Lymph Node Alterations in Cancer

癌症中的淋巴结改变

• 批准号: 8225378
• 负责人: M ALANNA RUDDELL
• 金额: $ 18.56万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-15 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8225378
• 关键词: Adjuvant Therapy; Antibody Formation; Apoptosis; B Cell Proliferation; B-Cell Development; B-Cell Neoplasm; B-Lymphocytes; Biological Assay; Breast; Cancer Patient; Cause of Death; Cell Survival; Cells; Colon; Development; Diagnosis; Diagnostic; Genetic; Growth; Growth Factor; Head and Neck Cancer; Human; Immune; Immune response; Immune system; Immunoassay; Immunoglobulin M; Immunoglobulins; Immunophenotyping; Immunosuppression; Immunotherapy; Incidence; Inflammatory; Injection of therapeutic agent; Lead; Location; Lymph; Lymphangiogenesis; Lymphatic; Lymphatic System; Lymphatic vessel; Lymphoma; Malignant Neoplasms; Mature B-Lymphocyte; Measures; Mediating; Messenger RNA; Modeling; Mus; Myelogenous; Myeloid Cells; Neoplasm Antibodies; Neoplasm Metastasis; Pathology; Pathway interactions; Primary Neoplasm; Production; Proteins; Route; Screening procedure; Sentinel; Serum; Signal Transduction; Signaling Molecule; Sinus; Solid Neoplasm; Squamous cell carcinoma; Staging; Stromal Cells; Testing; Therapeutic; Time; Transplantation; Tumor Antigens; Tumor Promotion; Vascular Endothelial Growth Factors; c-myc Genes; cDNA Arrays; cell growth; chemokine; cytokine; improved; in vivo; inhibitor/antagonist; insight; interest; lymph flow; lymph nodes; macrophage; melanoma; neoplastic cell; novel; prevent; programs; public health relevance; reconstitution; research study; response; tool; trafficking; tumor

DESCRIPTION (provided by applicant): The pathways and molecules regulating metastasis are of great interest, as tumor spread is the major cause of death in cancer patients. Sentinel- or tumor-draining lymph node (TDLN) pathology analysis currently provide the major diagnostic to assess metastatic potential and the need for adjuvant therapy in many human cancers, including melanoma, colon, breast, and head and neck cancers, suggesting that the lymph nodes are somehow involved in metastasis. We discovered extensive TDLN lymphatic sinus growth and increased lymph flow which precede and predict metastasis in murine models of melanoma, squamous cell carcinoma, and lymphoma. These TDLN alterations could actively promote tumor dissemination via the lymphatics. B cells are required for these TDLN alterations, suggesting the hypothesis that B cells or B cell-derived products drive LN lymphangiogenesis and metastasis. The mechanism of abnormal B cell accumulation in TDLNs will be investigated to determine if it involves abnormal entry, egress, or localization. Potential abnormalities of B cell development or activation will be tested that could promote TDLN lymphatic sinus growth and also result in the incomplete anti-tumor immune response. The contribution of B cell-derived immunoglobulins or other secreted components to TDLN lymphangiogenesis and metastasis will be tested by injection of serum from tumor-na¿ve or tumor-bearing mice into B cell-deficient mice developing melanomas, to determine whether they reconstitute TDLN lymphatic sinus growth and melanoma spread to the TDLN. B cells from different genetic backgrounds will also be transplanted to test the effects of tumor-specific versus no-specific B cells on TDLN alterations and metastasis. Macrophage/myeloid B cell involvement in B cell accumulation and TDLN alterations will be tested, as the innate immune response could promote B cell TDLN accumulation. Molecules induced by tumor-associated innate immune cells could drive B cell accumulation in TDLNs, and these will be screened for by cDNA microarray or immunoassay comparison of tumors, TDLNs, and normal LNs. B cell-derived factors that could drive TDLN lymphangiogenesis will be identified by comparison of TDLN and control LN B cell mRNA and proteins. The contribution of candidate B cell-derived factors to LN lymphangiogenesis and metastasis will then be tested in transplantation assays using B cells that are deficient for lymphatic growth factor expression. These studies will provide insight to the requirements for TDLN B cell accumulation, antitumor antibody response, and lymphangiogenic growth factors in the promotion of TDLN lymphangiogenesis and metastasis. These insights will inform strategies for the development of diagnostic tools and targeted therapies to identify and prevent metastasis in human cancer patients. PUBLIC HEALTH RELEVANCE: An understanding of the pathways of cancer spread could lead to improved diagnosis and to therapeutic approaches to block metastasis. Lymph node alterations were identified that could be involved in metastasis and in the immune system response to cancer. Our experiments will investigate the contribution of this lymph node response to tumor spread to draining lymph nodes and other locations in the body.

描述（由申请人提供）：由于肿瘤扩散是癌症患者死亡的主要原因，因此调节转移的途径和分子引起了极大的兴趣。 前哨淋巴结或肿瘤引流淋巴结（TDLN）病理学分析目前提供了主要的诊断，以评估转移潜力和对许多人类癌症（包括黑色素瘤、结肠癌、乳腺癌和头颈癌）辅助治疗的需求，这表明淋巴结在某种程度上参与了转移。 我们发现广泛的TDLN淋巴窦生长和增加的淋巴流量，在黑色素瘤、鳞状细胞癌和淋巴瘤的小鼠模型中，这是转移的先兆和预测因素。 这些TDLN的改变可以积极地促进肿瘤通过扩散。 这些TDLN的改变需要B细胞，这表明B细胞或B细胞衍生产物驱动LN淋巴管生成和转移的假设。 将研究TDLN中异常B细胞积聚的机制，以确定其是否涉及异常进入、流出或定位。 将检测B细胞发育或活化的潜在异常，这些异常可能促进TDLN淋巴窦生长，也可能导致不完全的抗肿瘤免疫应答。 将通过将来自肿瘤初治小鼠或荷瘤小鼠的血清注射到发生黑素瘤的B细胞缺陷小鼠中，以确定它们是否重建TDLN淋巴管生成和转移，来测试B细胞衍生的免疫球蛋白或其他分泌组分的贡献。 TDLN淋巴窦生长和黑色素瘤扩散到TDLN。 还将移植来自不同遗传背景的B细胞以测试肿瘤特异性与非特异性B细胞对TDLN改变和转移的影响。 将检测巨噬细胞/骨髓B细胞参与B细胞蓄积和TDLN改变，因为先天免疫应答可促进B细胞TDLN蓄积。 由肿瘤相关的先天免疫细胞诱导的分子可以驱动TDLN中的B细胞积累，并且这些将通过cDNA微阵列或肿瘤、TDLN和正常LN的免疫测定比较来筛选。 可驱动TDLN淋巴管生成的B细胞衍生因子将通过比较TDLN和对照LN B细胞mRNA和蛋白质来鉴定。 候选B细胞衍生因子对LN淋巴管生成和转移的贡献将在移植试验中使用淋巴生长因子表达缺陷的B细胞进行测试。 这些研究将提供对TDLN B细胞积累、抗肿瘤抗体应答和淋巴管生成生长因子在促进TDLN淋巴管生成和转移中的需求的了解。 这些见解将为诊断工具和靶向治疗的开发策略提供信息，以识别和预防人类癌症患者的转移。 公共卫生相关性：对癌症扩散途径的理解可能会导致诊断的改进和阻断转移的治疗方法。 淋巴结的改变被确定为可能参与转移和免疫系统对癌症的反应。 我们的实验将研究这种淋巴结反应对肿瘤扩散到引流淋巴结和体内其他部位的贡献。