ERBB1 AND ERBB2 IN TUMOR MOTILITY AND METASTASIS

描述(申请人提供)：本申请的目的是研究EGF受体家族成员ErbB1和ErbB2/ErbB3在体内运动、肿瘤细胞内血管和转移中的作用。更好地了解肿瘤细胞是如何进入血管的，将增强我们开发治疗和诊断测试的能力，以改善癌症患者的治疗。我们在上一个周期中发现，增加ErbB1或ErbB2/ErbB3信号可以促进肿瘤细胞的血管内皮细胞侵袭和转移，而不影响体内生长速度。我们假设，我们在体外观察到的增加的趋化反应和在体内观察到的增加的侵袭反应使转移的肿瘤细胞能够检测到泄漏的血管并向它们移动，导致血管内增强。在特定的目标1中，我们分析了ErbB2和ErbB3上的C末端酪氨酸，这是增强血管内和转移所必需的。在具体目标2中，我们使用多光子显微镜成像来评估肿瘤细胞相对于血管的迁移，并测试ERBbs和血管渗漏在直接刺激肿瘤细胞运动中的作用。在特定的目标3中，我们测试是否需要外部梯度的配体来增强肿瘤细胞的运动、血管内和转移。这项建议利用原位活体自发转移模型和原发肿瘤的活体成像，对ERBbs在血管内和转移中的作用进行独特的测量。

DESCRIPTION (provided by applicant): The objective of this application is to examine the contributions of the EGF receptor family members ErbB1 and ErbB2/ErbB3 in vivo motility, tumor cell intravasation and metastasis. A better understanding of how tumor cells enter blood vessels will enhance our ability to develop therapies and diagnostic tests for improving treatment of patients with cancer. We have found in the previous cycle that increased ErbB1 or ErbB2/ErbB3 signaling can enhance tumor cell intravasation and metastasis, without affecting in vivo growth rates. We hypothesize that the increased chemotactic responses that we observe in vitro and increased invasive responses observed in vivo enable metastatic tumor cells to detect leaky vessels and move towards them, resulting in enhanced intravasation. In Specific Aim 1, we perform an analysis of the C terminal tyrosines on ErbB2 and ErbB3 that are required for enhancement of intravasation and metastasis. In Specific Aim 2, we use multiphoton microscopy imaging to evaluate tumor cell migration in the primary tumor relative to blood vessels and test the roles of ErbBs and vessel leakiness in directly stimulating tumor cell motility. In Specific Aim 3, we test whether external gradients of ligand are required for enhancement of tumor cell motility, intravasation and metastasis. This proposal makes use of orthotopic, in vivo models of spontaneous metastasis together with intravital imaging of primary tumors to perform unique measurements of the contributions of ErbBs on intravasation and metastasis.