A Viral Cytokine as a Promoter of Tumor Progression

描述（由申请人提供）：2010年将有近20万新的乳腺癌病例被诊断出来，今年将有超过4万名妇女死于这种疾病。大多数癌症患者不是死于原发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，但有一个领域仍基本上未被探索，那就是传染病的影响。人类巨细胞病毒（HCMV）是一种广泛存在的病原体，感染了70-90%的普通人群。HCMV通常仅在免疫功能低下的个体中引起临床疾病，但最近的证据表明HCMV感染与几种类型的癌症有关。虽然以前的研究主要集中在HCMV基因产物增加病毒感染肿瘤细胞恶性程度的潜力上，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通过增强侵袭性和促进癌细胞的生长和存活来促进肿瘤进展。这一假设得到了cmvIL-10触发乳腺癌细胞中基质金属蛋白酶（MMPs）表达增加的初步数据的支持，并进一步基于人类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。其次，IL-10具有抑制癌细胞凋亡和促进癌细胞转移的作用。最后，IL-10刺激Stat3的激活，Stat3是一种与转移潜能增强和化疗耐药密切相关的转录因子。由于cmvIL-10是一种病毒编码的同源物，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，似乎病毒细胞因子也可能刺激转移。乳腺癌细胞将在cmvIL-10存在或不存在的情况下培养，以确定对MMP酶活性、细胞运动性和侵袭性的影响。此外，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将被评估。这项工作将增强对HCMV感染对乳腺癌进展的影响的理解。该结果有望阐明分泌的病毒细胞因子对未感染肿瘤细胞的作用，并可能在癌症的诊断和治疗中具有广泛的意义。

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.