Deficiency for the cysteine protease cathepsin L impairs Myc-induced tumorigenesis in a mouse model of pancreatic neuroendocrine cancer.
Motivated by the recent implication of cysteine protease cathepsin L as a potential target for anti-cancer drug development, we used a conditional MycERTAM;Bcl-xL model of pancreatic neuroendocrine tumorigenesis (PNET) to assess the role of cathepsin L in Myc-induced tumor progression. By employing a cysteine cathepsin activity probe in vivo and in vitro, we first established that cathepsin activity increases during the initial stages of MycERTAM;Bcl-xL tumor development. Among the cathepsin family members investigated, only cathepsin L was predominately produced by beta-tumor cells in neoplastic pancreata and, consistent with this, cathepsin L mRNA expression was rapidly upregulated following Myc activation in the beta cell compartment. By contrast, cathepsins B, S and C were highly enriched in tumor-infiltrating leukocytes. Genetic deletion of cathepsin L had no discernible effect on the initiation of neoplastic growth or concordant angiogenesis. However, the tumors that developed in the cathepsin L-deficient background were markedly reduced in size relative to their typical wild-type counterparts, indicative of a role for cathepsin L in enabling expansive tumor growth. Thus, genetic blockade of cathepsin L activity is inferred to retard Myc-driven tumor growth, encouraging the potential utility of pharmacological inhibitors of cysteine cathepsins in treating late stage tumors.
Swiss Institute for Experimental Cancer Research (ISREC), Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
Nicola R
NR
Brindle
Departments of Pathology and Department of Biochemistry and Biophysics, University of California San Francisco (UCSF), San Francisco, United States of America; Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
Johanna A
JA
Joyce
Departments of Pathology and Department of Biochemistry and Biophysics, University of California San Francisco (UCSF), San Francisco, United States of America.
Fanya
F
Rostker
Departments of Pathology and Department of Biochemistry and Biophysics, University of California San Francisco (UCSF), San Francisco, United States of America.
Elizabeth R
ER
Lawlor
Departments of Pathology and Department of Biochemistry and Biophysics, University of California San Francisco (UCSF), San Francisco, United States of America.
Lamorna
L
Swigart-Brown
Departments of Pathology and Department of Biochemistry and Biophysics, University of California San Francisco (UCSF), San Francisco, United States of America.
Gerard
G
Evan
Swiss Institute for Experimental Cancer Research (ISREC), Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
Douglas
D
Hanahan
Swiss Institute for Experimental Cancer Research (ISREC), Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland; Departments of Pathology and Department of Biochemistry and Biophysics, University of California San Francisco (UCSF), San Francisco, United States of America.
Ksenya
K
Shchors
D000818:Animals; D056668:Cathepsin L / Q000172:deficiency*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D051020:bcl-X Protein; D056668:Cathepsin L; C534278:Ctsl protein, mouse