Inflammatory Breast Cancer: Factors Contributing to Dissemination

炎性乳腺癌：导致传播的因素

• 批准号: 8258693
• 负责人: BONNIE F SLOANE
• 金额: $ 5.75万
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258693
• 关键词: Accounting; African American; American; Architecture; Axilla; Biological Assay; Biological Markers; Biological Models; Blood; Breast Cancer Cell; Cancer Patient; Carcinoma; Cathepsins; Cathepsins B; 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; Intervention; Laboratories; Libraries; Life; Lymphatic; Lymphatic vessel; Malignant Neoplasms; Mammary 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 Protease; Specimen; Staging; Stromal Cells; 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; inflammatory breast cancer; inhibitor/antagonist; macrophage; malignant breast neoplasm; malignant phenotype; monocyte; monolayer; neoplastic cell; neutralizing antibody; novel; novel therapeutics; parent grant; peripheral blood; preclinical study; programs; small hairpin RNA; tumor; tumor proteolysis; young woman

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.

IBC是原发性乳腺癌中最致命的形式，不成比例地针对年轻女性。 IBC占美国所有乳腺癌病例的<5%，但其发病率显著高于其他乳腺癌。 非洲裔美国人（10.1%）。在埃及，据报告，IBC的发病率为5- 占所有乳腺癌病例的10%，并且呈上升趋势。广泛真皮淋巴管浸润和肿瘤栓塞 其中导致淋巴阻塞，这是疾病的炎症性质的基础。我们有 表明巨噬细胞渗透到IBC微环境中，包围IBC栓子并存在于 IBC患者腋血。我们的工作假设在这个建议是， 巨噬细胞在肿瘤栓塞的形成和癌细胞的扩散中发挥着至关重要的作用。 这是IBC的两个表型标志。FIRCA提案的具体目标是 目的：1）建立IBC细胞的3D培养物和a）评估侵袭性表型; B）确定 c）定量细胞因子、趋化因子和/或细胞外基质的表达; 以及d）半胱氨酸组织蛋白酶的表达/分泌/活性; 2） 表征肿瘤栓子、肿瘤、阳性淋巴中的单核细胞/巨噬细胞表型和含量 淋巴结、腋支血和外周血; 3）分离 来自IBC腋支血和外周血的单核细胞，和a）定量分泌的单核细胞的表达， 细胞因子、趋化因子和生长因子，和B）半胱氨酸组织蛋白酶的表达/分泌/活性; 4)免疫染色石蜡块的IBC标本的细胞表面受体的选定细胞因子， 趋化因子和生长因子;和，5）建立IBC细胞和分离自单核细胞的单核细胞的3D共培养物。 IBC腋支血和外周血以及a）评估侵袭性表型; B）确定 c）定量细胞因子、趋化因子和/或细胞外基质的表达; 和条件培养基中的生长因子;和d）半胱氨酸组织蛋白酶的表达/分泌/活性; 和e）IBC样品中鉴定的细胞表面受体的免疫染色共培养物。未来方向 将使用在目标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 可能靶向降低IBC侵袭性表型的生长因子。咄咄逼人的 国际生物伦理委员会在埃及的表现意味着迫切需要制定研究计划， 为乳癌患者提供即时援助。我们预计，我们的结果将 有助于描述IBC的病理生物学基础，这是 优先考虑治疗干预的新靶点。 这项研究将主要在埃及开罗大学与莫纳穆斯塔法合作进行 Mohamed，作为NIH批准号R 01 CA 131990的扩展，8-01-2008至5-31-2013。

项目成果

Cytokines secreted by macrophages isolated from tumor microenvironment of inflammatory breast cancer patients possess chemotactic properties.

• DOI: 10.1016/j.biocel.2013.11.015
• 发表时间: 2014-01
• 期刊: INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
• 影响因子: 4
• 作者: Mohamed, Mona M.;El-Ghonaimy, Eslam A.;Nouh, Mohamed A.;Schneider, Robert J.;Sloane, Bonnie F.;El-Shinawi, Mohamed
• 通讯作者: El-Shinawi, Mohamed