A Viral Cytokine as a Promoter of Tumor Progression

病毒细胞因子作为肿瘤进展的促进剂

基本信息

批准号：
8098622
负责人：
JULIET VESCIO SPENCER
金额：
$ 41.27万
依托单位：
UNIVERSITY OF SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-04 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8098622
关键词：
Acceleration Affect Antibodies Antiviral Agents Apoptosis Area B-Lymphocytes Binding Biological Assay Biological Process Blood Vessels Breast Cancer Cell Breast Cancer Risk Factor Cancer Cell Growth Cancer Etiology Cancer Patient Caspase Cell Cycle Cell Survival Cells Cessation of life Characteristics Clinical Communicable Diseases Cytomegalovirus Cytomegalovirus Infections DNA Fragmentation Data Development Diagnosis Disease Distant Exposure to Extracellular Protein Gene Expression General Population Growth Homologous Gene Human Immune In Vitro Individual Interleukin-10 Invaded Lead Link Lymphatic System Malignant - descriptor Malignant Neoplasms Matrix Metalloproteinases Measures Metalloproteinase Gene Neoplasm Metastasis Organ Pilot Projects Play Population Primary Neoplasm Property Proteins Resistance Role Route Tissues Tumor Cell Invasion United States Viral Virus Woman Work base cancer cell cancer therapy cancer type cell growth cell motility collagenase 3 cytokine design enzyme activity human mortality improved insight malignant breast neoplasm migration neoplastic cell new therapeutic target novel outcome forecast pathogen promoter stromelysin 3 transcription factor treatment strategy tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Nearly 200,000 new cases of breast cancer will be diagnosed in 2010, and over 40,000 women will succumb to the disease this year. Most cancer patients do not die from local complications of their primary tumor growth, but rather from the development of metastases and malignant spread of the tumor. While there are many known risk factors for breast cancer, one area that remains largely unexplored is the impact of infectious disease. Human cytomegalovirus (HCMV) is a widespread pathogen that infects 70-90% of the general population. HCMV usually causes clinical disease only in immune compromised individuals, but recent evidence has linked HCMV infection to several types of cancer. While previous studies have focused on the potential of HCMV gene products to increase malignancy of virus infected tumor cells, this study examines the effect of a secreted viral cytokine on uninfected tumor cells. The specific hypothesis is that cmvIL-10 contributes to tumor progression by enhancing invasiveness and promoting the growth and survival of cancer cells. This hypothesis is supported by preliminary data showing that cmvIL-10 triggers increased expression of matrix-metalloproteinases (MMPs) in breast cancer cells and is further based on several key observations about human IL-10. First, elevated levels of IL-10 are found in several types of cancer and correlate with poor prognosis. Second, IL-10 has been shown to inhibit apoptosis and promote metastasis of cancer cells. Finally, IL-10 stimulates activation of Stat3, a transcription factor which is strongly associated with enhanced metastatic potential and chemoresistance. Because cmvIL-10 is a virally encoded homolog that retains many biological functions of human IL-10, including stimulation of B cell growth and activation of Stat3, it seems likely that the viral cytokine may also stimulate metastasis. Breast cancer cells will be cultured in the presence or absence of cmvIL-10 to determine effects on MMP enzyme activity, cell motility, and invasiveness. In addition, the ability of cmvIL-10 to stimulate breast cancer cell growth and protect tumor cells from apoptosis will be evaluated. This work will provide an enhanced understanding of the impact of HCMV infection on breast cancer progression. The results are expected to clarify the effect of a secreted viral cytokine on uninfected tumor cells, and could have broad implications in the diagnosis and treatment of cancer. PUBLIC HEALTH RELEVANCE: Breast cancer is the second leading cause of cancer deaths for women in the United States. Opportunistic pathogens like human cytomegalovirus (HCMV), which infect 70-90% of the general population, may play a role in the acceleration and malignant spread of breast cancer. By studying the molecular interactions between this pathogen and its human host, novel therapeutic targets may be identified, potentially leading to improved cancer treatments and decreased human mortality.

描述（申请人提供）： 2010年将有近20万新发乳腺癌病例，今年将有超过4万名女性死于该病。大多数癌症患者并不是死于原发肿瘤生长的局部并发症，而是死于肿瘤转移和恶性扩散。虽然乳腺癌有许多已知的危险因素，但传染病的影响仍然很大程度上未被探索。人类巨细胞病毒 (HCMV) 是一种广泛传播的病原体，感染 70-90% 的普通人群。 HCMV 通常仅在免疫受损的个体中引起临床疾病，但最近的证据已将 HCMV 感染与几种类型的癌症联系起来。虽然之前的研究重点关注 HCMV 基因产物增加病毒感染肿瘤细胞恶性程度的潜力，但本研究探讨了分泌的病毒细胞因子对未感染肿瘤细胞的影响。具体假设是 cmvIL-10 通过增强癌细胞的侵袭性并促进生长和存活来促进肿瘤进展。这一假设得到了初步数据的支持，初步数据显示 cmvIL-10 会触发乳腺癌细胞中基质金属蛋白酶 (MMP) 的表达增加，并且进一步基于对人 IL-10 的几个关键观察结果。首先，在几种类型的癌症中发现 IL-10 水平升高，并且与不良预后相关。其次，IL-10已被证明可以抑制细胞凋亡并促进癌细胞转移。最后，IL-10 刺激 Stat3 的激活，Stat3 是一种与增强的转移潜力和化疗耐药性密切相关的转录因子。由于 cmvIL-10 是病毒编码的同源物，保留了人类 IL-10 的许多生物学功能，包括刺激 B 细胞生长和激活 Stat3，因此病毒细胞因子似乎也可能刺激转移。将在存在或不存在 cmvIL-10 的情况下培养乳腺癌细胞，以确定对 MMP 酶活性、细胞运动性和侵袭性的影响。此外，还将评估 cmvIL-10 刺激乳腺癌细胞生长和保护肿瘤细胞免于凋亡的能力。这项工作将加深人们对 HCMV 感染对乳腺癌进展影响的了解。研究结果有望阐明分泌的病毒细胞因子对未感染肿瘤细胞的影响，并可能对癌症的诊断和治疗产生广泛的影响。公共卫生相关性：乳腺癌是美国女性癌症死亡的第二大原因。人巨细胞病毒 (HCMV) 等机会性病原体感染 70-90% 的普通人群，可能在乳腺癌的加速和恶性扩散中发挥作用。通过研究这种病原体与其人类宿主之间的分子相互作用，可以确定新的治疗靶点，从而有可能改善癌症治疗并降低人类死亡率。