Combined deletion of cathepsin protease family members reveals compensatory mechanisms in cancer

Autor: Alfred L. Garfall, Alison K. Spencer, Vasilena Gocheva, Marsha L. Quick, Jemila C. Kester, Robert L. Bowman, Leila Akkari, Johanna A. Joyce
Rok vydání: 2016
Předmět:
0301 basic medicine
Proteases
Carcinogenesis
Angiogenesis
medicine.medical_treatment
Apoptosis
Biology
medicine.disease_cause
Cathepsin B
Gene Knockout Techniques
Mice
03 medical and health sciences
Genetics
medicine
Animals
Neoplasm Invasiveness
Cathepsin
Tumor microenvironment
Protease
Neovascularization
Pathologic
Macrophages
Cancer
medicine.disease
Cathepsins
Apoptosis/genetics
Carcinogenesis/genetics
Carcinoma
Neuroendocrine/enzymology
Carcinoma
Neuroendocrine/genetics
Cathepsins/genetics
Cathepsins/metabolism
Disease Models
Animal
Gene Deletion
Gene Expression Regulation
Neoplastic
Macrophages/enzymology
Mice
Inbred C57BL
Neoplasm Invasiveness/genetics
Neovascularization
Pathologic/enzymology
Neovascularization
Pathologic/genetics
Pancreatic Neoplasms/enzymology
Pancreatic Neoplasms/genetics
Carcinoma
Neuroendocrine
Pancreatic Neoplasms
030104 developmental biology
Cancer research
Research Paper
Developmental Biology
Zdroj: Genes and Development, vol. 30, no. 2, pp. 220-232
ISSN: 1549-5477
0890-9369
Popis: 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.
Databáze: OpenAIRE
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