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ErbB 1和ErbB 2/ErbB 3在体内运动、肿瘤细胞内渗和转移中的作用。 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，增加ErbB 1或ErbB 2/ErbB 3信号可以增强肿瘤细胞的浸润和转移，而不影响体内生长速率。 我们推测，我们在体外观察到的趋化反应增加和在体内观察到的侵袭性反应增加使转移性肿瘤细胞能够检测到渗漏的血管并向其移动，从而导致增强的内渗。 在特定目标1中，我们对ErbB 2和ErbB 3上的C末端酪氨酸进行了分析，这些酪氨酸是增强血管内浸润和转移所必需的。 在特定目标2中，我们使用多光子显微镜成像来评估原发性肿瘤中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。 在特定目标3中，我们测试了是否需要外部配体梯度来增强肿瘤细胞的运动性、内渗和转移。 该建议利用原位，在体内模型的自发性转移连同原发性肿瘤的活体成像进行独特的测量的贡献的ErbBs的内渗和转移。

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.