Inflammation-Induced Hepatocellular Carcinoma Is Dependent on Ccr5 in Mice

Abstract

Human hepatocellular carcinoma (HCC) is an inflammation-induced cancer, which is the third-leading cause of cancer mortality worldwide. We investigated the role of the chemokine receptors, CCR5 and CCR1, in regulating inflammation and tumorigenesis in an inflammation-induced HCC model in mice. Multidrug resistance 2 gene (Mdr2)-knockout (Mdr2-KO) mice spontaneously develop chronic cholestatic hepatitis and fibrosis that is eventually followed by HCC. We generated two new strains from the Mdr2-KO mouse, the Mdr2:CCR5 and the Mdr2:CCR1 double knockouts (DKOs), and set out to compare inflammation and tumorigenesis among these strains. We found that in Mdr2-KO mice lacking the chemokine receptor, CCR5 (Mdr2:CCR5 DKO mice), but not CCR1 (Mdr2:CCR1 DKO), macrophage recruitment and trafficking to the liver was significantly reduced. Furthermore, in the absence of CCR5, reduced inflammation was also associated with reduced periductal accumulation of CD24 1 oval cells and abrogation of fibrosis. DKO mice for Mdr2 and CCR5 exhibited a significant decrease in tumor incidence and size. Conclusions: Our results indicate that CCR5 has a critical role in both the development and progression of liver cancer. Therefore, we propose that a CCR5 antagonist can serve for HCC cancer prevention and treatment. (HEPATOLOGY 2013;58:1021-1030

Prognostic Significance of the Neutrophil-to-Lymphocyte Ratio in Primary Liver Cancer: A Meta-Analysis

“…Accumulated evidence indicates that the progression of PLC is correlated closely with both inflammation[10] and immunocytes [11]. Recent studies suggest a potential prognostic role of the NLR in the treatment strategies of PLC, including hepatic resection,[12], [13], [14] liver transplantation,[15], [16], [17] radiofrequency ablation (RFA),[18], [19] and trans-arterial chemo-embolization (TACE)[20], [21].…”

Somatic Mutation Theory - Why it's Wrong for Most Cancers

“…On the one hand this process seems dependent on a protein which is on the surface of white blood cells, the C-C chemokine receptor type 5 (CCR5 or CD195) [132], while on the other hand, it is dependent on TGF-β induced Smad phospho-isoform signaling [131]. Neutrophil granulocytes significantly influence the concentration gradient of chemokines such as the cytokine chemokine (C-X-C motif) ligand 1 (CXCL1).…”

Role of chemokine pathways in hepatobiliary cancer

“…Using multidrug resistance 2 gene (Mdr2)-knockout (Mdr2-KO) mice developing HCCs in inflamed livers, the authors demonstrated that CCR5 seems to be more prominently involved in several pathways of tumor development, including both the inflammatory responses that induce oncogenic stress and the recruitment of macrophages that facilitates progression and maintenance of HCCs, than CCR1 [22]. However, with respect to CCR1, several reports were recently published demonstrating that a CCR1-mediated accumulation of positive myeloid cells in the liver microenvironment promotes liver metastasis development in mice, indicating that the therapeutic targeting of CCR1 could significantly contribute to the establishment of novel therapy options for patients suffering from liver metastasis [23,24,74,75].…”

“…Based on the fact that CCR1 and CCR5 both play a significant role in establishing a pro-inflammatory and pro-fibrotic milieu in injured livers, Barashi et al investigated the role of both chemokine receptors in regulating tumorigenesis in an inflammation-induced HCC model in mice [22]. Using multidrug resistance 2 gene (Mdr2)-knockout (Mdr2-KO) mice developing HCCs in inflamed livers, the authors demonstrated that CCR5 seems to be more prominently involved in several pathways of tumor development, including both the inflammatory responses that induce oncogenic stress and the recruitment of macrophages that facilitates progression and maintenance of HCCs, than CCR1 [22].…”