INVESTIGATION OF THE VASCULAR RESPONSE IN LYMPH NODE METASTASES

淋巴结转移血管反应的研究

• 批准号: 8783581
• 负责人: Dennis Jones
• 金额: $ 5.33万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8783581
• 关键词: Achievement; Address; Adjuvant; Adjuvant Therapy; Affect; Angiogenesis Inhibitors; Animal Model; Area; Biological; Biology; Blood Vessels; Blood capillaries; Breast Melanoma; Cancer Biology; Cancer Etiology; Cause of Death; Cell Survival; Cells; Clinic; Clinical; Clinical Trials; Detection; Disease; Disease-Free Survival; Distal; Distant; Drug Design; Environment; Epithelial; Evaluation; Excision; Exposure to; Goals; Growth; Health; High Endothelial Venule; Human; Human Development; Immune; Immune response; Immunologic Surveillance; Immunology; Immunosuppression; Immunosuppressive Agents; Investigation; Lead; Location; Lymph Node Involvement; Lymphatic Metastasis; Lymphocyte; Malignant Neoplasms; Measures; Mechanical Stress; Mentors; Metabolism; Metastatic Lesion; Metastatic Neoplasm to Lymph Nodes; Modeling; Molecular; Monitor; Morphology; Mus; Neoplasm Metastasis; Nodal; Normal Statistical Distribution; Organ; Outcome; PECAM1 gene; Patients; Pharmaceutical Preparations; Phase; Population; Prevention; Primary Neoplasm; Process; Prognostic Marker; Regimen; Research; Research Personnel; Resources; Role; Route; Sentinel Lymph Node; Site; Solid; Staging; Staining method; Stains; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Uses; Training; Translating; Vascular remodeling; Vascularization; Work; angiogenesis; antiangiogenesis therapy; base; bevacizumab; cancer cell; cancer therapy; cancer type; career; density; design; experience; improved; in vivo; inhibitor/antagonist; insight; killings; lymph nodes; mortality; mouse model; neoplastic cell; novel; novel therapeutics; prevent; programs; public health relevance; research study; residence; response; therapeutic angiogenesis; trafficking; tumor; tumor growth; tumor progression; tumor xenograft

DESCRIPTION (provided by applicant): Metastasis remains the principal cause of cancer mortality. Furthermore, lymph node status is the most significant prognostic indicator for patient outcome in human solid cancer. The presence of cancer cells in the lymph node is associated with an absolute reduction in the 5-year rate of disease-free survival. Therefore, in cancers such as breast and melanoma, removal of the sentinel lymph node has become a standard approach to treat patients. However, in patients with lymph node involvement who also received adjuvant therapy, disease-free survival was improved. This suggests that tumor cells may take undetected residence in distal nodes and organs. Thus, the challenge is how to treat cancer cells that have spread to lymph nodes or distant organs in order to prevent their growth and ideally eradicate them from the body. A well-known class of adjuvant therapy is anti-angiogenesis inhibitors. Although angiogenesis is critical for growth and establishment of primary tumors, it is unknown how significant this process is for cancer cells that have metastasized. Through establishment of improved metastasis models, this project aims to investigate the angiogenic response in lymph node metastases. Clinical trials using anti-angiogenesis therapy have not fared as well as predicted. One reason for this outcome may be that this therapy was developed against the primary tumor growing in its native microenvironment. However, it is clear that the local microenvironment in which tumor cells grow greatly affects the growth rate, metabolism, vascularization and ultimately response to therapeutic intervention. Preliminary results in Aim 1 of this proposal suggest that the classical sprouting angiogenesis observed in the primary tumor site is not necessary for tumor growth in the lymph node, once cancer cells arrive. I hypothesize that the molecular and cellular mechanisms regulating tumor growth in early and late metastatic lymph nodes are independent of the formation of new blood vessels, contrary to what is seen in the primary tumor. In Aim 1, I will use a combination of novel mouse models to test and reproduce these observations in vivo. Interestingly, within the metastatic tumor mass in the lymph nodes, the density of CD31 staining is significantly decreased with respect to the non-tumor area. While there is a normal distribution of blood capillaries in the metastatic lesions, there is a noticeable absence of high endothelial venules compared to the "normal" lymph node regions. Preliminary results in Aim 2 of the proposal suggest that remodeling of the lymph node vasculature leads to an inhibition of the immune response against cancer cells. I hypothesize that due to mechanical stress by tumor cells or a vascular dedifferentiation program induced by tumor cells, high endothelial venules lose the capacity to for lymphocyte trafficking and ultimately leads to loss of immune surveillance. In Aim 2, I will investigate this mechanism and attempt to therapeutically intervene in order to enhance immune access to tumor cells. Collectively, these studies will contribute to understanding the progression of metastases in the lymph node, and may have implications for metastasis biology in general. Understanding mechanisms of cancer growth and survival in metastatic sites such as the lymph node is critical for the rational design and use of therapeutics, such as anti-angiogenesis adjuvants.

描述（由申请人提供）：转移仍然是癌症死亡的主要原因。此外，淋巴结状态是人类实体癌患者预后的最重要的预后指标。淋巴结中癌细胞的存在与 5 年无病生存率的绝对降低相关。因此，在乳腺癌和黑色素瘤等癌症中，切除前哨淋巴结已成为治疗患者的标准方法。然而，在接受辅助治疗的淋巴结受累患者中，无病生存率有所改善。这表明肿瘤细胞可能在远端节点和器官中未被发现地驻留。因此，挑战在于如何治疗已扩散到淋巴结或远处器官的癌细胞，以防止其生长并理想地将其从体内根除。一类众所周知的辅助治疗是抗血管生成抑制剂。尽管血管生成对于原发性肿瘤的生长和建立至关重要，但尚不清楚该过程对于已转移的癌细胞有多重要。通过建立改进的转移模型，该项目旨在研究淋巴结转移中的血管生成反应。 使用抗血管生成疗法的临床试验进展并不如预期。造成这一结果的一个原因可能是这种疗法是针对在其天然微环境中生长的原发肿瘤而开发的。然而，很明显，肿瘤细胞生长的局部微环境极大地影响生长速率、代谢、血管化以及最终对治疗干预的反应。该提案目标 1 的初步结果表明，一旦癌细胞到达，在原发肿瘤部位观察到的经典发芽血管生成对于淋巴结中的肿瘤生长来说并不是必需的。我假设调节早期和晚期转移淋巴结中肿瘤生长的分子和细胞机制独立于新血管的形成，这与原发肿瘤中观察到的情况相反。在目标 1 中，我将使用新型小鼠模型的组合来测试和重现体内的这些观察结果。 有趣的是，在淋巴结转移性肿瘤块内，CD31 染色的密度相对于非肿瘤区域显着降低。虽然存在正态分布 在转移性病灶中的毛细血管中，与“正常”淋巴结区域相比，明显缺乏高内皮微静脉。该提案目标 2 的初步结果表明，淋巴结脉管系统的重塑会抑制针对癌细胞的免疫反应。我推测，由于肿瘤细胞的机械应力或肿瘤细胞诱导的血管去分化程序，高内皮微静脉失去了淋巴细胞运输的能力，并最终导致免疫监视的丧失。在目标 2 中，我将研究这一机制并尝试进行治疗干预，以增强免疫系统对肿瘤细胞的接触。 总的来说，这些研究将有助于了解淋巴结转移的进展，并可能对转移生物学产生总体影响。了解淋巴结等转移部位的癌症生长和存活机制对于合理设计和使用抗血管生成佐剂等治疗药物至关重要。