Understanding How Breast Cancers Activate and Respond to the Systemic Environment

描述(申请人提供)：乳腺癌是全世界女性中最常见的恶性肿瘤。乳腺癌根据其分子和组织病理学特征被分为不同的类别。虽然疾病的严重程度可以分层，但一个深刻的问题是，目前的许多治疗方案缺乏有效性。乳腺癌管理中最大的挑战之一是复发疾病，30%的乳腺癌患者会受到影响，而且通常是无法治愈的。部分问题是某些肿瘤细胞 在很长一段时间内不会在体内被发现，然后突然爆发为公开的、威胁生命的癌症。某些类型的乳腺癌患者在最初确诊后的几个月内会复发，而其他患者在治疗后15-20年内才会复发。很难预测已经扩散到患者体内的肿瘤细胞是否会保持不活跃，或者它们是否会开始生长，如果是的话，是什么触发了它们的生长。我们建议通过使用我们的新的实验性小鼠模型系统来解决这些临床问题，该系统为我们提供了对乳腺癌病理生理学的重要见解。我们了解到，一些原本处于休眠状态的肿瘤可以对某些生长因子和骨髓来源的细胞做出反应，这些细胞在全身循环，我们统称为全身环境。然而，肿瘤不仅仅是循环生长因子和细胞的被动接受者。相反，某些肿瘤积极地创造了一个有利于播散性肿瘤细胞生长的系统环境，否则这些细胞不会在正常的、不受干扰的系统环境中生长。我们认为，乳腺癌生物学的许多方面只能通过对全身环境的激活和反应的详细了解来解释。我们建议以我们的基本观察为基础，以下列具体目标为基础： 1.确定哪些类型的乳腺癌能够建立支持肿瘤的系统环境，以及它们如何做到这一点。 2.定义能够对促进肿瘤的全身环境做出反应的乳腺癌的特性。 3.确定抑制促癌环境的某些方面是否会阻止原本不起作用的肿瘤的生长。 了解某些肿瘤是如何激活全身环境的，应该有助于我们设计抑制其促肿瘤功能的治疗方法。同样重要的是，了解对这些系统性因素做出反应的肿瘤细胞的特性应该能够让我们确定患者是否拥有这些反应细胞。这些机制研究有可能为更有效的乳腺癌治疗铺平道路。

DESCRIPTION (provided by applicant): Breast cancer is the most common malignancy among women worldwide. Breast cancers are classified into different categories based on their molecular and histopathological features. While disease severity can be stratified, a profound problem is the lack of effectiveness of many of the current treatment regimens. One of the greatest challenges in breast cancer management is recurrent disease, which affects 30 percent of breast cancer patients and is usually incurable. Part of the problem is that certain tumor cells remain undetected in the body for extended periods of time before they suddenly erupt into overt, life-threatening cancers. Patients with some types of breast cancers experience recurrence within months of their original diagnosis, while other patients relapse as late as 15-20 years after treatment. It is difficult to predict whether tumor cells that have spread throughou a patient's body will remain inactive or whether they will begin to grow and, if so, what triggers their growth. We propose to address these clinical problems by using our novel experimental mouse model system that gave us important insights into breast cancer pathophysiology. We learned that some tumors that would otherwise remain dormant can respond to certain growth factors and bone marrow-derived cells that circulate throughout the body, which we collectively refer to as the systemic environment. However, tumors are not just passive recipients of circulating growth factors and cells. Instead, certain tumors actively create a systemic environment that is favorable to the growth of disseminated tumor cells that otherwise would not grow in the normal, unperturbed systemic environment. We contend that many aspects of breast cancer biology can only be explained by a detailed understanding of both activation and response to the systemic environment. We propose to build upon our fundamental observations with the following specific aims: 1. Determine which types of breast cancers are capable of establishing a tumor-supportive systemic environment and how they do so. 2. Define the properties of breast cancers that are capable of responding to a tumor-promoting systemic environment. 3. Determine whether inhibiting certain aspects of the tumor-promoting environment will prevent the growth of otherwise indolent tumors. Understanding how certain tumors activate the systemic environment should help us to design therapies to inhibit their pro-tumorigenic functions. As importantly, understanding the properties of tumor cells that respond to these systemic factors should allow us to determine whether a patient harbors these responsive cells. These mechanistic studies have the potential to pave the way for more effective breast cancer therapies.