Abstract: Toll-like receptor (TLR) signaling has been implicated in inflammatory-related cancers. The upregulation of TLR signaling in hepatocellular carcinoma (HCC) suggests that it may play an essential role in the prognosis of chronic and inflammatory diseases that ultimately culminate in HCC. Here, we provide evidence about the involvement of the TLR pathway in the initiation, progression, and metastasis of HCC. The differential expression of TLR in epithelial cells has also been discussed. In particular, we emphasize the physiological role of TLR4 in the development and pathogenesis of HCC and propose novel and promising approaches for HCC therapeutics with the aid of TLR ligands.

Keywords: hepatocarcinogenesis, inflammation, signal pathway, immune therapy

Introduction

According to the World Health Organization, hepatocellular carcinoma (HCC) is a worldwide cause of cancer-related death second to lung cancer.1 It is particularly prevalent in Southeast Asia and sub-Saharan Africa due to hepatitis B virus (HBV) or hepatitis C virus (HCV) infection and toxins in the food and water supply. Chronic hepatitis and cirrhosis caused by HBV and HCV infection are the major risk factors of primary HCC.1 HCC can currently be treated only with surgery at the early and middle stages. The efficacies of chemotherapy and radiotherapy are far from satisfactory. Recurrence is quite common in patients with HCC who have had a radical resection, and the survival rate is 30%–40% at 5 years postsurgery.2 This is because those malignant cells developed intricate mechanisms that enable them to inhibit immune cells through the secretion of specific cytokines that create an immunosuppressive environment.3 Although many factors are involved in the pathogenesis and progression of HCC, its underlying mechanisms remain unknown. Recent research demonstrated that Toll-like receptor (TLR)4 expression levels were strongly associated with microvascular invasion and early recurrence.4 It has been reported in murine models that specific HBV or HCV proteins can induce HCC without other oncogenic alterations.5 The excessive compensatory proliferation of differentiated hepatocytes caused by chronic liver injury is thought to be one of the major pathogenic mechanisms underlying HCC development.6,7


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Innate immunity that is conserved through evolution represents the first line of protection against microbial pathogens. Innate immunity discriminates and eventually clears a variety of pathogens and their nonpathogenic symbiotic bacteria via pattern-recognition receptors such as TLRs. TLRs detect invading microbes and recognize intracellular anomalies to which they mount an immune response, thereby playing a cardinal role in the homeostasis of the human immune system.8,9 As an important pathogen recognition molecule, TLRs activated in the immune cells play a critical role in the host’s defense and eventually lead to adaptive immune responses.10 On the other hand, TLR stimulation can also directly or indirectly enhance the immunosuppressive function of regulatory T-cells that favors tumor development.11–13 It was previously thought that TLR was mainly expressed in immune cells. However, emerging evidence suggests that TLRs are expressed in some types of tumor cells, and that signaling of TLRs can promote tumor proliferation and survival, immune evasion, and drug sensitivity.14,15 The endogenous ligands released by cellular stress or apoptotic cells can activate TLR4 and lead to aseptic inflammation. Abnormal TLR activation can jeopardize normal physiological processes and cause several inflammatory diseases, cancers, and autoimmune diseases.16,17 Research over the past decade has focused on elucidating various TLR-associated functions, intermediate molecules, and ligands. There is a well-established link between TLR-induced inflammation and cancer development and progression.18,19 Similarly, TLRs are known to play a vital role in HCC. In this review, we will focus on reports concerning TLR4 signaling and its involvement in HCC development and progression, as well as on the therapeutic benefits that could arise from TLR4 stimulation.