Abstract
Hepatocellular carcinoma (HCC) is a health problem worldwide due to its high mortality rate, and the tumor microenvironment (TME) plays a key role in the HCC progression. The current ineffective therapies to fight the disease still warrant the development of preventive strategies. Quercetin has been shown to have different antitumor activities; however, its effect on TME components in preneoplastic lesions has not been fully investigated yet. Here, we aimed to evaluate the effect of quercetin (10 mg/kg) on TME components during the early stages of HCC progression induced in the rat. Histopathological and immunohistochemical analyses showed that quercetin decreases the size of preneoplastic lesions, glycogen and collagen accumulation, the expression of cancer stem cells and myofibroblasts markers, and that of the transporter ATP binding cassette subfamily C member 3 (ABCC3), a marker of HCC progression and multi-drug resistance. Our results strongly suggest that quercetin has the capability to reduce key components of TME, as well as the expression of ABCC3. Thus, quercetin can be an alternative treatment for inhibiting the growth of early HCC tumors.
Highlights
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and is ranked as the third leading cause of cancer death worldwide [1]
We evaluate the effect of quercetin on some tumor microenvironment (TME) components in the early hepatocarcinogenesis stages in an HCC rat model
Through histopathological and immunohistochemical analyses, we demonstrate that the administration of quercetin decreases preneoplastic lesions, fibrogenesis, glycogen accumulation, the expression of cancer stem cells (CSCs) and myofibroblasts markers, the development of drug resistance denoted by decreased ATP binding cassette subfamily C member 3 (ABCC3) expression, and, as a result, the HCC progression
Summary
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and is ranked as the third leading cause of cancer death worldwide [1]. Its development is promoted by different risk factors, such as aflatoxin exposure, excessive alcohol consumption, chronic infection by hepatitis B and C virus, metabolic syndrome, diabetes, obesity, and nonalcoholic fatty liver disease. Either alone or in combination, these factors cause chronic liver damages that induce genetic and epigenetic alterations and as a result, several components of the microenvironment are modified [2]. Hepatocarcinogenesis is a complex process involving at least three well-categorized stages, initiation, promotion, and progression [3]. The early HCC stages are characterized by the development of preneoplastic lesions promoted by chronic liver damage, which. Antioxidants 2022, 11, 358 eventually progress to established tumors [4,5]. It has been described that the tumor microenvironment (TME) plays a key role during hepatocarcinogenesis. The TME encompasses both cellular and noncellular components. The noncellular component is made up by cytokines, growth factors, and extracellular matrix (ECM) proteins, such as collagen and fibronectin
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