Combined deletion of cathepsin protease family members reveals compensatory mechanisms in cancer.
Genes Dev
; 30(2): 220-32, 2016 Jan 15.
Article
en En
| MEDLINE
| ID: mdl-26773004
ABSTRACT
Proteases are important for regulating multiple tumorigenic processes, including angiogenesis, tumor growth, and invasion. Elevated protease expression is associated with poor patient prognosis across numerous tumor types. Several multigene protease families have been implicated in cancer, including cysteine cathepsins. However, whether individual family members have unique roles or are functionally redundant remains poorly understood. Here we demonstrate stage-dependent effects of simultaneously deleting cathepsin B (CtsB) and CtsS in a murine pancreatic neuroendocrine tumor model. Early in tumorigenesis, the double knockout results in an additive reduction in angiogenic switching, whereas at late stages, several tumorigenic phenotypes are unexpectedly restored to wild-type levels. We identified CtsZ, which is predominantly supplied by tumor-associated macrophages, as the compensatory protease that regulates the acquired tumor-promoting functions of lesions deficient in both CtsB and CtsS. Thus, deletion of multiple cathepsins can lead to stage-dependent, compensatory mechanisms in the tumor microenvironment, which has potential implications for the clinical consideration of selective versus pan-family cathepsin inhibitors in cancer.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias Pancreáticas
/
Catepsinas
/
Eliminación de Gen
/
Carcinoma Neuroendocrino
Límite:
Animals
Idioma:
En
Revista:
Genes Dev
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2016
Tipo del documento:
Article
País de afiliación:
Suiza