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Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix

During the process of tumor progression, cancer cells can produce the requisite growth- and invasion-promoting factors and can also rely on noncancerous cells in the tumor microenvironment as an alternative, cell-extrinsic source. However, whether the cellular source influences the function of such...

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Autores principales: Akkari, Leila, Gocheva, Vasilena, Kester, Jemila C., Hunter, Karen E., Quick, Marsha L., Sevenich, Lisa, Wang, Hao-Wei, Peters, Christoph, Tang, Laura H., Klimstra, David S., Reinheckel, Thomas, Joyce, Johanna A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180975/
https://www.ncbi.nlm.nih.gov/pubmed/25274726
http://dx.doi.org/10.1101/gad.249599.114
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author Akkari, Leila
Gocheva, Vasilena
Kester, Jemila C.
Hunter, Karen E.
Quick, Marsha L.
Sevenich, Lisa
Wang, Hao-Wei
Peters, Christoph
Tang, Laura H.
Klimstra, David S.
Reinheckel, Thomas
Joyce, Johanna A.
author_facet Akkari, Leila
Gocheva, Vasilena
Kester, Jemila C.
Hunter, Karen E.
Quick, Marsha L.
Sevenich, Lisa
Wang, Hao-Wei
Peters, Christoph
Tang, Laura H.
Klimstra, David S.
Reinheckel, Thomas
Joyce, Johanna A.
author_sort Akkari, Leila
collection PubMed
description During the process of tumor progression, cancer cells can produce the requisite growth- and invasion-promoting factors and can also rely on noncancerous cells in the tumor microenvironment as an alternative, cell-extrinsic source. However, whether the cellular source influences the function of such tumor-promoting factors remains an open question. Here, we examined the roles of the cathepsin Z (CtsZ) protease, which is provided by both cancer cells and macrophages in pancreatic neuroendocrine tumors in humans and mice. We found that tumor proliferation was exclusively regulated by cancer cell-intrinsic functions of CtsZ, whereas tumor invasion required contributions from both macrophages and cancer cells. Interestingly, several of the tumor-promoting functions of CtsZ were not dependent on its described catalytic activity but instead were mediated via the Arg–Gly–Asp (RGD) motif in the enzyme prodomain, which regulated interactions with integrins and the extracellular matrix. Together, these results underscore the complexity of interactions within the tumor microenvironment and indicate that cellular source can indeed impact molecular function.
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spelling pubmed-41809752015-04-01 Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix Akkari, Leila Gocheva, Vasilena Kester, Jemila C. Hunter, Karen E. Quick, Marsha L. Sevenich, Lisa Wang, Hao-Wei Peters, Christoph Tang, Laura H. Klimstra, David S. Reinheckel, Thomas Joyce, Johanna A. Genes Dev Research Paper During the process of tumor progression, cancer cells can produce the requisite growth- and invasion-promoting factors and can also rely on noncancerous cells in the tumor microenvironment as an alternative, cell-extrinsic source. However, whether the cellular source influences the function of such tumor-promoting factors remains an open question. Here, we examined the roles of the cathepsin Z (CtsZ) protease, which is provided by both cancer cells and macrophages in pancreatic neuroendocrine tumors in humans and mice. We found that tumor proliferation was exclusively regulated by cancer cell-intrinsic functions of CtsZ, whereas tumor invasion required contributions from both macrophages and cancer cells. Interestingly, several of the tumor-promoting functions of CtsZ were not dependent on its described catalytic activity but instead were mediated via the Arg–Gly–Asp (RGD) motif in the enzyme prodomain, which regulated interactions with integrins and the extracellular matrix. Together, these results underscore the complexity of interactions within the tumor microenvironment and indicate that cellular source can indeed impact molecular function. Cold Spring Harbor Laboratory Press 2014-10-01 /pmc/articles/PMC4180975/ /pubmed/25274726 http://dx.doi.org/10.1101/gad.249599.114 Text en © 2014 Akkari et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research Paper
Akkari, Leila
Gocheva, Vasilena
Kester, Jemila C.
Hunter, Karen E.
Quick, Marsha L.
Sevenich, Lisa
Wang, Hao-Wei
Peters, Christoph
Tang, Laura H.
Klimstra, David S.
Reinheckel, Thomas
Joyce, Johanna A.
Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix
title Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix
title_full Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix
title_fullStr Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix
title_full_unstemmed Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix
title_short Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix
title_sort distinct functions of macrophage-derived and cancer cell-derived cathepsin z combine to promote tumor malignancy via interactions with the extracellular matrix
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180975/
https://www.ncbi.nlm.nih.gov/pubmed/25274726
http://dx.doi.org/10.1101/gad.249599.114
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