Ron Receptor Tyrosine Kinase Signaling in Breast Cancer

乳腺癌中的 Ron 受体酪氨酸激酶信号转导

• 批准号: 9898147
• 负责人: Susan E Waltz
• 金额: --
• 依托单位: CINCINNATI VA MEDICAL CENTER RESEARCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898147
• 关键词: Affect; Age; Aging; American; American Cancer Society; Autocrine Communication; Biochemical; Biological Markers; Blood Circulation; Bone Marrow; Breast; Breast Cancer Cell; Breast Cancer Model; Breast Cancer cell line; Breast Epithelial Cells; Breast cancer metastasis; CD8-Positive T-Lymphocytes; Cancer Cell Growth; Cancer Etiology; Cell physiology; Cells; Cessation of life; Coculture Techniques; Cytotoxic T-Lymphocytes; Data; Death Rate; Dependence; Detection; Development; Diagnosis; Disease; Endothelial Cells; Epithelial; Epithelial Cells; Epithelium; Exhibits; Expenditure; Female; Functional disorder; Genetic; Genotype; Growth; Growth Factor; Hepatocyte; Human; Immune; Immune response; Immunosuppression; Implant; Incidence; Institution; Knowledge; Laboratories; Ligands; Macrophage Activation; Maintenance; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mammospheres; Mediating; Messenger RNA; Metastatic Neoplasm to the Liver; Metastatic Neoplasm to the Lung; Metastatic breast cancer; Modality; Modeling; Molecular; Morbidity - disease rate; Mouse Mammary Tumor Virus; Mouse Protein; Mus; Myelogenous; Myeloid Cells; Neoplasm Metastasis; Oncogenic; Paracrine Communication; Pathway interactions; Patient Care; Patients; Pattern; Population; Prevalence; Receptor Activation; Receptor Protein-Tyrosine Kinases; Recording of previous events; Regulation; Reporting; Role; Signal Pathway; Signal Transduction; Site; Source; T cell response; T-Cell Proliferation; T-Lymphocyte; Testing; Transgenic Mice; Tyrosine Phosphorylation; United States Department of Veterans Affairs; Up-Regulation; Vascularization; Veterans; Woman; angiogenesis; anti-tumor immune response; arginase; base; beta catenin; breast tumorigenesis; cancer diagnosis; cancer initiation; clinically relevant; combat; cytotoxicity; experimental study; genetic approach; high risk; inhibitor/antagonist; macrophage; macrophage stimulating protein; malignant breast neoplasm; mammary epithelium; men; migration; mortality; mortality risk; neoplastic cell; new therapeutic target; novel; novel diagnostics; novel strategies; outcome forecast; overexpression; paracrine; protein reconstitution; public health relevance; receptor; reconstitution; recruit; screening; self-renewal; statistics; stem-like cell; tumor; tumor growth; tumor initiation; tumor microenvironment; tumor progression

 DESCRIPTION (provided by applicant): Breast cancer (BC) is the most commonly diagnosed cancers in women, and approximately 2.5 million American women with a personal history of breast cancer are alive today. Late stage cancer comes with a high risk of mortality, making BC the second leading cause of cancer-related deaths in women in the US. Despite major advances in screening and detection, BC is still a major killer of women and the identification of novel pathways to combat BC is urgently needed. The Ron receptor is overexpressed in ~50% of human BC and is an independent predictor of metastases and poor prognosis in women with this disease. While Ron overexpression is an important factor in human BC and metastasis, a significant gap exists in our knowledge about the mechanisms by which Ron promotes the development of aggressive disease. To examine Ron further, transgenic mice were generated that produce mammary-specific Ron overexpression. These mice, referred to as the MMTV-Ron mice, mimic the aggressive disease pattern observed in human patients with all female mice developing highly metastatic breast tumors. In this clinically relevant model, we discovered that mammary tumors upregulate the Ron ligand, hepatocyte growth factor-like protein (HGFL), despite the presence of this growth factor in the circulation. Utilizing MMTV-Ron mice deficient in HGFL, our preliminary studies show the importance of HGFL for oncogenic Ron activation and mammary tumor growth and progression. Utilizing HGFL deficient mammary tumor cells, we show that reconstitution of HGFL promoted tumor cell autonomous survival, migration and invasion. Further, we show that global HGFL loss also dramatically affected the tumor microenvironment by regulating immune cell recruitment, macrophage polarization, breast cancer stem-like cell/tumor initiating cell (BCSC) numbers, and angiogenesis. Analysis of bone marrow derived macrophages shows that HGFL augments Stat3 activation and promotes the expression of markers of alternative macrophage activation, supporting a role for HGFL-induced Ron signaling in suppressing anti-tumor immune responses. These studies are further supported by recent reports showing that Ron signaling in myeloid cells, and specifically in macrophages, is critical for suppressing cytotoxic T-cell responses and promoting tumor growth. Combined, these data support both tumor cell intrinsic and extrinsic functions for HGFL-induced Ron activation in promoting mammary tumor growth and metastasis. In this revised renewal application, we will directly define the functions of the Ron signaling pathway in macrophages and epithelial cells during breast tumorigenesis and will examine the significance of tumor cell produced HGFL in directing tumor growth and immunosuppression through autocrine and paracrine signaling. We will test the hypothesis that tumor cell produced HGFL promotes aggressive BC through the cooperative activation of myeloid and epithelial Ron signaling within the tumor microenvironment. To test this hypothesis, three Specific Aims are proposed: (i) to elucidate the mechanism(s) by which myeloid Ron signaling augments breast tumor growth; (ii) to determine the source and mechanism by which HGFL supports BC growth and metastasis, and (iii) to define the function of tumor cell-specific Ron expression in promoting breast tumorigenesis. In total, we hope to understand the role of the HGFL-Ron signaling axis in the development and spread of BC and provide a rationale for new diagnostic or treatment modalities that target both the tumor proper and immune response to mitigate BC mortality.

