Cathepsin cysteine proteases are effectors of invasive growth and angiogenesis during multistage tumorigenesis.
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.
Joyce
Johanna A
JA
Department of Biochemistry and Biophysics, Diabetes and Comprehensive Cancer Centers, University of California at San Francisco, 94143, USA.
Baruch
Amos
A
Chehade
Kareem
K
Meyer-Morse
Nicole
N
Giraudo
Enrico
E
Tsai
Fong-Ying
FY
Greenbaum
Doron C
DC
Hager
Jeffrey H
JH
Bogyo
Matthew
M
Hanahan
Douglas
D
D000818:Animals; D018273:Carcinoma, Islet Cell / Q000098:blood supply / Q000473:pathology; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007515:Islets of Langerhans / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D009856:Oncogene Proteins, Viral / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000473:pathology*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000502:physiology
C119724:AGFG1 protein, human; D015853:Cysteine Proteinase Inhibitors; C093478:E1 protein, Human papillomavirus 16; D028861:Nuclear Pore Complex Proteins; D009856:Oncogene Proteins, Viral; D016601:RNA-Binding Proteins; D002403:Cathepsins