Abstract
By breeding TRAMP mice with S100A9 knock-out (S100A9−/−) animals and scoring the appearance of palpable tumors we observed a delayed tumor growth in animals devoid of S100A9 expression. CD11b+ S100A9 expressing cells were not observed in normal prostate tissue from control C57BL/6 mice but were readily detected in TRAMP prostate tumors. Also, S100A9 expression was observed in association with CD68+ macrophages in biopsies from human prostate tumors. Delayed growth of TRAMP tumors was also observed in mice lacking the S100A9 ligand TLR4. In the EL-4 lymphoma model tumor growth inhibition was observed in S100A9−/− and TLR4−/−, but not in RAGE−/− animals lacking an alternative S100A9 receptor. When expression of immune-regulating genes was analyzed using RT-PCR the only common change observed in mice lacking S100A9 and TLR4 was a down-regulation of TGFβ expression in splenic CD11b+ cells. Lastly, treatment of mice with a small molecule (ABR-215050) that inhibits S100A9 binding to TLR4 inhibited EL4 tumor growth. Thus, S100A9 and TLR4 appear to be involved in promoting tumor growth in two different tumor models and pharmacological inhibition of S100A9-TLR4 interactions is a novel and promising target for anti-tumor therapies.
Highlights
The TRAMP prostate cancer model is an established spontaneous model of prostate cancer in immune competent mice
We have shown here that the absence of S100A9 or Toll like receptor 4 (TLR4) expression delays tumor incidence in a spontaneous prostate cancer model
After the initiation of the current investigation, Cheng et al [36] published an elegant study where they showed that S100A92/2 animals were protected from growth of transplantable tumors (EL4 lymphoma)
Summary
The TRAMP prostate cancer model is an established spontaneous model of prostate cancer in immune competent mice. The TRAMP model has been used to study metastasis and changes in the immune function of animals at different stages of tumor development [3,4]. MDSCs are a heterogeneous population of cells (reviewed in [5,6],[7]) characterized by the expression of CD11b and Gr-1 in the mouse [8] [9]. These cells are strongly immuno-suppressive and can be found in virtually all models of solid tumors and functionally similar cells may accumulate during autoimmune conditions and chronic inflammation Functionally similar granulocytic and monocytic sub-populations could be defined
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