Evaluating the effects of stress on spontaneous tumor development: A new paradigm

描述(申请人提供)：ErbB-2(Her2/neu)是一种癌基因，编码185kDA(P185neu)酪氨酸激酶受体，参与细胞分化、黏附和运动。转基因未激活的大鼠neu/erbB-2[FVB/N-TG(MMTVneu)202-1/J]的小鼠表现出较高的乳腺癌发病率和侵袭性进展。在这个模型中，局灶性乳腺肿瘤在4个月大的小鼠中首次出现，50%的小鼠的中位发病率为205天。肿瘤以乳腺增生性/非增生性病灶出现，8月龄荷瘤小鼠约70%发生肺转移。此外，有大量证据表明，用IL12进行细胞因子基因治疗会导致这些小鼠肿瘤的消退。因此，该转基因小鼠是研究应激对乳腺癌发生发展和抗肿瘤免疫影响的有效模型。我们建议将慢性应激模型与自发性肿瘤模型结合使用，以记录应激对肿瘤发展的影响，评估导致肿瘤发展增强的机制，并评估应激对肿瘤免疫的负面影响。此外，我们还将研究应激对IL12肿瘤免疫治疗效果的影响。目的：1.研究慢性应激源对ErbB-2转基因[FVB/N-TG(Mmtwneu)202-J]转基因小鼠乳腺肿瘤发生和肺转移的影响。目的2.探讨慢性应激对ErbB-2转基因小鼠抗肿瘤免疫功能的影响。该项目涉及在转基因小鼠模型中评估应激对乳腺癌进展的影响，以及可能的启动。在这个模型中，大约一半的小鼠会自发发生乳腺肿瘤；我们将确定压力是否增加到肿瘤发展的速度，以及它是否增加了发展成肿瘤的小鼠的数量。我们还将检查应激是否影响小鼠介导乳腺癌抗肿瘤免疫反应的能力。这可能为监测应激对癌症影响的实验方法提供一个重要的进步。

DESCRIPTION (provided by applicant): ErbB-2 (Her2/neu) is an oncogene encoding a 185 kDA (p185neu) tyrosine kinase receptor involved in cell differentiation, adhesion and motility. Mice made transgenic for the unactivated form of rat neu/erbB-2 [FVB/N-Tg(MMTVneu)202Mul/J] display a high incidence and aggressive progression of mammary carcinogenesis. In this model, focal mammary tumors are first apparent at 4 months of age in >50% of the mice, with a median incidence of 205 days. The tumors arise as hyperplastic/dysplastic foci in mammary glands; and ~70% of tumor-bearing mice >8 months of age develop lung metastases. Also, there is substantial evidence that cytokine gene therapy with IL12 results in regression of tumors in these mice. Therefore, this transgenic mouse is a highly useful model for studying the effects of stress on incidence and development of breast cancer and anti-tumor immunity to those tumors. We propose to use chronic stress models in combination with this spontaneous tumor model to document the effects of stress on tumor development, to evaluate the mechanisms resulting in enhanced tumor development, and to assess the negative effects of stress on tumor immunity. In addition, we will examine the effects of stress on the efficacy of tumor immunotherapy with IL12. Our specific aims include: Aim 1. Determine the effects of chronic stressors on mammary tumor development and lung metastases in Erbb-2 transgenic [FVB/N- Tg(Mmtvneu)202Mul/J] mice. Aim 2. Determine the effects of chronic stress on anti-tumor immunity in Erbb-2 transgenic [FVB/N-Tg(Mmtvneu)202Mul/J] mice. This project deals with the evaluation of the effects of stress on the progression, and possibly initiation, of breast cancer in a transgenic mouse model. In this model, breast tumors spontaneously develop in about half the mice; and we will determine whether stress increases to rapidity of tumor development and whether it increases the number of mice that develop tumors. We will also examine whether stress affects the ability of the mice to mediate anti- tumor immune responses to breast cancer. This may provide an important advance in the experimental approaches available to monitor the effects of stress on cancer.