Understanding How Breast Cancers Activate and Respond to the Systemic Environment

了解乳腺癌如何激活和响应全身环境

• 批准号: 8437610
• 负责人: Sandra S McAllister
• 金额: $ 34.17万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-18 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8437610
• 关键词: Address; Affect; Aftercare; Biological Models; Blood Circulation; Bone Marrow; Bone Marrow Cells; Cancer Biology; Cancer Patient; Cancer Relapse; Categories; Cells; Clinical; Cues; Desmoplastic; Development; Diagnosis; Disease; Distant; Effectiveness; Environment; Event; Fibroblasts; Functional disorder; Growth; Growth Factor; Hematopoietic; Hematopoietic stem cells; Heterogeneity; Human; Indolent; Knowledge; Learning; Life; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Mammary Neoplasms; Mediating; Microarray Analysis; Molecular; Neoplasm Metastasis; PTPRC gene; Patients; Play; Process; Property; Recruitment Activity; Recurrence; Recurrent disease; Relapse; Role; Severity of illness; Signal Transduction; Site; Staging; Testing; Therapeutic; Time; Tissue Microarray; Treatment Protocols; Tumor Subtype; Tumor Tissue; Up-Regulation; Woman; base; cancer therapy; cohort; cytokine; design; experience; granulin; insight; malignant breast neoplasm; mouse model; neoplastic cell; novel; osteopontin; pre-clinical; prevent; prognostic; research study; response; therapy design; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor progression; tumorigenic

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. PUBLIC HEALTH RELEVANCE: We propose to elucidate the pathophysiology of breast cancer relapse by building on our observations that have yielded fundamental insights into tumor progression. These observations suggest that cancer is a disease that is capable of creating and responding to a pro-tumorigenic host systemic environment. The knowledge we obtain from our proposed experiments should provide entry points for preclinical development of specific breast cancer therapies.

描述（由申请人提供）： 乳腺癌是全世界妇女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许多治疗方案缺乏有效性。乳腺癌管理的最大挑战之一是复发性疾病，这影响了30%的乳腺癌患者，并且通常无法治愈。部分问题在于某些肿瘤细胞 在突然爆发成明显的、危及生命的癌症之前，它们在体内长时间未被发现。某些类型的乳腺癌患者在最初诊断后的几个月内复发，而其他患者在治疗后15-20年复发。很难预测已经扩散到病人体内的肿瘤细胞是否会保持不活动状态，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实验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源性细胞产生反应，这些细胞在整个身体中循环，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有利于播散性肿瘤细胞生长的全身环境，否则这些细胞不会在正常的、未受干扰的全身环境中生长。我们认为，乳腺癌生物学的许多方面只能通过详细了解激活和对全身环境的反应来解释。我们建议以我们的基本意见为基础，具体目标如下： 1.确定哪些类型的乳腺癌能够建立肿瘤支持性系统环境以及它们如何做到这一点。 2.定义乳腺癌的特性，这些特性能够对促肿瘤的全身环境做出反应。 3.确定抑制促肿瘤环境的某些方面是否会阻止其他惰性肿瘤的生长。 了解某些肿瘤如何激活全身环境应该有助于我们设计治疗方法来抑制其促肿瘤功能。同样重要的是，了解肿瘤细胞对这些系统性因素的反应特性应该使我们能够确定患者是否含有这些反应细胞。这些机制研究有可能为更有效的乳腺癌治疗铺平道路。 公共卫生关系：我们建议阐明乳腺癌复发的病理生理学的基础上，我们的观察，产生了对肿瘤进展的基本见解。这些观察结果表明，癌症是一种能够产生并响应于促肿瘤发生宿主全身环境的疾病。我们从我们提出的实验中获得的知识应该为特定乳腺癌疗法的临床前开发提供切入点。