Molecular profiling of human hepatocellular cancer

人类肝癌在美国的发病率越来越高，是世界上第五大最常见的恶性疾病。它是导致癌症死亡的第三大原因，每年约有100万人死于癌症。肝细胞癌（HCC）是原发性肝癌的主要类型。HCC被认为是一种绝症，目前在发现有效的治疗方法方面进展甚微。这主要是由于缺乏早期诊断的方法和缺乏与HCC发展相关的表型变化的信息。我们的目标是确定负责HCC发生和进展的常见基因簇，并发现对病毒性肝炎介导的HCC至关重要的新基因。我们正在使用cDNA微阵列和microRNA微阵列来分析与肝脏疾病不同阶段相关的临床标本。例如，通过比较具有不同程度发展为肝细胞癌风险的慢性肝病患者的肝脏样本，我们已经确定了一个独特的特征，可能有助于诊断早期发病的肝癌患者。几种血清蛋白已被确定为HCC的潜在诊断标志物，这些血清蛋白在早期或甲胎蛋白阴性时出现。利用cDNA微阵列技术，我们还开发了一种基于转移性原发性HCC标本基因表达的独特分子标记，以预测HCC患者的预后和转移。骨桥蛋白被确定为该特征的先导基因，并被发现对HCC的转移表型至关重要。由于肝细胞癌通常存在于因纤维化、肝硬化和/或慢性肝炎而发炎的肝脏中，我们还基于肝细胞癌患者肝脏微环境的基因表达开发了一种独特的分子预后标记，并提示肝细胞癌转移倾向可能由局部组织微环境决定和/或影响。有趣的是，肿瘤的特征与肝脏微环境的特征主要不同。我们证明CSF1可能是转移性HCC患者肝脏微环境中出现的独特特征的原因。我们的研究表明，主要的体液细胞因子谱发生在转移性肝脏环境中，并且向抗炎/免疫抑制反应的转变可能促进HCC转移。我们已经确定了新的预后HCC亚型，其特征是EpCAM和甲胎蛋白的表达与肝发生的某些阶段相似。我们还证明，这种分类系统可以通过预测独特的分子靶向治疗的药理反应来促进HCC的预后。目前，我们正在探索这些基因在肝癌发生和转移中的作用。我们的发现非常富有成效，因为它们不仅可以为患者管理提供实用工具，而且还可以挑战当前肿瘤进化的范式。显然，基因表达谱扩展了我们对肝癌发生的全局变化的认识，并为这种疾病的分子机制提供了许多见解。此外，这些研究无疑将有助于建立具有潜在诊断和预后价值的新标志物，以及直接临床干预该疾病的潜在治疗靶点。

Human liver cancer, with increasing occurrence in the United States, is the 5th most prevalent malignant disease in the world. It is the third leading cause of cancer mortality, which accounts for an estimated 1 million deaths annually. Hepatocellular carcinoma (HCC) is a major type of primary liver cancer. HCC is considered to be a terminally ill disease and currently, there is little progress toward the discovery of efficient therapies leading to regression. This is due largely to the lack of a method for early diagnosis and the lack of information on the phenotypic changes associated with the development of HCC. Our goals are to identify common gene clusters that are responsible for initiation and progression of HCC and to discover new genes critical for viral hepatitis-mediated HCC. We are using cDNA microarray and microRNA microarray to profile clinical specimens that are associated with different stages of liver diseases. For example, by comparing liver samples from chronic liver disease patients with varying degrees of risk for developing hepatocellular carcinoma, we have identified a unique signature that may be useful in diagnosing patients with early onset of liver cancer. Several serum proteins have been identified as potential diagnostic markers for HCC that are presented in an early stage or in those negative for alpha fetoprotein. Using cDNA microarray, we have also developed a unique molecular signature based on the gene expression of metastatic primary HCC specimens to predict prognosis and metastasis of HCC patients. Osteopontin was identified as a lead gene in this signature and was found to be critical for the metastatic phenotype of HCC. Since HCC is usually present in inflamed liver, due to fibrosis, cirrhosis and/or chronic hepatitis, we also developed a unique molecular prognostic signature based on gene expression of the liver microenvironment of HCC patients, and suggested that HCC metastatic propensity may be determined and/or influenced by the local tissue microenvironment. Interestingly, the tumor signature is principally different from that of liver microenvironment. We demonstrated that CSF1 may be responsible for the unique signature presented in the liver microenvironment of metastatic HCC patients. Our studies indicate that a predominant humoral cytokine profile occurs in the metastatic liver milieu and that a shift toward anti-inflammatory/immune-suppressive responses may promote HCC metastases. We have identified novel prognostic HCC subtypes, characterized by EpCAM and alpha-fetoprotein expression that resemble certain stages of hepatogenesis. We have also demonstrated that this classification system may facilitate HCC prognosis by enabling the prediction of pharmacological responses to a unique molecular targeted therapy. Currently, we are exploring the roles of these genes in liver cancer initiation and metastasis. Our findings have been extremely fruitful as they may not only offer utilities to patient managements, but also challenge the current paradigm of tumor evolution. Clearly, gene expression profiling has expanded our knowledge of the global changes that occur in liver cancer, and has provided numerous insights into the molecular mechanisms of this disease. In addition, these studies will undoubtedly contribute to the establishment of novel markers with potential diagnostic and prognostic value, as well as potential therapeutic targets for direct clinical intervention of this disease.