Abstract
Hepatocellular carcinoma (HCC), the most common type of liver cancer, is the second leading cause of cancer-related mortality worldwide. Processes involved in HCC progression and development, including cell transformation, proliferation, metastasis, and angiogenesis, are inflammation-associated carcinogenic processes because most cases of HCC develop from chronic liver damage and inflammation. Inflammation has been demonstrated to be a crucial factor inducing tumor development in various cancers, including HCC. Cytokines play critical roles in inflammation to accelerate tumor invasion and metastasis by mediating the migration of immune cells into damaged tissues in response to proinflammatory stimuli. Currently, surgical resection followed by chemotherapy is the most common curative therapeutic regimen for HCC. However, after chemotherapy, drug resistance is clearly observed, and cytokine secretion is dysregulated. Various chemotherapeutic agents, including cisplatin, etoposide, and 5-fluorouracil, demonstrate even lower efficacy in HCC than in other cancers. Tumor resistance to chemotherapeutic drugs is the key limitation of curative treatment and is responsible for treatment failure and recurrence, thus limiting the ability to treat patients with advanced HCC. Therefore, the capability to counteract drug resistance would be a major clinical advancement. In this review, we provide an overview of links between chemotherapeutic agents and inflammatory cytokine secretion in HCC. These links might provide insight into overcoming inflammatory reactions and cytokine secretion, ultimately counteracting chemotherapeutic resistance.
Highlights
Introduction published maps and institutional affilHepatocellular carcinoma (HCC), the most common type of primary liver cancer, is the most aggressive malignancy, with a median survival time of 7 to 9 months worldwide [1].The mortality and incidence of HCC have even increased in the last decade [2,3]
The inflammatory microenvironment of liver tumors possesses a crucial role in facilitating HCC by inducing liver fibrosis, epithelial–mesenchymal transition, tumor invasion and metastasis [117]
Several types of cytokines and chemokines modulate the interaction between infiltrated immune cells and liver cancer cells, which in turn leads to remodeling of the liver microenvironment into profibrotic, proinflammatory, and proangiogenic signalings and becomes a tumor microenvironment [118]
Summary
Cisplatin is an effective and broad-spectrum chemotherapeutic drug for treating HCC. several side effects of cisplatin are displayed. Cisplatin has been displayed to increase DNA crosslink formation to induce inflammation by the ATM-NF-kB signaling pathway through the TonEBP-ERCC1/XPF complex (Table 1). Cisplatin induces the interaction between chromatin and the ERCC1/XPF dimer in a TonEBP-dependent manner, resulting in DNA repair and cisplatin resistance [33]. YC-1 has been determined to play a novel anticancer role to enhance the HCC cell chemosensitivity to cisplatin in a STAT3-dependent manner (Table 1) [34]. STAT3 has been determined to be associated with drug resistance [35]; tumor growth was reduced and cisplatin-induced chemo-cytotoxicity was enhanced after silencing of STAT3 expression. Cisplatin modulates various pathways, such as the ATR, p53, p73, and MAPK signaling, to elicit a sequential responses in the cell, including DNA repair, drug resistance, and apoptosis (Table 1) [40]
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