Cathepsin cysteine proteases are effectors of invasive growth and angiogenesis during multistage tumorigenesis

Johanna A Joyce; Amos Baruch; Kareem Chehade; Nicole Meyer-Morse; Enrico Giraudo; Fong-Ying Tsai; Doron C Greenbaum; Jeffrey H Hager; Matthew Bogyo; Douglas Hanahan

doi:10.1016/s1535-6108(04)00111-4

Cathepsin cysteine proteases are effectors of invasive growth and angiogenesis during multistage tumorigenesis

Cancer Cell. 2004 May;5(5):443-53. doi: 10.1016/s1535-6108(04)00111-4.

Authors

Johanna A Joyce¹, Amos Baruch, Kareem Chehade, Nicole Meyer-Morse, Enrico Giraudo, Fong-Ying Tsai, Doron C Greenbaum, Jeffrey H Hager, Matthew Bogyo, Douglas Hanahan

Affiliation

¹ Department of Biochemistry and Biophysics, Diabetes and Comprehensive Cancer Centers, University of California at San Francisco, 94143, USA.

PMID: 15144952
DOI: 10.1016/s1535-6108(04)00111-4

Abstract

Tumors develop through successive stages characterized by changes in gene expression and protein function. Gene expression profiling of pancreatic islet tumors in a mouse model of cancer revealed upregulation of cathepsin cysteine proteases. Cathepsin activity was assessed using chemical probes allowing biochemical and in vivo imaging, revealing increased activity associated with the angiogenic vasculature and invasive fronts of carcinomas, and differential expression in immune, endothelial, and cancer cells. A broad-spectrum cysteine cathepsin inhibitor was used to pharmacologically knock out cathepsin function at different stages of tumorigenesis, impairing angiogenic switching in progenitor lesions, as well as tumor growth, vascularity, and invasiveness. Cysteine cathepsins are also upregulated during HPV16-induced cervical carcinogenesis, further encouraging consideration of this protease family as a therapeutic target in human cancers.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Animals
Carcinoma, Islet Cell / blood supply
Carcinoma, Islet Cell / pathology
Cathepsins / antagonists & inhibitors
Cathepsins / metabolism*
Cell Transformation, Neoplastic
Cysteine Proteinase Inhibitors / pharmacology
Female
Gene Expression Profiling
Humans
Islets of Langerhans / enzymology
Islets of Langerhans / pathology
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neoplasm Invasiveness
Neoplasm Staging
Neovascularization, Pathologic / enzymology*
Neovascularization, Pathologic / metabolism*
Nuclear Pore Complex Proteins / genetics
Nuclear Pore Complex Proteins / physiology
Oligonucleotide Array Sequence Analysis
Oncogene Proteins, Viral / physiology
Pancreatic Neoplasms / blood supply*
Pancreatic Neoplasms / pathology*
RNA-Binding Proteins / genetics
RNA-Binding Proteins / physiology

Substances

AGFG1 protein, human
Cysteine Proteinase Inhibitors
E1 protein, Human papillomavirus 16
Nuclear Pore Complex Proteins
Oncogene Proteins, Viral
RNA-Binding Proteins
Cathepsins