Molecular Regulation of Breast Cancer Progression

 描述(由申请人提供)： 乳腺癌进展的分子调控乳腺癌(BRCA)是女性最常见的肿瘤，对黑人女性的影响最严重，军人女性患BRCA的风险增加。死亡率和发病率是由扩散和转移引起的。局限的原发癌通常被切除，治愈率高达80%。一旦癌症扩散，目前的治疗方法，甚至是较新的生物制剂，只能延长几年的生命。传播会导致发病率和死亡率，即使在被认为治愈的妇女中也有10%-30%。能够使这些播散性肿瘤转移存活和生长的信号是关键的过渡点，也是我们过去和正在进行的研究的重点。我们在目前和以前的获奖期间的研究表明，在扩散到异位微环境后，实质细胞引导肿瘤细胞重新表达上皮标记物，包括定义的E-钙粘附素。这种细胞-细胞凝聚力标记形成异型结合，使肿瘤细胞对化疗和致死性细胞因子的杀伤更具抵抗力。正在进行的实验表明，这种对死亡信号的保护是通过E-钙粘素触发的信号进行的。不祥的是，这种上皮逆转还可能导致肿瘤细胞休眠，这是肿瘤扩散的可怕并发症。休眠的静止可能只是化疗耐药的部分原因，因为初步研究发现，E-钙粘附素甚至可以保护周期细胞免受化疗的影响。我们对此进行了建模，以证明增殖停滞是休眠的基础，但这种非增殖状态是可塑性的，受刺激的细胞被唤醒并重新获得侵袭性的间质表型，从而生长为临床上明显的转移。我们和其他人有迹象表明，应激源激活支持的非实质细胞会导致突起生长，本文将对此进行研究。因此，我们的基本模型假设，E-钙粘素连接信号通过选择细胞内途径来促进肿瘤细胞的存活，这些途径可以被靶向逆转化疗耐药。此外，这些部分保护肿瘤细胞的隐蔽微转移的休眠状态，可以通过激活组织中的基质、免疫和内皮细胞的应激源来逆转。通过识别操作信号和途径，我们可以开发针对新出现的乳腺癌细胞的微转移的新方法。因此，我们假设，肿瘤细胞与转移微环境细胞的相互作用决定了对肿瘤靶向治疗的反应性和休眠/生长。这一假说现在引出了三个相互关联的问题--什么是赋予转移的化疗耐药性的机制，为什么肿瘤细胞后来从这个休眠阶段出来生长为致命的播散性肿瘤，以及这些新出现的癌细胞是否可以被靶向，正如所探索的：1.定义E-钙粘素下游的关键肿瘤细胞信号Nexi，在微转移的利基中提供对杀伤的抵抗。确定肝脏非实质细胞的激活是否触发从休眠中苏醒。确定靶向间充质癌细胞是否限制新生癌细胞的生长。这些实验的成功完成将为乳腺癌中颠覆以促进进展的细胞行为的意想不到的分子控制提供新的线索。这些研究使用最先进的技术来测试新的假设。验证我们的基础模型的甚至组件和我们最初的翻译工作将突出Rational的未来途径 对癌症治疗难治阶段、临床无法检测到的微转移的干预。在更直接的情况下，这些发现将影响替代治疗方法的选择，因为针对转移性癌症的治疗方案将包括旨在保持细胞停滞的药物，以及攻击退出静止的细胞的药物。

 DESCRIPTION (provided by applicant): Molecular Regulation of Breast Cancer Progression Cancer of the breast (BrCa) is the most frequent tumor in women, affecting black women most severely, with military women at increased risk of BrCa. Mortality and morbidity are due to spread and metastasis. Localized primary carcinomas are often removed, with curative effect for up to 80%. Once the cancer has disseminated, current therapies, even newer biologics, prolong life for just a few years. Dissemination leads to morbidity and mortality even in 10-30% of women deemed cured. The signals that enable metastatic survival and outgrowth of these disseminated tumors are critical transition points, and the focus of our past and ongoing studies. Our investigations during the present and previous Award periods demonstrated that upon dissemination to the ectopic microenvironment, the parenchymal cells direct the tumor cells to re-express epithelial markers including the defining E-cadherin. This cell-cell cohesion marker forms heterotypic binding that renders the tumor cells more resistant to killing by chemotherapies and death cytokines. Ongoing experiments have shown that this protection from death signals proceeds through E-cadherin-triggered signaling. Ominously, this epithelial reversion also likely leads to tumor cell dormancy, a dreaded complication of tumor dissemination. The quiescence of dormancy is likely only partly responsible for the chemoresistance, as initial studies have found that E-cadherin protects even cycling cells from chemotherapy. We have modeled this to demonstrate that proliferative quiescence underlies the dormancy, but that this non-proliferative state is plastic with stimulated cells being `awakened' and regaining an aggressive mesenchymal phenotype, thus growing into clinically evident metastases. We and others have indications that activation of the supporting nonparenchymal cells by stressors leads to outgrowth that will be investigated herein. Thus, our foundational model posits that E-cadherin-ligandation signals promote tumor cell survival via select intracellular pathways that can be targeted to reverse the chemoresistance. Further, the dormancy of these cryptic micrometastases, that partially protect the tumor cells, can be reversed by stressors activating stromal, immune and endothelial cells in the tissue. By discerning the operative signals and pathways we can develop novel approaches to micrometastases in targeting the emergent breast cancer cells. Thus, we hypothesize that the interplay of the tumor cells with cells of the metastatic microenvironment dictate both responsiveness to tumor targeted therapies and dormancy/outgrowth. This hypothesis now leads to three linked questions - what are the mechanisms that confer the chemoresistance of metastasis, why do the tumor cells then later emerge from this dormant stage to grow as lethal disseminated tumors, and can these emergent carcinoma cells be targeted, as explored by: I. Defining the key tumor cell signaling nexi downstream from E-cadherin that provide for resistance to killing in the micrometastatic niche. II. Determining whether activation of liver nonparenchymal cells trigger emergence from dormancy. III. Determining whether targeting mesenchymal carcinoma cells limits outgrowth of emergent carcinoma cells. The successful completion of these experiments will shed new light on unexpected molecular controls of cell behavior that are subverted in breast carcinoma to promote progression. These studies test novel hypotheses using state of the art techniques. Validation of even components of our foundational model and our initial translational effort would highlight future avenues for rational interventions for the therapeutically refractory stage of cancer, clinically undetectable micrometastases. In the more immediate term, the findings would impact the choice of alternative approaches, in that therapeutic regimens aimed at metastatic cancer would include agents designed to keep cells in stasis in addition to attacking those that exit quiescence.