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肿瘤。它是癌症死亡的第三大原因，估计每年有100万人死于癌症。肝细胞癌是原发性肝癌的一种主要类型。肝细胞癌被认为是一种晚期疾病，目前，在发现导致消退的有效治疗方法方面进展甚微。这在很大程度上是由于缺乏早期诊断的方法，以及缺乏与肝细胞癌发展相关的表型变化的信息。我们的目标是确定共同的基因簇，负责肝细胞癌的发生和发展，并发现对病毒性肝炎介导的肝细胞癌至关重要的新基因。我们正在使用cDNA微阵列和微RNA微阵列来分析与肝脏疾病不同阶段相关的临床标本。例如，通过比较患有不同程度肝细胞癌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，该特征可能对诊断早期肝癌患者有用。几种血清蛋白已被确定为肝癌的潜在诊断标记物，这些标记物出现在早期或甲胎蛋白阴性的病例中。利用基因芯片，我们还开发了一种基于转移性原发肝癌标本基因表达的独特的分子标志物来预测肝癌患者的预后和转移。骨桥蛋白在这一信号中被确认为先导基因，并被发现对肝细胞癌的转移表型至关重要。由于肝细胞癌通常存在于炎症的肝脏，由于肝纤维化、肝硬变和/或慢性肝炎，我们还根据肝细胞癌患者肝脏微环境的基因表达发展了一个独特的分子预后标志，并提示肝细胞癌的转移倾向可能是由局部组织微环境决定和/或影响的。有趣的是，肿瘤的征象与肝脏微环境的征象有很大不同。我们证明CSF1可能与转移性肝细胞癌患者肝脏微环境中出现的独特信号有关。我们的研究表明，在转移性肝环境中存在主要的体液细胞因子，向抗炎/免疫抑制反应的转变可能促进肝细胞癌的转移。我们已经确定了新的预后肝细胞癌亚型，其特征是EPCAM和甲胎蛋白的表达类似于肝发生的某些阶段。我们还证明，这种分类系统可以通过预测对一种独特的分子靶向治疗的药理学反应来促进肝癌的预后。目前，我们正在探索这些基因在肝癌发生和转移中的作用。我们的发现是非常有成效的，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的肿瘤进化范式。显然，基因表达谱扩大了我们对肝癌发生的全球变化的了解，并为这种疾病的分子机制提供了大量的见解。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记物，以及直接临床干预的潜在治疗靶点。

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.