Lymph Node Alterations in Cancer

描述(申请人提供)：由于肿瘤扩散是癌症患者死亡的主要原因，人们对调节转移的途径和分子非常感兴趣。前哨或肿瘤引流淋巴结(TDLN)病理分析目前为评估许多人类癌症(包括黑色素瘤、结肠癌、乳腺癌和头颈癌)的转移潜能和辅助治疗的必要性提供了主要的诊断方法，这表明淋巴结以某种方式参与了转移。在黑色素瘤、鳞状细胞癌和淋巴瘤的小鼠模型中，我们发现广泛的TDLN淋巴窦生长和淋巴流量增加是转移的先兆和预测。这些TDLN改变可以积极地促进肿瘤通过淋巴管的扩散。这些TDLN改变需要B细胞，这表明假设B细胞或B细胞衍生产物驱动LN淋巴管生成和转移。将对TDLN中异常B细胞聚集的机制进行研究，以确定其是否涉及异常进入、离开或定位。将测试潜在的B细胞发育或激活异常，这些异常可能促进TDLN淋巴窦生长，并导致抗肿瘤免疫反应不完全。B细胞来源的免疫球蛋白或其他分泌成分在TDLN淋巴管生成和转移中的作用将通过将肿瘤或荷瘤小鼠的血清注射到B细胞缺陷的黑色素瘤小鼠身上来测试，以确定它们是否会重建 TDLN淋巴窦生长和黑色素瘤扩散至TDLN。来自不同遗传背景的B细胞也将被移植，以测试肿瘤特异性B细胞与非特异性B细胞对TDLN改变和转移的影响。巨噬细胞/髓系B细胞参与B细胞积聚和TDLN的改变将被测试，因为先天免疫反应可以促进B细胞TDLN积聚。肿瘤相关先天免疫细胞诱导的分子可促使B细胞聚集在TDLN中，这将通过基因芯片或免疫分析比较肿瘤、TDLN和正常LNS进行筛选。通过对TDLN和对照LN B细胞的mRNA和蛋白质的比较，确定可能驱动TDLN淋巴管生成的B细胞来源的因子。候选B细胞衍生因子对LN淋巴管生成和转移的贡献将在使用缺乏淋巴生长因子表达的B细胞的移植试验中进行测试。这些研究将为促进TDLN淋巴管生成和转移中对TDLN B细胞聚集、抗肿瘤抗体应答和淋巴管生成生长因子的需求提供洞察力。这些洞察力将为开发诊断工具和靶向治疗以识别和预防人类癌症患者转移的战略提供参考。 公共卫生相关性：对癌症传播途径的了解可能会导致改进诊断和治疗方法，以阻止转移。发现可能与转移和免疫系统对癌症的反应有关的淋巴转移改变。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位置的贡献。

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.