Notch Signaling Is Activated in Human Hepatocellular Carcinoma and Induces Tumor Formation in Mice

Targeting Notch signaling pathway to overcome drug resistance for cancer therapy.

Signaling pathways have become a major source of targets for novel therapies in hepatocellular carcinoma (HCC). Survival benefits achieved with sorafenib, a multikinase inhibitor, are unprecedented and underscore the importance of improving our understanding of how signaling networks interact in transformed cells. Numerous signaling modules are de-regulated in HCC, including some related to growth factor signaling (e.g., IGF, EGF, PDGF, FGF, HGF), cell differentiation (WNT, Hedgehog, Notch), and angiogenesis (VEGF). Intracellular mediators such as RAS and AKT/MTOR may also play a role in HCC development and progression. Different molecular mechanisms have been shown to induce aberrant pathway activation. These include point mutations, chromosomal aberrations, and epigenetically driven down-regulation. The use of novel molecular technologies such as next-generation sequencing in HCC research has enabled the identification of novel pathways previously underexplored in the HCC field, such as chromatin remodeling and autophagy. Considering recent failures of molecular therapies in advanced clinical trials (e.g., sunitinib, brivanib), survey of these and other new pathways may provide alternative therapeutic targets.

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Emerging Signaling Pathways in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality, accounting for almost 90% of total liver cancer burden. Surgical resection followed by adjuvant and systemic chemotherapy are the most meticulously followed treatment procedures but the complex etiology and high metastatic potential of the disease renders surgical treatment futile in majority of the cases. Another hindrance to the scenario is the acquired resistance to drugs resulting in relapse of the disease. Hence, to provide insights into development of novel therapeutic targets and diagnostic biomarkers, this review focuses on the various molecular mechanisms underlying chemoresistance in HCC. We have provided a comprehensive summary of the various strategies adopted by HCC cells, extending from apoptosis evasion, autophagy activation, drug expulsion to epigenetic transformation as modes of therapy resistance. The role of stem cells in imparting chemoresistance is also discussed. Furthermore, the review also focuses on how this knowledge might be exploited for the development of an effective, prospective therapy against HCC.

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Resistance a major hindrance to chemotherapy in hepatocellular carcinoma: an insight

Silymarin modulates doxorubicin-induced oxidative stress, Bcl-xL and p53 expression while preventing apoptotic and necrotic cell death in the liver.

https://www.journal-of-hepatology.eu/article/S0168-8278(09)00064-6/pdf

F. Lago

Papers

Selective ablation of Notch3 in HCC enhances doxorubicin's death promoting effect by a p53 dependent mechanism.