Inflammatory Breast Cancer: Factors Contributing to Dissemination

炎性乳腺癌：导致传播的因素

• 批准号: 7852993
• 负责人: BONNIE F SLOANE
• 金额: $ 6.46万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7852993
• 关键词: Accounting; African American; American; Architecture; Axilla; Biological Assay; Biological Markers; Biological Models; Blood; Breast; Breast Cancer Cell; Cancer Patient; Carcinoma; Cathepsins; Cell Surface Receptors; Cells; Coculture Techniques; Collaborations; Collagen Type IV; Colonic Neoplasms; Conditioned Culture Media; Cysteine; Cysteine Protease; Dermal; Diagnosis; Disease; Egypt; Embolism; Endocytosis; Engineering; Enhancers; Exhibits; Extracellular Matrix Proteins; Family; Fibroblasts; Functional Imaging; Future; Goals; Grant; Growth Factor; Immunodeficient Mouse; Implant; In Vitro; Incidence; Individual; Inflammatory; Inflammatory Infiltrate; Intervention; Laboratories; Libraries; Life; Lymphatic; Lymphatic vessel; Malignant Neoplasms; Mammary gland; Matrix Metalloproteinases; Modeling; Myoepithelial cell; Nature; Noninfiltrating Intraductal Carcinoma; Obstruction; Paraffin; Pathway interactions; Patients; Peptide Hydrolases; Phenotype; Play; Positive Axillary Lymph Node; Premalignant; Proteins; Proteolysis; Protocols documentation; Reagent; Reporting; Research; Research Personnel; Role; Screening procedure; Serine; Specimen; Staging; Stromal Cells; Sum; Therapeutic; Therapeutic Intervention; Tumor Cell Invasion; United States; United States National Institutes of Health; Universities; Woman; Work; Xenograft procedure; breast lesion; cancer cell; cathepsin F; cathepsin V; cell type; chemokine; cytokine; implantation; improved; in vitro Model; in vivo; infiltrating duct carcinoma; inhibitor/antagonist; macrophage; malignant breast neoplasm; malignant phenotype; monocyte; monolayer; neoplastic cell; neutralizing antibody; novel; novel therapeutics; parent grant; peripheral blood; preclinical study; programs; public health relevance; small hairpin RNA; tumor; tumor proteolysis

DESCRIPTION (provided by applicant): IBC is the most lethal form of primary breast cancer and disproportionately targets younger women. IBC accounts for <5% of all breast cancer cases in the United States, but its incidence is significantly higher among African-American women (10.1%). In Egypt, the incidence of IBC is reported to be from 5- 10% of all breast cancer cases and is on the rise. Extensive dermal lymphatic invasion and tumor emboli therein result in lymphatic obstruction that underlies the inflammatory nature of the disease. We have shown that macrophages infiltrate the IBC microenvironment, surround IBC emboli and are present in axillary blood of IBC patients. Our working hypothesis in this proposal is that IBC-associated macrophages play a crucial role in the formation of tumor emboli and dissemination of the cancer cells in the lymphatics, two of the phenotypic hallmarks of IBC. The Specific Aims of this FIRCA proposal are to: 1) Establish 3D cultures of IBC cells and a) assess invasive phenotype; b) determine expression/localization of putative IBC marker proteins; c) quantify expression of cytokines, chemokines and growth factors in conditioned media; and d) expression/secretion/activity of cysteine cathepsins; 2) Characterize monocyte/macrophage phenotype and content in tumor emboli, tumors, positive lymph nodes, axillary tributary blood and peripheral blood from IBC and non-IBC patients; 3) Isolate monocytes from IBC axillary tributary blood and peripheral blood and a) quantify expression of secreted cytokines, chemokines and growth factors, and b) expression/secretion/activity of cysteine cathepsins; 4) Immunostain paraffin blocks of IBC specimens for cell surface receptors of selected cytokines, chemokines and growth factors; and, 5) Establish 3D cocultures of IBC cells and monocytes isolated from IBC axillary tributary blood and peripheral blood and a) assess invasive phenotype; b) determine expression/localization of putative IBC marker proteins; c) quantify expression of cytokines, chemokines and growth factors in conditioned media; and d) expression/secretion/activity of cysteine cathepsins; and, e) immunostain cocultures for cell surface receptors identified in IBC specimens. Future directions will use the information obtained in Aims 1-5 to select cysteine cathepsins, cytokines, chemokines and growth factors that might be targeted to reduce the invasive phenotype of IBC. The aggressive manifestation of IBC in Egypt means that there is a pressing need to develop research programs that can be of immediate assistance to patients suffering from breast cancer. We anticipate that our results will contribute to the characterization of the pathobiological underpinnings of IBC, a prerequisite for prioritizing novel targets for therapeutic intervention. This research will be done primarily in Egypt at Cairo University in collaboration with Mona Mostafa Mohamed, as an extension of NIH Grant No. R01CA131990, 8-01-2008 to 5-31-2013. PUBLIC HEALTH RELEVANCE: This proposal brings together a multi-disciplinary team of Egyptian and American investigators in a collaborative effort with the ultimate goal of identifying druggable pathways that can be targeted for new therapies against IBC, a highly lethal cancer that is found disproportionately in young women and has a high incidence in Egypt. Successful completion of the studies proposed in this application will result in validated in vitro model systems that can be used for preclinical studies screening new therapeutics and may also identify biomarkers for IBC. Our intent is to improve the diagnosis and eventually the therapeutic management of this devastating cancer.

