Article

Deletion of cathepsin H perturbs angiogenic switching, vascularization and growth of tumors in a mouse model of pancreatic islet cell cancer.

Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Biological Chemistry (Impact Factor: 2.69). 08/2010; 391(8):937-45. DOI: 10.1515/BC.2010.080
Source: PubMed

ABSTRACT Proteases can regulate many aspects of tumor development as their actions, which include degradation of the extracellular matrix, proteolytic processing of chemokines and activation of other enzymes, influence several key tumorigenic processes. Members of one protease class, the cysteine cathepsins, have received increasing recognition for their involvement in cancer development, and numerous clinical studies have reported correlations between elevated cathepsin levels and malignant progression. This is also the case for cathepsin H, a member of the cysteine cathepsin family, and its utility as a prognostic marker has been analyzed extensively. However, there is limited information available on its specific functions in tumor development and progression. To gain further insight into the role of this protease in cancer, we crossed cathepsin H-deficient mice with the RIP1-Tag2 model of pancreatic islet carcinogenesis. Deletion of cathepsin H significantly impaired angiogenic switching of the pre-malignant hyperplastic islets and resulted in a reduction in the subsequent number of tumors that formed. Moreover, the tumor burden in cathepsin H null RT2 mice was significantly reduced, in association with defects in the blood vasculature and increased apoptosis. Thus, we demonstrate here for the first time important tumor-promoting roles for cathepsin H in vivo using a mouse model of human cancer.

Full-text

Available from: Vasilena Gocheva, May 25, 2015
0 Followers
 · 
84 Views
  • Journal of Neuroinflammation 12/2015; 12(1). DOI:10.1186/s12974-015-0268-x · 4.90 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The intracellular bacterial pathogen Legionella pneumophila provokes strong host responses and has proven to be a valuable model for the discovery of novel immunosurveillance pathways. Our previous work revealed that an environmental isolate of L. pneumophila induces a noncanonical form of cell death, leading to restriction of bacterial replication in primary mouse macrophages. Here we show that such restriction also occurs in infections with wild type clinical isolates. Importantly, we found that a lysine to arginine mutation at residue 88 (K88R) in the ribosome protein RpsL that not only confers bacterial resistance to streptomycin, but more importantly, severely attenuated the induction of host cell death and enabled L. pneumophila to replicate in primary mouse macrophages. Although conferring similar resistance to streptomycin, a K43N mutation in RpsL does not allow productive intracellular bacterial replication. Further analysis indicated that RpsL is capable of effectively inducing macrophage death via a pathway involved in lysosomal membrane permeabilization; the K88R mutant elicits similar responses but is less potent. Moreover, cathepsin B, a lysosomal protease that causes cell death after being released into the cytosol upon the loss of membrane integrity, is required for efficient RpsL-induced macrophage death. Furthermore, despite the critical role of cathepsin B in delaying RpsL-induced cell death, macrophages lacking cathepsin B do not support productive intracellular replication of L. pneumophila harboring wild type RpsL. This suggests the involvement of other yet unidentified components in the restriction of bacterial replication. Our results identified RpsL as a regulator in the interactions between bacteria such as L. pneumophila and primary mouse macrophages by triggering unique cellular pathways that restrict intracellular bacterial replication.
    PLoS Pathogens 03/2015; 11(3):e1004704. DOI:10.1371/journal.ppat.1004704 · 8.06 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: During the process of tumor progression, cancer cells can produce the requisite growth- and invasion-promoting factors and can also rely on noncancerous cells in the tumor microenvironment as an alternative, cell-extrinsic source. However, whether the cellular source influences the function of such tumor-promoting factors remains an open question. Here, we examined the roles of the cathepsin Z (CtsZ) protease, which is provided by both cancer cells and macrophages in pancreatic neuroendocrine tumors in humans and mice. We found that tumor proliferation was exclusively regulated by cancer cell-intrinsic functions of CtsZ, whereas tumor invasion required contributions from both macrophages and cancer cells. Interestingly, several of the tumor-promoting functions of CtsZ were not dependent on its described catalytic activity but instead were mediated via the Arg-Gly-Asp (RGD) motif in the enzyme prodomain, which regulated interactions with integrins and the extracellular matrix. Together, these results underscore the complexity of interactions within the tumor microenvironment and indicate that cellular source can indeed impact molecular function.
    Genes & Development 10/2014; 28(19):2134-50. DOI:10.1101/gad.249599.114 · 12.64 Impact Factor