Bimodal role of Kupffer cells during colorectal cancer liver metastasis

被引:61
作者
Wen, Shu Wen [1 ,2 ]
Ager, Eleanor I. [1 ,3 ,4 ]
Christophi, Christopher [1 ]
机构
[1] Univ Melbourne, Dept Surg, Austin Hlth, Heidelberg, Vic, Australia
[2] Queensland Inst Med Res, Tumor Microenvironm Lab, Herston, Qld 4006, Australia
[3] Massachusetts Gen Hosp, Edwin L Steele Lab Tumor Biol, Boston, MA 02114 USA
[4] Harvard Univ, Sch Med, Boston, MA USA
基金
澳大利亚国家健康与医学研究理事会;
关键词
macrophage; tumor-associated macrophages; Kupffer cell; liver metastases; colorectal cancer; TUMOR-ASSOCIATED MACROPHAGES; HUMAN PROSTATE-CANCER; NITRIC-OXIDE; HEPATIC METASTASIS; RAT-LIVER; FUNCTIONAL-HETEROGENEITY; GADOLINIUM CHLORIDE; PROGNOSTIC VALUE; T-CELLS; PROGRESSION;
D O I
10.4161/cbt.24593
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Kupffer cells (KCs) are resident liver macrophages that play a crucial role in liver homeostasis and in the pathogenesis of liver disease. Evidence suggests KCs have both stimulatory and inhibitory functions during tumor development but the extent of these functions remains to be defined. Using KC depletion studies in an orthotopic murine model of colorectal cancer (CRC) liver metastases we demonstrated the bimodal role of KCs in determining tumor growth. KC depletion with gadolinium chloride before tumor induction was associated with an increased tumor burden during the exponential growth phase. In contrast, KC depletion at the late stage of tumor growth (day 18) decreased liver tumor load compared with non-depleted animals. This suggests KCs exhibit an early inhibitory and a later stimulatory effect. These two opposing functions were associated with changes in iNOS and VEGF expression as well as T-cell infiltration. KC depletion at day 18 increased numbers of CD3(+) T cells and iNOS-expressing infiltrating cells in the tumor, but decreased the number of VEGF-expressing infiltrating cells. These alterations may be responsible for the observed reduction in tumor burden following depletion of pro-tumor KCs at the late stage of metastatic growth. Taken together, our results indicate that the bimodal role of KC activity in liver tumors may provide the key to timing immunomodulatory intervention for the treatment of CRC liver metastases.
引用
收藏
页码:606 / 613
页数:8
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