Cathepsin S from both tumor and tumor-associated cells promote cancer growth and neovascularization

Abstract

Recent murine studies have demonstrated that tumor-associated macrophages in the tumor microenvironment are a key source of the pro-tumorigenic cysteine protease, cathepsin S. We now show in a syngeneic colorectal carcinoma murine model that both tumor and tumor-associated cells contribute cathepsin S to promote neovascularization and tumor growth. Cathepsin S depleted and control colorectal MC38 tumor cell lines were propagated in both wild type C57Bl/6 and cathepsin S null mice to provide stratified depletion of the protease from either the tumor, tumor-associated host cells, or both. Parallel analysis of these conditions showed that deletion of cathepsin S inhibited tumor growth and development, and revealed a clear contribution of both tumor and tumor-associated cell derived cathepsin S. The most significant impact on tumor development was obtained when the protease was depleted from both sources. Further characterization revealed that the loss of cathepsin S led to impaired tumor vascularization, which was complemented by a reduction in proliferation and increased apoptosis, consistent with reduced tumor growth. Analysis of cell types showed that in addition to the tumor cells, tumor-associated macrophages and endothelial cells can produce cathepsin S within the microenvironment. Taken together, these findings clearly highlight a manner by which tumor-associated cells can positively contribute to developing tumors and highlight cathepsin S as a therapeutic target in cancer. What's new? Cathepsin S is a protease that is upregulated in many types of malignant tumors. In this study, the authors examined whether cathepsin S is produced mainly by tumor cells, or by tumor-associated cells. They found that both types of cells can contribute the enzyme. These results reveal a mechanism by which tumor cells cooperate with recruited cells to enhance tumor development. They also validate cathepsin S as a potential target to develop anti-angiogenic and anti-proliferative drugs. Copyright © 2013 UICC.