Kupffer cells decrease metastasis of colon cancer cells to the liver in the early stage

Abstract

although Kupffer cells (Kcs) play an important role in the liver's immune response, their role in colon cancer metastasis to the liver is unclear. We here analyzed the relationship between Kcs and tumor cells (tcs) in colon cancer metastasis to the liver. fischer 344 (f344) rats were divided into control group (Kc+ group) and Kc elimination group (Kc-group), in which Kc elimination was induced by cl 2 MDP liposome injection. rcn-H4 colon cancer cells were injected into the rats of both groups, and the relationship between the two types of cells was observed by intravital microscopy (iVM) for 6 h. Moreover, to investigate the effect of Kcs on liver metastasis formation, Kcs were eliminated at different time points before and after the tc injection. the number of metastatic nodules 2 weeks after the injection was evaluated. in the Kc-group, iVM revealed that the number of adherent tcs had increased 1.5-fold at 6 h after the tc injection as compared with in the Kc+ group. Moreover, in the Kc+ group, 74% of the tcs adhered to the Kcs, and Kc activation and Kc phagocytosis of the tcs were observed. two weeks after the injection, the number of metastatic nodules was significantly increased in rats in which the Kcs had been eliminated before the injection, but not in rats in which the Kcs had been eliminated after the injection. Kc activation and Kc phagocytosis of tcs decreased colon cancer cell metastasis to the liver. Materials and methodsAnimals. Male fischer 344 (f344) rats, weighing 200-250 g, were obtained from clea japan, inc. (tokyo, japan). the animal experiments were carried out in a humane manner after approval was received from the animal experiment committee of the university of tsukuba.Cell lines. rcn-H4 cells (17,18), derived from liver metastasis of an f344 rat colon adenocarcinoma cell line, were provided by the riken cell Bank (ibaraki, japan). the cells were maintained in rPMi-1640 medium supplemented with 10% heat-inactivated fBS, 100 u/ml penicillin g, and 100 g/ml streptomycin in humidified 95% air-5% CO 2 at 37˚C. KC elimination. Kcs were eliminated by use of cl 2 MDP liposomes, as reported by van rooijen et al (19). The Kupffer cells decrease metastasis of colon cancer cells to the liver in the early stageHiDeKi MatSuMura, taDaSHi KonDo, KoicHi ogaWa, taKafuMi taMura, KiyoSHi fuKunaga, SoicHiro Murata and noBuHiro oHKoHcHi

Role of the Microenvironment in Liver Metastasis: From Pre- to Prometastatic Niches

“…This tumoricidal effect may require cooperation with local or recruited NK cells (48), and its efficiency in removing cancer cells likely depends on the tumor load (49). An intravital microscopy study (50) recently revealed that 74% of intra-arterially injected rat colon cancer cells adhered to the KCs within 6 hours, and this was associated with increased liver TNFa and IL1b levels, consistent with our own findings (51, 52) and indicative of KC activation. Extensive phagocytosis of tumor cells was observed within 2 hours postinjection.…”

“…Extensive phagocytosis of tumor cells was observed within 2 hours postinjection. Interestingly, although elimination of KCs 2 days prior to tumor injection increased liver metastasis, it had no significant effect up to 1 week after tumor injection, suggesting that KCs exerted their most potent antitumor effect within the first 24 hours of tumor cell entry into the liver (50). A bimodal effect of KC depletion was also documented in another study of murine colorectal cancer, and it was attributed to decreased VEGF and increased iNOS levels in livers subjected to late-stage KC depletion (53).…”

Fatty change of the liver microenvironment influences the metastatic potential of colorectal cancer

“…However, the role of Kupffer cells in metastasis is controversial. [23][24][25] Tumour-infiltrating lymphocytes (TILs) such as cytotoxic T cells are present locally in solid cancers and represent the anti-tumour response of the host. Gooden et al reported in a meta-analysis that CD8 + cell infiltration is a good prognostic factor.…”

Grapefruit-derived nanovectors deliver miR-18a for treatment of liver metastasis of colon cancer by induction of M1 macrophages

“…Liver macrophages (Kupffer cells; KCs) play a crucial role in the pathogenesis of liver tumor metastasis and are a major component of the microenvironment of primary and metastatic liver tumors. Direct and indirect activation of KCs results in the production of factors and cytokines capable of facilitating both anti-tumor [ 1 – 5 ] and pro-tumor effects [ 6 – 8 ]. More importantly, Kupffer cells are situated in the hepatic sinusoids to encounter circulating T cells, as well as natural killer (NK) and natural killer T (NKT) cells, and modulate activity of these lymphocytes.…”