Drug Delivery and Translational Research

, Volume 3, Issue 2, pp 152–164

Tumor-initiating stem-like cells and drug resistance: carcinogenesis through Toll-like receptors, environmental factors, and virus

Review Article

DOI: 10.1007/s13346-012-0115-x

Cite this article as:
Machida, K. Drug Deliv. and Transl. Res. (2013) 3: 152. doi:10.1007/s13346-012-0115-x


Neoplasms contain distinct subpopulations of cells known as tumor-initiating stem-like cells (TICs) that have been identified as key drivers of tumor growth and malignant progression with drug resistance. Stem cells normally proliferate through self-renewing divisions in which the two daughter cells differ markedly in their proliferative potential, with one displaying the differentiation phenotypes and another retaining self-renewing activity. Therefore, understanding the molecular mechanisms of hepatocarcinogenesis will be required for the eventual development of improved therapeutic modalities for treating hepatocellular carcinoma (HCC). Hepatitis C virus (HCV) and hepatitis B virus is a major cause of HCC. Compelling epidemiologic evidence identifies obesity and alcohol as co-morbidity factors that can increase the risk of HCV patients for HCC, especially in alcoholics or obese patients. The mechanisms underlying liver oncogenesis, and how environmental factors contribute to this process, are not yet understood. The HCV–Toll-like receptor 4 (TLR4)–Nanog signaling network is established since alcohol/obesity-associated endotoxemia then activates TLR4 signaling, resulting in the induction of the stem cell marker Nanog expression and liver tumors. Liver TICs are highly sensitized to leptin and exposure of TICs to leptin increases the expression and activity of an intrinsic pluripotency-associated transcriptional network comprised of signal transducer and activator of transcription 3, SOX2, OCT4, and Nanog. Stimulation of the pluripotency network may have significant implications for hepatocellular oncogenesis via genesis and maintenance of TICs. It is important to understand how HCV induces liver cancer through genesis of TICs so that better prevention and treatment can be found. This article reviews the oncogenic pathways to generate TICs.


Cancer stem cell Tumor-initiating stem-like cells Drug resistance TLR HCV Alcohol Obesity 



Tumor-initiating stem-like cells


Toll-like receptor


Hepatitis C virus


Hepatitis B virus

Copyright information

© Controlled Release Society 2012

Authors and Affiliations

  1. 1.Department of Molecular Microbiology and ImmunologyResearch Center for ALPD and Cirrhosis, University of Southern California School of MedicineLos AngelesUSA

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