of uPAR/α5β1/ FAK pathway modulation on residual disease and recurrence. By probing the biology of RTCs and the pathways that contribute to tumor recurrence, the proposed studies will advance the therapeutic goals of maintaining tumor cells in a dormant state, inducing their death by targeting their survival mechanisms, or blocking preferred pathways of recurrence. We anticipate that this knowledge will facilitate the development of more effective therapeutic approaches to recurrence that could improve the treatment options available to millions of breast cancer survivors.