Molecular profiling of human hepatocellular cancer

我们正在使用基于最先进的微阵列技术的全球基因表达谱方法来分析与肝脏疾病不同阶段相关的临床样本。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。我们还开发了一种基于转移性原发肝癌标本的mRNA基因表达的独特的分子标记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，我们还发展了一个基于肝微环境mRNA基因表达的独特的分子预后标志，并提示肝细胞癌的转移倾向可能决定和/或受局部组织微环境的影响。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。我们已经确定了五个基因，这些基因可以作为肝细胞癌早期发病的生物标志物，特别是那些甲胎蛋白(AFP)阴性的基因。我们还披露了新的预后肝细胞癌亚型，其特征是EPCAM和AFP的表达类似于肝发生的某些阶段。我们已经证明，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，特别是它们在肝癌干细胞中的作用。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。

We are using global gene expression profiling approach based on the state-of-the-art microarray technology 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. We have also developed a unique molecular signature based on the mRNA 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 mRNA 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 five genes that may serve as biomarkers for early onset of HCC, especially for those that are negative for alpha-fetoprotein (AFP). We have also disclosed novel prognostic HCC subtypes, characterized by EpCAM and AFP expression that resemble certain stages of hepatogenesis. We have 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, particularly their roles in liver cancer stem cells. 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.