Abstract
Cathepsins S (CatS) has been implicated in numerous tumourigenic processes and here we document for the first time its involvement in CCL2 regulation within the tumour microenvironment. Analysis of syngeneic tumours highlighted reduced infiltrating macrophages in CatS depleted tumours. Interrogation of tumours and serum revealed genetic ablation of CatS leads to the depletion of several pro-inflammatory chemokines, most notably, CCL2. This observation was validated in vitro, where shRNA depletion of CatS resulted in reduced CCL2 expression. This regulation is transcriptionally mediated, as evident from RT-PCR analysis and CCL2 promoter studies. We revealed that CatS regulation of CCL2 is modulated through CD74 (also known as the invariant chain), a known substrate of CatS and a mediator of NFkB activity. Furthermore, CatS and CCL2 show a strong clinical correlation in brain, breast and colon tumours. In summary, these results highlight a novel mechanism by which CatS controls CCL2, which may present a useful pharmacodynamic marker for CatS inhibition.
Highlights
Unraveling the complexity of interactions within the microenvironment has become a major focus of biomedical research within recent years
MC38 colon carcinoma cells expressing non-targeting control (NT) and Cathepsins S (CatS) shRNA constructs (Supplementary Fig. 1) were grown in wild type C57BL/6 mice and macrophage infiltration was examined by flow cytometry
Whilst tumour cells lacking CatS grew more slowly than control cells expressing the protease, in agreement with our previous findings (Fig. 1a), a difference in infiltrating macrophages was difficult to interrogate by flow cytometry due to the small but highly encapsulated nature of these tumours
Summary
Unraveling the complexity of interactions within the microenvironment has become a major focus of biomedical research within recent years. CatS is a lysosomal cysteine protease, the expression of which has been associated with a number of inflammatory diseases including rheumatoid arthritis, atherosclerosis and cancer. CatS expression has been shown to be elevated within tissues from these conditions, with genetic ablation or therapeutic targeting strategies diminishing disease severity and/or progression [1,2,3,4]. We have previously shown that CatS expression is associated with a number of malignancies including astrocytomas and colorectal carcinomas, and that depletion of CatS can result in the attenuation of tumourigenesis [5,6,7,8]. We have identified that CatS is a key mediator of tumour invasion and angiogenesis in tumourigenesis [6, 9, 10]
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