INVESTIGATION OF THE VASCULAR RESPONSE IN LYMPH NODE METASTASES

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有关。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，无病生存得到改善。这表明肿瘤细胞可能在远端淋巴结和器官中未被发现。因此，挑战在于如何治疗已经扩散到淋巴结或远处器官的癌细胞，以防止它们的生长，并在理想情况下将它们从体内清除。一类众所周知的辅助治疗是抗血管生成抑制剂。尽管血管生成对原发肿瘤的生长和形成至关重要，但对于已经转移的癌细胞来说，这一过程有多重要尚不清楚。本项目旨在通过建立改进的转移模型，探讨淋巴结转移的血管生成反应。使用抗血管生成疗法的临床试验进展不如预期。这一结果的一个原因可能是这种疗法是针对原发肿瘤在其原生微环境中生长而开发的。然而，很明显，肿瘤细胞生长的局部微环境极大地影响了肿瘤细胞的生长速度、代谢、血管化以及最终对治疗干预的反应。本研究目的1的初步结果表明，一旦癌细胞到达淋巴结，在原发肿瘤部位观察到的经典发芽血管生成对于肿瘤生长不是必需的。我假设在早期和晚期转移性淋巴结中调节肿瘤生长的分子和细胞机制独立于新血管的形成，这与原发肿瘤中所看到的相反。在目标1中，我将使用新型小鼠模型的组合来测试和再现这些观察结果。有趣的是，在淋巴结转移性肿瘤内，CD31染色密度相对于非肿瘤区域明显降低。而这是正态分布

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.