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Stromal SPOCK1 supports invasive pancreatic cancer growth

Pancreatic ductal adenocarcinoma (PDAC) is marked by an abundant stromal deposition. This stroma is suspected to harbor both tumor‐promoting and tumor‐suppressing properties. This is underscored by the disappointing results of stroma targeting in clinical studies. Given the complexity of tumor–strom...

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Autores principales: Veenstra, Veronique L., Damhofer, Helene, Waasdorp, Cynthia, Steins, Anne, Kocher, Hemant M., Medema, Jan P., van Laarhoven, Hanneke W., Bijlsma, Maarten F
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537700/
https://www.ncbi.nlm.nih.gov/pubmed/28486750
http://dx.doi.org/10.1002/1878-0261.12073
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author Veenstra, Veronique L.
Damhofer, Helene
Waasdorp, Cynthia
Steins, Anne
Kocher, Hemant M.
Medema, Jan P.
van Laarhoven, Hanneke W.
Bijlsma, Maarten F
author_facet Veenstra, Veronique L.
Damhofer, Helene
Waasdorp, Cynthia
Steins, Anne
Kocher, Hemant M.
Medema, Jan P.
van Laarhoven, Hanneke W.
Bijlsma, Maarten F
author_sort Veenstra, Veronique L.
collection PubMed
description Pancreatic ductal adenocarcinoma (PDAC) is marked by an abundant stromal deposition. This stroma is suspected to harbor both tumor‐promoting and tumor‐suppressing properties. This is underscored by the disappointing results of stroma targeting in clinical studies. Given the complexity of tumor–stroma interaction in PDAC, there is a need to identify the stromal proteins that are predominantly tumor‐promoting. One possible candidate is SPOCK1 that we previously identified in a screening effort in PDAC. We extensively mined PDAC gene expression datasets, and used species‐specific transcript analysis in mixed‐species models for PDAC to study the patterns and driver mechanisms of SPOCK1 expression in PDAC. Advanced organotypic coculture models with primary patient‐derived tumor cells were used to further characterize the function of this protein. We found SPOCK1 expression to be predominantly stromal. Expression of SPOCK1 was associated with poor disease outcome. Coculture and ligand stimulation experiments revealed that SPOCK1 is expressed in response to tumor cell‐derived transforming growth factor‐beta. Functional assessment in cocultures demonstrated that SPOCK1 strongly affects the composition of the extracellular collagen matrix and by doing so, enables invasive tumor cell growth in PDAC. By defining the expression pattern and functional properties of SPOCK1 in pancreatic cancer, we have identified a stromal mediator of extracellular matrix remodeling that indirectly affects the aggressive behavior of PDAC cells. The recognition that stromal proteins actively contribute to the protumorigenic remodeling of the tumor microenvironment should aid the design of future clinical studies to target specific stromal targets.
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spelling pubmed-55377002017-08-15 Stromal SPOCK1 supports invasive pancreatic cancer growth Veenstra, Veronique L. Damhofer, Helene Waasdorp, Cynthia Steins, Anne Kocher, Hemant M. Medema, Jan P. van Laarhoven, Hanneke W. Bijlsma, Maarten F Mol Oncol Research Articles Pancreatic ductal adenocarcinoma (PDAC) is marked by an abundant stromal deposition. This stroma is suspected to harbor both tumor‐promoting and tumor‐suppressing properties. This is underscored by the disappointing results of stroma targeting in clinical studies. Given the complexity of tumor–stroma interaction in PDAC, there is a need to identify the stromal proteins that are predominantly tumor‐promoting. One possible candidate is SPOCK1 that we previously identified in a screening effort in PDAC. We extensively mined PDAC gene expression datasets, and used species‐specific transcript analysis in mixed‐species models for PDAC to study the patterns and driver mechanisms of SPOCK1 expression in PDAC. Advanced organotypic coculture models with primary patient‐derived tumor cells were used to further characterize the function of this protein. We found SPOCK1 expression to be predominantly stromal. Expression of SPOCK1 was associated with poor disease outcome. Coculture and ligand stimulation experiments revealed that SPOCK1 is expressed in response to tumor cell‐derived transforming growth factor‐beta. Functional assessment in cocultures demonstrated that SPOCK1 strongly affects the composition of the extracellular collagen matrix and by doing so, enables invasive tumor cell growth in PDAC. By defining the expression pattern and functional properties of SPOCK1 in pancreatic cancer, we have identified a stromal mediator of extracellular matrix remodeling that indirectly affects the aggressive behavior of PDAC cells. The recognition that stromal proteins actively contribute to the protumorigenic remodeling of the tumor microenvironment should aid the design of future clinical studies to target specific stromal targets. John Wiley and Sons Inc. 2017-06-05 2017-08 /pmc/articles/PMC5537700/ /pubmed/28486750 http://dx.doi.org/10.1002/1878-0261.12073 Text en © 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Veenstra, Veronique L.
Damhofer, Helene
Waasdorp, Cynthia
Steins, Anne
Kocher, Hemant M.
Medema, Jan P.
van Laarhoven, Hanneke W.
Bijlsma, Maarten F
Stromal SPOCK1 supports invasive pancreatic cancer growth
title Stromal SPOCK1 supports invasive pancreatic cancer growth
title_full Stromal SPOCK1 supports invasive pancreatic cancer growth
title_fullStr Stromal SPOCK1 supports invasive pancreatic cancer growth
title_full_unstemmed Stromal SPOCK1 supports invasive pancreatic cancer growth
title_short Stromal SPOCK1 supports invasive pancreatic cancer growth
title_sort stromal spock1 supports invasive pancreatic cancer growth
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537700/
https://www.ncbi.nlm.nih.gov/pubmed/28486750
http://dx.doi.org/10.1002/1878-0261.12073
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