Clinical and epidemiologic studies have suggested an association between chronic inflammation and cancer. Today it is estimated that many malignancies are initiated by inflammation and account for 25% of malignancies worldwide. However, the molecular and cellular mechanisms linking chronic inflammation to tumorigenesis remain largely unresolved. We proposed that chemokine and chemokine receptors play an essential role in the chronic inflammation stage and can induce tumor formation. To test this hypothesis, we studied the Mdr2 knockout mouse strain, which spontaneously develops chronic liver inflammation and fibrosis followed by HCC, a model for inflammation induced cancer. We generated two new strains from the Mdr2-KO mouse the Mdr2:CCR5 and the Mdr2:CCR1 double knockouts (DKO) and set out to compare inflammation and tumorigenesis among these strains.
We found that in mice lacking CCR5 but not CCR1 receptor, inflammation was significantly reduced with a significant reduction of macrophages recruitment to the liver parenchyma. The diminished macrophage accumulation in the liver of Mdr2:CCR5 double KO mice was associated with reduced periductal proliferation and abrogation of fibrosis. Furthermore, the pre-neoplastic lesions that are represented by dysplastic changes in the liver of Mdr2 KO mice are absent in the Mdr2:CCR5 double KO mice. Indeed Mdr2:CCR5 double KO mice 60% decrease in tumor incidence. Interestingly, although knocking out CCR1 did not attenuate liver inflammation and tumor initiation, reduction in tumor growth was found both in Mdr2:CCR1 and Mdr2:CCR5 DKO mice. Moreover we found that inflammation in Mdr2 KO mice induces oval cell proliferation that is absent in the Mdr2:CCR5 DKO strain, suggesting an involvement of progenitor cell proliferation in tumorigenesis in this model. Our results indicate that CCR5 has a critical and unique role in the development of liver cancer that is induced by chronic liver inflammation, and can serve as a potential target for cancer prevention and treatment.
