Probiotics: An Approach for the Treatment of Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the second leading cause of all-cancer related deaths in the world. It is a disease with poor prognosis with unsatisfactory long-term survival of patients, and thus new strategies to control this disease are warranted. Probiotics have been reported to relieve chronic inflammatory diseases in animal and in human intervention studies. It is believed that probiotics regulate signals to gut antigen-presenting cells, which act as the pivot in modulating the systemic immune responses and inactivated bacteria also exhibited immunomodulatory effects in this regard. T helper (Th) 17 cells and IL-17 have recently been detected with increased frequency in a number of tumors including HCC. Its role in tumor remains controversial but its presence in HCC has been linked to disease progression, possibly involving angiogenesis. Accordingly, it was hypothesized that oral feeding of probiotics to HCC-bearing animals may affect Th17 polarization and distribution and thereby modulate tumor microenvironment, which may have beneficial effect in tumor development, possibly via affecting angiogenesis. To address this hypothesis, wild-type C57BL/6 mice were fed with different heat-inactivated or viable probiotics– Lactobacillus rhamnosus GG (LGG), Escherichia coli Nissle 1917 (EcN), VSL#3 or mixture of probiotics − Prohep (heat-inactivated LGG, heat-inactivated VSL#3 and viable EcN) either one week in advance or at the time of subcutaneous tumor inoculation. Probiotics feeding had improved survival in tumor-bearing mice, slowed down tumor growth and reduced tumor burden when monitored for 38 days. Probiotics had shown better efficacy when feeding was given in advance. The anti-tumor effect was related to reduced angiogenesis and reduced IL-17 serum and gene expression within tumor. Mechanistic link between IL-17 modulation and tumor development was further studied in animals by IL-17 neutralization, and have found lost of anti-tumor efficacy in probiotics in relation to tumor growth and angiogenesis, which was linked to recruitment of myeloid suppressor cells. Since cells from both adaptive and innate immune systems could secrete IL-17, we next sort to identify source of IL-17 production and found that Th17 was the major IL-17 secretor being modulated by probiotic feeding. Reduced homing of Th17 to tumor via circulation, with a tendency being recruited from gut was observed. Probiotics mediated Th17 cell modulation in gut by inducing the skewing of IL-10 secreting type1 regulatory T cells via dendritic cells may link to limited IL-17 mediated angiogenesis in tumor microenvironment. With better understanding on the immunomodulation of probiotics prophylactic or therapeutic efficacy in management of other inflammation-associated cancer can be availed.