A Viral Cytokine as a Promoter of Tumor Progression

描述（由申请人提供）：2010年将诊断出近20万例乳腺癌新病例，今年将有4万多名妇女死于这种疾病。大多数癌症患者不是死于原发性肿瘤生长的局部并发症，而是死于肿瘤的转移和恶性扩散。虽然有许多已知的乳腺癌风险因素，但传染病的影响在很大程度上仍未被探索。人巨细胞病毒（HCMV）是一种广泛的病原体，感染70-90%的一般人群。HCMV通常仅在免疫受损的个体中引起临床疾病，但最近的证据将HCMV感染与几种类型的癌症联系起来。虽然以前的研究集中在HCMV基因产物增加病毒感染的肿瘤细胞恶性程度的潜力，但本研究检查了分泌的病毒细胞因子对未感染的肿瘤细胞的影响。具体的假设是，cmvIL-10通过增强侵袭力和促进癌细胞的生长和存活而促进肿瘤进展。这一假设得到了初步数据的支持，初步数据显示cmvIL-10触发乳腺癌细胞中基质金属蛋白酶（MMP）的表达增加，并进一步基于关于人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，并与预后不良相关。第二，IL-10已经显示出抑制癌细胞的凋亡和促进癌细胞的转移。最后，IL-10刺激Stat 3的活化，Stat 3是一种与增强的转移潜能和化学抗性强烈相关的转录因子。由于cmvIL-10是病毒编码的同源物，保留了人IL-10的许多生物学功能，包括刺激B细胞生长和激活Stat 3，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，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。这项工作将提供对HCMV感染对乳腺癌进展的影响的进一步了解。这些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，并可能在癌症的诊断和治疗中具有广泛的意义。 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。感染70-90%普通人群的人类巨细胞病毒（HCMV）等病原体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，从而可能改善癌症治疗并降低人类死亡率。

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.