Synergistic antitumor effects of combined cathepsin B and cathepsin Z deficiencies on breast cancer progression and metastasis in mice

Abstract

The lysosomal cysteine proteases cathepsin B (Ctsb) and cathepsin Z (Ctsz, also called cathepsin X/P) have been implicated in cancer pathogenesis. Compensation of Ctsb by Ctsz in Ctsb −/− mice has been suggested. To further define the functional interplay of these proteases in the context of cancer, we generated Ctsz null mice, crossed them with Ctsb-deficient mice harboring a transgene for the mammary duct–specific expression of polyoma middle T oncogene (PymT), and analyzed the effects of single and combined Ctsb and Ctsz deficiencies on breast cancer progression. Single Ctsb deficiency resulted in delayed detection of first tumors and reduced tumor burden, whereas Ctsz-deficient mice had only a prolonged tumor-free period. However, only a trend toward reduced metastatic burden without statistical significance was detected in both single mutants. Strikingly, combined loss of Ctsb and Ctsz led to additive effects, resulting in significant and prominent delay of early and advanced tumor development, improved histopathologic tumor grading, as well as a 70% reduction in the number of lung metastases and an 80% reduction in the size of these metastases. We conclude that the double deficiency of Ctsb and Ctsz exerts significant synergistic anticancer effects, whereas the single deficiencies demonstrate at least partial reciprocal compensation.

Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer

“…JPM treatment did not significantly affect tumor growth (Fig. 4B), despite the abundant cathepsin activity we observed in tumors, the reduction in PyMT tumorigenesis observed when cathepsins B and Z are deleted (Sevenich et al 2010), and the efficacy of this compound in other tumor models (Joyce et al 2004). We confirmed that JPM inhibits cathepsin activity in the PyMT tumors using the cathepsin ABP DCG04 (P = 0.0016) (Supplemental Fig.…”

Alternative activation of tumor-associated macrophages by IL-4

“…81 Our group and others have identified critical roles for cathepsins in tumor growth, angiogenesis, invasion and metastasis using both genetic and pharmacological strategies in mouse models of cancer. [82][83][84][85][86][87] For example, during sequential stages of tumor development in the RIP1-Tag2 (RT2) model of pancreatic islet carcinogenesis, 88 we found that expression of a subset of cathepsins (B, C, H, L, S, X/Z) progressively increased. 82 Moreover, most of these cathepsins, except cathepsin L, were provided predominantly by infiltrating TAMs in different tumor microenvironments.…”

Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix

“…The generation and characterization of RT2 and CtsZ À/À mice (mutant Ctsz allele, referred to here as CtsZ) have been previously reported (Hanahan 1985;Sevenich et al 2010). CtsZ heterozygous mice were backcrossed into the C57BL/6 background for nine generations before crossing to RT2 mice.…”

“…We next sought to determine the functional contribution of CtsZ to tumor formation and progression by crossing CtsZ À/À mice (Sevenich et al 2010) into the RT2 background. We first confirmed that CtsZ mRNA expression was indeed absent in the CtsZ À/À RT2 tumors and that expression of other cathepsin family members (CtsB, CtsH, CtsL, and CtsS) did not change between CtsZ À/À and wild-type RT2 tumors (Supplemental Fig.…”