Molecular Regulation of Breast Cancer Progression

 描述（由申请人提供）： 乳腺癌（BrCa）是女性中最常见的肿瘤，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于扩散和转移。局限性原发癌常行手术切除，有效率可达80%。一旦癌症扩散，目前的治疗方法，甚至是更新的生物制剂，只能延长几年的生命。传播导致发病和死亡，即使在10-30%被认为治愈的妇女中也是如此。使这些播散性肿瘤转移存活和生长的信号是关键的转变点，也是我们过去和正在进行的研究的重点。 我们在当前和以前的奖项期间的调查表明，在传播到异位微环境，实质细胞指导肿瘤细胞重新表达上皮标志物，包括定义E-钙粘蛋白。这种细胞-细胞凝聚标志物形成异型结合，使肿瘤细胞对化疗和死亡细胞因子的杀伤更具抗性。正在进行的实验表明，这种对死亡信号的保护通过E-钙粘蛋白触发的信号传导进行。不幸的是，这种上皮逆转也可能导致肿瘤细胞休眠，这是肿瘤扩散的一种可怕并发症。休眠的静止可能只是化学抗性的部分原因，因为最初的研究发现，E-钙粘蛋白甚至可以保护周期细胞免受化疗。我们对此进行了建模，以证明增殖性静止是休眠的基础，但是这种非增殖状态是可塑的，刺激的细胞被“唤醒”并恢复侵袭性间充质表型，从而生长成临床上明显的转移。我们和其他人有迹象表明，支持非实质细胞的激活应激导致的生长，将在本文中进行调查。 因此，我们的基础模型假定E-钙粘蛋白配体化信号通过选择细胞内途径促进肿瘤细胞存活，所述细胞内途径可以靶向逆转化疗耐药性。此外，部分保护肿瘤细胞的这些隐蔽微转移的休眠可以通过激活组织中的基质细胞、免疫细胞和内皮细胞的应激物来逆转。通过识别操作信号和途径，我们可以开发新的方法来微转移靶向新兴的乳腺癌细胞。 因此，我们假设肿瘤细胞与转移性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。这一假设现在导致三个相关的问题-赋予转移的化学抗性的机制是什么，为什么肿瘤细胞随后从这个休眠阶段出现生长为致命的播散性肿瘤，以及这些出现的癌细胞是否可以被靶向，如以下所探索的：I.确定E-钙粘蛋白下游的关键肿瘤细胞信号传导连接，其提供对微转移小生境中杀伤的抗性。二.确定肝脏非实质细胞的激活是否触发休眠的出现。三.确定靶向间充质癌细胞是否限制了新出现的癌细胞的生长。 这些实验的成功完成将为乳腺癌中细胞行为的意外分子控制提供新的线索，这些细胞行为在乳腺癌中被破坏以促进进展。这些研究使用最先进的技术测试新的假设。我们的基础模型和我们最初的翻译工作的验证甚至组件将突出未来的合理途径， 癌症的治疗难治性阶段的干预，临床上检测不到的微转移。从更直接的角度来看，这些发现将影响替代方法的选择，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，以及攻击那些退出静止状态的药物。

 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.