Lymph Node Alterations in Cancer

描述（由申请人提供）：肿瘤扩散是癌症患者死亡的主要原因，因此调控转移的途径和分子是人们非常感兴趣的。前哨淋巴结或肿瘤引流淋巴结（TDLN）病理学分析目前是评估转移潜力和辅助治疗需求的主要诊断方法，包括黑色素瘤、结肠癌、乳腺癌和头颈癌，这表明淋巴结在某种程度上参与了转移。我们在小鼠黑色素瘤、鳞状细胞癌和淋巴瘤模型中发现了广泛的TDLN淋巴窦生长和淋巴流量增加，这是预测转移的前兆。这些TDLN的改变可以积极促进肿瘤通过淋巴传播。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。我们将研究异常B细胞在tdln中积累的机制，以确定它是否涉及异常的进入、退出或定位。B细胞发育或激活的潜在异常将被测试，可能促进TDLN淋巴窦生长，也可能导致不完全的抗肿瘤免疫反应。B细胞来源的免疫球蛋白或其他分泌成分对TDLN淋巴管生成和转移的贡献将通过将无瘤或荷瘤小鼠的血清注射到发展为黑色素瘤的B细胞缺陷小鼠中来测试，以确定它们是否重建

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.