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Review

Notch signaling in hepatocellular carcinoma: molecular targeting
Notch signaling in hepatocellular carcinoma: molecular targeting
in an advanced disease
in an advanced disease

Kevin M. Sokolowski, Mariappan Balamurugan, Selvi Kunnimalaiyaan, T. Clark Gamblin,
Muthusamy Kunnimalaiyaan
Department of Surgery, Division of Surgical Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA

ABSTRACT
The use of alternative therapeutic approaches in advanced carcinogenesis is a growing investigative base. One such cancer,
primary liver cancer, is one of the most commonly occurring cancers worldwide and often presents in late stage disease
consequently preventing traditional curative modalities. As a result, hepatocellular carcinoma (HCC), representing the majority
of primary liver cancer, is the third most common cause of cancer-related deaths globally. Survival rates are linked to stage
of presentation as well as concomitant cirrhosis limiting the 5-year survival in these patients to < 20%. Alternative strategies
are in dire need as patients in this cohort have limited palliative options. Currently, sorafenib is the only approved systemic
therapy; however, it has a limited survival advantage and low effi cacy prompting the empirical need for further evaluation.
Understanding of cancer therapy has led to an enhanced focus on the Notch pathway as a potential target for advanced
HCC. Notch signaling is a critical component of development and cell fate and has been linked to various modalities including
liver regeneration and as a key driver in carcinogenesis. In this review, we will provide a review of the current status of the
Notch signaling in liver cancer and of Notch as an alternative potential strategy for advanced HCC.

Key words: Hepatocellular carcinoma; liver regeneration; Notch inhibitors; Notch signaling; sorafenib

Address for correspondence:
Dr. Muthusamy Kunnimalaiyaan, Department of Surgery, Translational and Biomedical Research Center, Medical College of Wisconsin,
Milwaukee, WI 53226, USA. E-mail: mkunnima@mcw.edu
Received: 28-01-2015, Accepted: 05-03-2015

INTRODUCTION Approximately one-third of patients are amendable to
curative therapy through the use of localized radiofrequency
Hepatocellular carcinoma (HCC) is a significant health concern ablation or resection. [6,7] Moderate stage disease indicative of
representing the sixth most common cancer globally. Over multifocal intrahepatic carcinogenesis has led to alternative
[1]
the past 20 years, HCC has become one of the most frequent approaches such as trans-arterial chemoembolization (TACE).
occurring tumors worldwide with the incidence in the United TACE has provided a relatively efficacious avenue for patients
States steadily increasing. [2-5] In addition, coupled with an in this category. [7-10] Patients progressing to or presenting
increase in the incidence, HCC mortality has also increased as late stage disease have limited treatment options.
substantially. Currently, it is the third most common cause Approximately, 70% of patients will initially or eventually
of cancer-related deaths throughout the world. present at this late stage. Consequently, this leads to a 5-year
survival in patients with HCC of < 20%. In addition, HCC is
[11]
characteristically coupled with concomitant cirrhosis, further
Access this article online
[12]
Quick Response Code exacerbating disease morbidity and mortality. Therefore,
Website: there is an urgent and critical need to expand alternative
http://www.hrjournal.net/ and effective approaches to these patients in advanced,
nonresectable disease. This need for additional therapy and
DOI: the evolving understanding of molecular pathways has led
10.4103/2394-5079.154132 to a concentrated focus on therapeutic molecular targeting
in many organ-specific cancers as well as HCC.

Hepatoma Research | Volume 1 | Issue 1 | April 15, 2015 11