Volume 11, Nº 6 (2011)

Liver cancer, hepatocellular carcinoma (HCC) in particular, is one of the most deadly cancers worldwide, and the incidence of HCC is increasing rapidly in the United States and other developed countries. Epidemiological studies have identified major risk factors for HCC, including infection with hepatitis B and C virus (HBV and HCV), exposure to certain chemicals, high intake of alcohol, as well as metabolic diseases such as obesity and diabetes that are rapidly rising in the US. Although the etiologies for liver carcinogenesis are relatively well defined, the exact mechanism and pathways leading to cancer development are still unclear. Chronic liver injury, followed by inflammation and irregular liver regeneration has been suggested as an important step in hepatocarcinogenesis. Therefore, the identification of key factors that protect the liver from injury and inflammation could provide valuable insight into the development of HCC. In this review, we will summarize the recent findings in HCC studies, mainly focusing on the new molecular link among inflammation, liver repair and HCC.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality in the world because current treatments, including both surgical and non-surgical ones, cannot effectively cure this disease. Increasing evidence has revealed the importance of cancer stem cells (CSCs) in hepatocarcinogenesis, and the idea of targeting CSCs sheds light on more effective therapeutic strategies for HCC. In this review, normal stem cells and putative CSCs in the liver are briefly introduced. Studies about signaling pathways that regulate pathophysiological activities of liver CSCs and the therapeutic potential by targeting CSCs are also summarized and discussed.

Glypican-3 (GPC3) is a developmentally-regulated oncofetal protein that has been established as a clinically-relevant biomarker for early hepatocellular carcinoma (HCC). It is one of the first transcripts to appear during malignant hepatocyte transformation, and is expressed at the protein level in approximately half of high-grade dysplastic macronodules in cirrhotic liver. Several studies show it is expressed in most (75 to 100%) of HCCs confirmed by histopathology. The protein is anchored to the hepatocyte membrane by a glycosyl-phosphatidylinositol (GPI) anchor and shows consistent membrane immunostaining pattern, making it a viable target for immunotherapeutic approaches. Targeting GPC3 for therapeutic intervention is a promising approach for the clinical management of HCC and selected other tumors that express the marker.

Hepatocellular cancer (HCC) is the fifth most common malignancy worldwide with 660,000 deaths annually. Studies of the molecular pathophysiology of HCC have shown that growth factors and their corresponding receptors are commonly overexpressed and/or dysregulated in HCC. Activation of these receptors and their downstream signaling pathways can lead to angiogenesis, cell proliferation, survival and metastasis of HCC. Hence, agents that specifically block their activation and signaling cascades would be valuable for treatment of HCC. Many small molecular tyrosine kinase inhibitors (TKIs) and antibodies have been tested in various phases of clinical trials. Although sorafenib has been shown to improve overall survival of patients with advanced HCC, the improvement is marginal and many patients eventually turn out to be refractory to this therapy. Thus, there is a pressing need to identify new drugs and effective treatments for this fatal disease. This review summarizes the pre-clinical and clinical data on the efficacy of the emerging tyrosine kinase inhibitors as well as the rationale for combination therapies for advanced HCC treatment. Understanding the mechanisms of action of these therapeutic agents and methods of combining these drugs may help to increase their efficacy, reduce toxicity, and improve overall survival and quality of life in patients with HCC.

Gallium is antiproliferative to many types of cancer, due primarily to its ability to act as a non-functional mimic of ferric iron (Fe3+). Because Fe3+ is needed for ribonucleotide reductase activity — and thus DNA synthesis — gallium can inhibit DNA production and cell division. Diagnostic gallium scans have shown that hepatocellular carcinoma (HCC) is commonly avid for gallium. Furthermore, in vitro studies have found that gallium nitrate, and particularly gallium maltolate (GaM), have dose-dependent antiproliferative activity against HCC cell lines. Rationale thus exists to use GaM, an orally active compound that has been well tolerated in Phase I clinical trials, to treat patients whose HCC is gallium-avid in a gallium scan. Because gallium absorbed from orally administered GaM is bound predominately to serum transferrin, which travels to all tissues in the body, GaM has the potential to treat even distant metastases. A patient with advanced HCC (20 x 10 cm primary tumor, ascites around liver and spleen, resistant to sorafenib (Nexavar®)), whose cancer was highly gallium-avid in a 67Ga-scan, was treated with oral gallium maltolate at 1500 mg/day q.d. After four weeks of treatment, the patient had a large reduction in pain, with greatly increased mobility and quality of life, and significantly lowered serum bilirubin and inflammation- related liver enzymes. At eight weeks, CT scans showed apparent necrosis of the tumor.