ERBB1 AND ERBB2 IN TUMOR MOTILITY AND METASTASIS

描述（由申请人提供）：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、肿瘤细胞内浸润和转移中的作用。更好地了解肿瘤细胞如何进入血管将提高我们开发治疗方法和诊断测试的能力，以改善癌症患者的治疗。我们在前一个周期中发现，ErbB1或ErbB2/ErbB3信号的增加可以增强肿瘤细胞的内增殖和转移，而不影响体内生长速度。我们假设，我们在体外观察到的趋化反应的增加和体内观察到的侵袭性反应的增加使转移性肿瘤细胞能够检测泄漏血管并向它们移动，从而增强了内渗。在Specific Aim 1中，我们分析了ErbB2和ErbB3上的C端酪氨酸，它们是增强体内浸润和转移所必需的。在Specific Aim 2中，我们使用多光子显微镜成像来评估肿瘤细胞在原发肿瘤中相对于血管的迁移，并测试erbb和血管渗漏在直接刺激肿瘤细胞运动中的作用。在Specific Aim 3中，我们测试了是否需要配体的外部梯度来增强肿瘤细胞的运动、内渗和转移。本研究利用原位、体内自发转移模型和原发肿瘤的活体成像，对erbb在体内转移和转移中的作用进行了独特的测量。

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.