Liver Cancer and Its Tumor Microenvironment: the Role of Mesenchymal Stromal Cells and SMADs

Abstract

Liver cancer is one of most devastating malignancies. Hepatocellular carcinoma (HCC) accounts for >90% of primary liver malignancies and is the third leading cause of cancer-related deaths worldwide. Major risk factors for hepatocellular carcinoma include infection with hepatitis B (HBV) or C (HCV) virus, alcoholic liver disease, and probably nonalcoholic fatty liver disease1. Especially chronic infection with HBV or HCV is a main risk factor for HCC, the recurrent viral infection characteristic for these diseases causes the body’s immune system to attack liver cells is associated by repetitive damage of the genomic material, which leads to mistakes during its repair and in turn provoke carcinogenesis2. For patients with early-stage hepatocellular carcinoma, they may undergo resection for curative treatment and for patients who are not candidates for resection, liver transplantation should be offered with specific criteria3. In the case of unresectable limited disease, systemic treatment may be preceded and aided by locoregional therapies such as ablation (ie, radiofrequency, cryoablation, percutaneous alcohol injection, or microwave), transarterial chemoembolization, radioembolization, or stereotactic body radiotherapy and external-body radiotherapy. Systemic treatments are recommended for unresectable and advanced metastatic disease in patients with a Child-Pugh score of A or B (moderate operative risk). For the majority of advanced HCC cases, curative treatments are not possible and the prognosis is dismal because of underlying cirrhosis as well as poor tumor response to standard chemotherapy4. For patients with advanced disease, representing the majority of patients at diagnosis, the only tumor-directed palliative option is sorafenib (Nexavar), an oral multi-kinase inhibitor, which increases patient survival with approximately 3 months5. Evidently, new therapeutic options are urgently needed for advanced or metastatic HCC. In this thesis I aim to explore the possibility of targeting of the intra-tumoral stromal compartment as well as modulation of the cross-talk between the stromal compartment and the tumor cell through SMAD proteins as novel avenues for the potential treatment in this disease.