Molecular Regulation of Cancer Progression

描述(由申请人提供)： 有待研究的问题：前列腺癌和其他器官的治疗面临的主要挑战是转移性疾病。不幸的是，这些病变不能手术或放射治疗，也不能以类似于原发病变的方式对系统治疗作出反应。我们无法治疗这些致命的先兆是因为对癌细胞在转移环境中的行为缺乏了解。在我们目前的资助期间，我们发现前列腺癌细胞在转移的生态位中改变了它们的细胞行为和表型；这些发现的普遍性得到了乳腺癌相似行为(但不同的分子控制)的支持。为了逃离原发肿瘤块，这些细胞去分化为更具间充质样功能的细胞--一种活跃的迁移和增殖。然而，在转移的小生境中，细胞似乎恢复到更分化的状态。这似乎是由靶器官发出的信号驱动的。阻碍了我们的治疗方法，这种上皮状态以及与常驻组织的连接似乎也促进了癌细胞的存活。因此，我们假设了肿瘤细胞行为可塑性的基本模型，该模型由它们所处环境的线索决定。假设和目的：癌细胞在转移微环境的驱动下发生表型变化，以便在扩散和随后的生长过程中能够进行病理生存。我们假设E-钙粘素连接在转移性播种期间重新建立(可能是暂时的)，促进了转移性播种、静止和对细胞杀伤的抵抗。这三种截然不同但互为补充的行为，其中任何一种都会混淆治疗，需要我们在处理转移性前列腺癌的方法上进行新的思考。我们建议在创新的器官类型培养系统以及定向培养和动物模型中测试这一新的肿瘤-实质沟通的基本模型。在目标1中，我们将确定转移部位向更高分化状态的逆转是否能保护癌细胞免于死亡，无论是由炎症、化疗还是细胞饥饿引起的--这些都是转移细胞要克服的挑战。这和它背后的分子基础以及E-钙粘素信号是否是主要贡献者，将在体内进行评估，并在二维和三维复合体中阐明分子控制，以及一个独特的器官培养模型系统。在目标2中，我们将进一步探索重新分化的肿瘤细胞的分子基础，以建立转移。我们将重点研究E-钙粘附素在靶器官中的表达和与非癌细胞的联系，以及这些是否对微转移至关重要。这将在动物模型和一种新型的体外肝脏器官型生物反应器中进行测试，以更好地解析癌症和宿主的贡献。意义和创新：这些实验的成功完成将为前列腺癌和其他癌症中被颠覆以促进进展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。主要的影响将是我们在最初的转移播种时对肿瘤生物学的基本理解，这是一个未被充分研究但在传播过程中的关键步骤。由于肝脏生物反应器提供了新的工具，我们可以探索这一点。以前检查已建立的转移的工具可能错过了在这个播种过程中发生的最初的表型可塑性。转化为临床影响将以离散的步骤进行。即使只是对我们的基础模型的一部分进行验证，也会改变我们对初始转移和隐蔽转移的理解。首先，在转移性播种过程中，表型回复到上皮型、静止表型的建立可能会促进针对非和慢周期细胞的药物的使用。其次，在初始种植过程中上皮标志物的上调可能允许成像更好地检测这些微转移。最后，从长远来看，精选的分子指纹或信号级联可以作为未来药物的靶标。

DESCRIPTION (provided by applicant): Problem to be investigated: The main challenges in dealing with carcinoma of the prostate and other organs are posed by metastatic disease. Unfortunately, these are not surgically or radiologically amenable, nor do they respond to systemic therapies in a manner similar to the primary lesion. Our inability to treat these deadly harbingers derives from a paucity of knowledge of carcinoma cell behaviors in the metastatic environment. In our current grant period, we found that prostate carcinoma cells change their cell behavior and phenotype in the metastatic niche; the generalizability of these findings was supported by similar behaviors (but distinct molecular controls) in breast carcinomas. To escape the primary tumor mass, these cells dedifferentiate to a more mesenchymal-like cell functioning - one of active migration and proliferation. However, in the metastatic niche, the cells appear to revert back towards a more differentiated state. This is seemingly driven by signals from the target organ. Thwarting our therapeutic approaches, such an epithelial state along with connections to the resident tissue also appears to promote cancer cell survival. Thus, we posit a foundational model of behavioral plasticity of the tumor cells as determined by cues from their environment. Hypothesis and Objectives: That carcinoma cells undergo phenotypic changes driven by the metastatic microenvironment so as to enable pathological survival during dissemination and subsequent growth. We posit that E-cadherin connections re-established (possibly transiently) during metastatic seeding promote metastatic seeding, quiescence and resistance to cell killing. These three distinct but complementary behaviors, any one of which would confound treatment, would require new thinking in our approaches to metastatic prostate cancer. We propose to test this novel foundational model of carcinoma-parenchymal communications in an innovative organotypic culture system as well as in directed culture and animal models. In Objective 1, we will determine whether the reversion to a more differentiated state at the metastatic site protects carcinoma cells from death, whether caused by inflammation, chemotherapy or cellular starvation - all challenges for a metastatic cell to overcome. This, and the molecular basis underlying it and whether E- cadherin signaling is the major contributor, will be assessed in vivo and the molecular controls elucidated in both two- and three-dimensional complex, and a unique organ culture model system. In Objective 2 we will further probe the molecular underpinnings of the redifferentiated tumor cells to establish metastases. We will focus on the E-cadherin expression and connections with non-cancer cells in the target organs and whether these are critical for micrometastases. This will be tested in animal models and a novel ex vivo liver organotypic bioreactor to better parse the carcinoma and host contributions. Significance and Innovation: The successful completion of these experiments will shed new light on molecular controls that are subverted in prostate and other carcinomas to promote progression. These studies test novel hypotheses using state-of-the-art techniques. The major impact would be on our fundamental understanding of the tumor biology at initial metastasis seeding, an understudied yet critical step in dissemination. We can probe this due to the novel tools available with the liver bioreactor. Previous tools examining established metastases may have missed the initial phenotypic plasticity that occurs during this seeding event. The translation to clinical impact would occur in discrete steps. The validation of even just parts of our foundational model would alter our understanding of initial and cryptic metastases. First, the establishment of phenotypic reversion to an epithelial, quiescent phenotype during metastatic seeding may promote use of agents that target non- and slow-cycling cells. Second, upregulation of epithelial markers during initial seeding may allow for imaging to better detect these micrometastases. Lastly, in the longer term, select molecular fingerprints or signaling cascades could be developed as targets for future agents.