描述（由申请人提供）：IBC 是最致命的原发性乳腺癌，主要针对年轻女性。在美国，IBC 占所有乳腺癌病例的比例<5%，但其在非裔美国女性中的发病率明显更高（10.1%）。据报道，在埃及，IBC 的发病率占所有乳腺癌病例的 5-10%，并且呈上升趋势。广泛的真皮淋巴侵入和其中的肿瘤栓子导致淋巴阻塞，这是该疾病的炎症本质。我们已经证明巨噬细胞浸润 IBC 微环境、包围 IBC 栓子并存在于 IBC 患者的腋血中。我们在本提案中的工作假设是，IBC 相关巨噬细胞在肿瘤栓子的形成和癌细胞在淋巴管中的传播中发挥着至关重要的作用，这是 IBC 的两个表型特征。该 FIRCA 提案的具体目标是： 1) 建立 IBC 细胞的 3D 培养物，以及 a) 评估侵袭表型； b) 确定假定的 IBC 标记蛋白的表达/定位； c) 量化条件培养基中细胞因子、趋化因子和生长因子的表达； d) 半胱氨酸组织蛋白酶的表达/分泌/活性； 2）表征IBC和非IBC患者的肿瘤栓子、肿瘤、阳性淋巴结、腋支血和外周血中的单核细胞/巨噬细胞表型和含量； 3) 从 IBC 腋支支血和外周血中分离单核细胞，a) 定量分泌细胞因子、趋化因子和生长因子的表达，b) 半胱氨酸组织蛋白酶的表达/分泌/活性； 4) IBC 标本的免疫染色石蜡块，用于选定细胞因子、趋化因子和生长因子的细胞表面受体； 5) 建立从 IBC 腋下支流血和外周血分离的 IBC 细胞和单核细胞的 3D 共培养物，并 a) 评估侵袭表型； b) 确定假定的 IBC 标记蛋白的表达/定位； c) 量化条件培养基中细胞因子、趋化因子和生长因子的表达； d) 半胱氨酸组织蛋白酶的表达/分泌/活性； e) IBC 样本中鉴定的细胞表面受体的免疫染色共培养物。未来的方向将利用目标 1-5 中获得的信息来选择半胱氨酸组织蛋白酶、细胞因子、趋化因子和生长因子，以减少 IBC 的侵袭表型。 IBC 在埃及的侵袭性表现意味着迫切需要制定可以为乳腺癌患者提供即时帮助的研究计划。我们预计我们的结果将有助于表征 IBC 的病理生物学基础，这是优先考虑治疗干预新靶点的先决条件。这项研究将主要在埃及开罗大学与 Mona Mostafa Mohamed 合作进行，作为 NIH 拨款号 R01CA131990（2008 年 1 月 8 日至 2013 年 5 月 31 日）的延伸。 公共健康相关性：该提案汇集了埃及和美国研究人员的多学科团队，共同努力，最终目标是确定可针对 IBC 新疗法的药物途径，IBC 是一种高度致命的癌症，在年轻女性中发病率不成比例，在埃及发病率很高。成功完成本申请中提出的研究将产生经过验证的体外模型系统，该系统可用于筛选新疗法的临床前研究，还可以识别 IBC 的生物标志物。我们的目的是改善这种毁灭性癌症的诊断并最终改善治疗管理。