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

评估压力对自发性肿瘤发展的影响：一个新范式

• 批准号: 7473228
• 负责人: DANA H. BOVBJERG
• 金额: $ 14.85万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-20 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7473228
• 关键词: Achievement; Adhesions; Affect; Age-Months; Breast; Cell Differentiation process; Chronic; Chronic stress; Colon Carcinoma; Condition; Cytokine Gene; Development; Disease regression; Evaluation; Hyperplasia; Immune response; Immunity; Immunotherapy; Incidence; Interleukin-12; Lung; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Mediating; Modeling; Monitor; Mus; Neoplasm Metastasis; Numbers; Oncogenes; Patients; Population; Psychological Stress; Rattus; Receptor Protein-Tyrosine Kinases; Stress; Study models; System; Transgenic Mice; Transgenic Organisms; Tumor Immunity; cancer risk; cell motility; day; gene therapy; human study; immune function; lung development; malignant breast neoplasm; mouse model; preclinical study; stressor; tumor; tumor progression

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.

描述（由申请人提供）：ERBB-2（HER2/neu）是一种编码185 kDa（P185NEU）酪氨酸激酶受体的癌基因，涉及细胞分化，粘附和运动。小鼠为大鼠neu/erbb-2 [fvb/n-tg（mmtvneu）202mul/j]无激活形式的转基因表现出很高的乳腺癌发生率和侵略性进展。在此模型中，局灶性乳腺肿瘤在> 50％的小鼠中首先在4个月大时出现，中位发生率为205天。这些肿瘤作为乳腺中的增生/异型局灶性出现。约有70％的肿瘤小鼠> 8个月大的小鼠发展出肺转移。此外，有大量证据表明，用IL12的细胞因子基因治疗导致这些小鼠的肿瘤消退。因此，该转基因小鼠是研究应力对乳腺癌发病率和对这些肿瘤的抗肿瘤免疫力的影响的非常有用的模型。我们建议将慢性应激模型与该自发肿瘤模型结合使用，以记录压力对肿瘤发育的影响，以评估导致肿瘤发育增强的机制，并评估压力对肿瘤免疫的负面影响。此外，我们将检查压力对IL12肿瘤免疫疗法功效的影响。我们的具体目的包括：目标1。确定慢性应激源对ERBB-2转基因[FVB/N- TG（MMTVNEU）202MUL/J]小鼠中乳腺肿瘤发育和肺转移的影响。 AIM 2。确定慢性应激对ERBB-2转基因[FVB/N-TG（MMTVNEU）202MUL/J]小鼠中抗肿瘤免疫的影响。该项目介绍了在转基因小鼠模型中对压力对乳腺癌进展的影响，甚至可能启动的评估。在该模型中，乳腺肿瘤在大约一半的小鼠中自发发展。我们将确定压力是否会增加肿瘤发育的速度以及增加肿瘤的小鼠数量。我们还将检查压力是否影响小鼠介导抗肿瘤免疫反应对乳腺癌的能力。这可能为监测压力对癌症的影响的实验方法提供了重要的进步。