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

Genes & Development
Leila AkkariJohanna A Joyce

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 ...Continue Reading

References

May 5, 1997·FEBS Letters·M OkabeY Nishimune
Jun 27, 1998·The Journal of Biological Chemistry·I SantamaríaC López-Otín
Sep 21, 2000·The Journal of Clinical Investigation·W HalangkJ Deussing
Mar 30, 2002·Science·Lisa M CoussensLynn M Matrisian
Dec 4, 2004·Biological Chemistry·Christopher Jedeszko, Bonnie F Sloane
Sep 22, 2005·Nature Reviews. Immunology·Michael Karin, Florian R Greten
Dec 21, 2005·The Journal of Biological Chemistry·Bing WangGuo-Ping Shi
Feb 17, 2006·Genes & Development·Vasilena GochevaJohanna A Joyce
Sep 23, 2006·Nature Reviews. Cancer·Mona Mostafa Mohamed, Bonnie F Sloane
Oct 4, 2006·Cancer Metastasis Reviews·A Ben-Baruch
Nov 30, 2006·Nucleic Acids Research·Mikhail PachkovErik van Nimwegen
Jan 25, 2007·Cell Cycle·Vasilena Gocheva, Johanna A Joyce
Nov 3, 2007·Biological Chemistry·Ulrich auf dem KellerChristopher M Overall
May 21, 2008·The Journal of Experimental Medicine·Thorsten HagemannFrances R Balkwill
Jun 14, 2008·Nature Reviews. Immunology·John A Hamilton
Jul 25, 2008·The Journal of Biological Chemistry·Carlos López-Otín, Judith S Bond
Apr 21, 2009·Methods in Molecular Biology·Nesrine I AffaraLisa M Coussens
Dec 17, 2009·Cytokine & Growth Factor Reviews·Alberto MantovaniRaffaella Bonecchi
Feb 6, 2010·Proceedings of the National Academy of Sciences of the United States of America·Lisa SevenichThomas Reinheckel
Apr 8, 2010·Cell·Bin-Zhi Qian, Jeffrey W Pollard
Jan 15, 2011·Trends in Cell Biology·Steven D Mason, Johanna A Joyce
May 4, 2011·Molecular Carcinogenesis·Fernando BenavidesClaudio J Conti
Oct 26, 2011·Biochimica Et Biophysica Acta·Vito TurkDušan Turk
Sep 4, 2012·Genome Biology·Tengfei YinMichael Lawrence
Apr 2, 2013·Trends in Pharmacological Sciences·Antoine Dufour, Christopher M Overall
Sep 26, 2013·Genes & Development·Brian RuffellLisa M Coussens
Nov 10, 2013·Nature Medicine·Daniela F Quail, Johanna A Joyce
May 29, 2014·PLoS Biology·Nikolaus FortelnyChristopher M Overall
Nov 5, 2014·Genes & Development·Lisa Sevenich, Johanna A Joyce

❮ Previous
Next ❯

Citations

Feb 10, 2017·Proceedings of the National Academy of Sciences of the United States of America·Sachin RustgiSteffen Reinbothe
Aug 16, 2016·American Journal of Physiology. Gastrointestinal and Liver Physiology·Laura E Edgington-MitchellNigel W Bunnett
Apr 27, 2018·International Journal of Cancer. Journal International Du Cancer·Sebastian KrugPatrick Michl
Apr 14, 2017·Oncotarget·Siyuan ChenHong Guo
Jul 8, 2020·Cytometry. Part a : the Journal of the International Society for Analytical Cytology·Vanessa F Arnaud-SampaioClaudiana Lameu
Dec 22, 2016·Biological Chemistry·Barbara BreznikTamara Lah Turnšek
May 23, 2019·Molecular Medicine Reports·Xiaobing YaoJinzhuo Ning
Jul 12, 2018·Disease Models & Mechanisms·Spencer A Hobson-Gutierrez, Carlos Carmona-Fontaine
Sep 27, 2019·Frontiers in Immunology·Tanja JakošJanko Kos
May 10, 2020·Cellular and Molecular Life Sciences : CMLS·Alejandro Gomez-AuliThomas Reinheckel
Dec 11, 2020·Journal of the American Chemical Society·Jonathan H BoyceIan B Seiple
Jul 3, 2017·Trends in Pharmacological Sciences·Lovro KramerBoris Turk

❮ Previous
Next ❯

Related Concepts

Related Feeds

Carcinoma, Islet Cell (Keystone)

Islet Cell Carcinoma or Pancreatic Neuroendocrine Tumours arise in the hormone producing cells of the pancreas. These tumors can be either malignant or benign. Discover the latest research on islet cell carcinoma in this feed.

Carcinoma, Islet Cell

Islet Cell Carcinoma or Pancreatic Neuroendocrine Tumours arises in the hormone producing cells of the pancreas. These tumors can be either malignant or benign. Discover the latest research on Islet Cell Carcinoma here.

Angiogenesis Inhibitors to Treat Cancer

Cancer treatments including angiogenesis inhibitors prevent tumor cells from receiving nutrients and oxygen. Here is the latest research on angiogenesis inhibitors for the treatment of cancer.

Adenoma, Islet Cell

Islet Cell Adenoma arises in the islet cells, which are insulin producing cells of the pancreas. These tumors can be either malignant or benign. Discover the latest research on Islet Cell Adenoma here.