 描述(由申请人提供)： 乳腺癌(BC)是女性最常见的癌症，目前约有250万有乳腺癌个人病史的美国女性健在。晚期癌症伴随着很高的死亡率，使卑诗省成为美国女性癌症相关死亡的第二大原因。尽管在筛查和检测方面取得了重大进展，但BC仍然是妇女的主要杀手，迫切需要确定与BC作斗争的新途径。RON受体在约50%的人BC中过度表达，是女性这种疾病转移和预后不良的独立预测因子。虽然RON的过度表达是人类BC和转移的一个重要因素，但我们对RON促进侵袭性疾病发展的机制的了解存在着显著的差距。为了进一步检测RON，建立了产生乳腺特异性RON过表达的转基因小鼠。这些小鼠被称为MMTV-RON小鼠，模拟了在人类患者中观察到的侵袭性疾病模式，所有雌性小鼠都患有高度转移性乳腺肿瘤。在这个临床相关的模型中，我们发现乳腺肿瘤上调了RON配体，即肝细胞生长因子样蛋白(HGFL)，尽管循环中存在这种生长因子。利用HGFL缺陷的MMTV-RON小鼠，我们的初步研究表明HGFL在致癌RON激活和乳腺肿瘤生长发展中的重要性。利用HGFL缺陷的乳腺肿瘤细胞，我们发现HGFL的重组促进了肿瘤细胞的自主存活、迁移和侵袭。此外，我们还表明，全球HGFL缺失还通过调节免疫细胞募集、巨噬细胞极化、乳腺癌干细胞/肿瘤启动细胞(BCSC)数量和血管生成，显著影响肿瘤微环境。对骨髓来源的巨噬细胞的分析表明，HGFL增强了STAT3的激活，并促进了巨噬细胞交替激活的标志物的表达，支持了HGFL诱导的RON信号在抑制抗肿瘤免疫反应中的作用。最近的报道进一步支持了这些研究，表明髓系细胞中的RON信号，特别是巨噬细胞中的RON信号，对于抑制细胞毒性T细胞反应和促进肿瘤生长至关重要。综上所述，这些数据支持肿瘤细胞在HGFL诱导的RON激活促进乳腺肿瘤生长和转移方面的内在和外在功能。在这一修订的更新应用中，我们将直接确定巨噬细胞和上皮细胞中RON信号通路在乳腺肿瘤发生过程中的功能，并将检测肿瘤细胞产生的HGFL通过自分泌和旁分泌信号在指导肿瘤生长和免疫抑制中的意义。我们将验证这一假设，即肿瘤细胞产生的HGFL通过在肿瘤微环境中髓系和上皮RON信号的协同激活来促进侵袭性BC。为了验证这一假说，我们提出了三个具体的目标：(I)阐明髓系RON信号促进乳腺肿瘤生长的机制(S)；(Ii)确定hGFL支持BC生长和转移的来源和机制；(Iii)确定肿瘤细胞特异性RON表达在促进乳腺肿瘤发生中的作用。总之，我们希望了解HGFL-RON信号轴在BC的发生和扩散中的作用，并为针对肿瘤本身和免疫反应的新的诊断或治疗模式提供理论基础，以降低BC的死亡率。