Host stromal versican is essential for cancer-associated fibroblast function to inhibit cancer growth

© 2015 UICC. The stroma provides a microenvironment that regulates tumor cell behavior. The extracellular matrix (ECM) has long been recognized to be important in tumor cell behavior, and previous studies have revealed the impact of individual matrix molecules on tumor progression. Although several...

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Main Authors: Kanda Fanhchaksai, Futoshi Okada, Naoko Nagai, Peraphan Pothacharoen, Prachya Kongtawelert, Sonoko Hatano, Shinji Makino, Tomoyuki Nakamura, Hideto Watanabe
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Published: 2018
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http://cmuir.cmu.ac.th/jspui/handle/6653943832/55312
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spelling th-cmuir.6653943832-553122018-09-05T03:11:21Z Host stromal versican is essential for cancer-associated fibroblast function to inhibit cancer growth Kanda Fanhchaksai Futoshi Okada Naoko Nagai Peraphan Pothacharoen Prachya Kongtawelert Sonoko Hatano Shinji Makino Tomoyuki Nakamura Hideto Watanabe Biochemistry, Genetics and Molecular Biology Medicine © 2015 UICC. The stroma provides a microenvironment that regulates tumor cell behavior. The extracellular matrix (ECM) has long been recognized to be important in tumor cell behavior, and previous studies have revealed the impact of individual matrix molecules on tumor progression. Although several reports have highlighted some central roles of tumor cell-expressed versican, the role of host stromal versican is not yet understood. In this study, we demonstrate that versican is an important molecule in the functional ECM structure and maintaining cancer-associated fibroblasts, using versican-negative QRsP11 fibrosarcoma cells. By their subcutaneous injection with cre-expressing adenoviruses to versican-floxed mice, we demonstrate that loss of host stromal versican facilitates tumor cell proliferation, and following angiogenesis, decreases cancer-associated fibroblasts, diminishes collagen fibers and alters hyaluronan distribution, concomitant with upregulation of hyaluronan, TGFβ and VEGF-mediated signaling. When the versican V3 variant consisting of G1 and G3 domains was expressed in tumor cells, it was integrated into the ECM, regained collagen fibers and cancer-associated fibroblasts and resulted in successful recovery of tumor growth inhibition, indicating that whatever cells produce, the G1 and G3 domains are adequate for versican function. Collectively, our results indicate a dynamic function of versican in the ECM that regulates tumor cell behavior. A greater understanding of the regulation of versican expression may contribute to the development of cancer therapies. What's new? The dynamic behavior of tumor cells is closely tied to the extracellular matrix (ECM) and changes in its composition and regulation that occur during tumorigenesis. In this study, loss of the stromal protein versican in mice was found to facilitate changes in the ECM that are conducive to tumor growth. Specifically, versican ablation led to declines in cancer-associated fibroblasts and collagen fibers and to changes in hyaluronan regulation. It also facilitated angiogenesis via elevated VEGF signaling. Further understanding of the factors that control versican expression could provide important insight for the development of novel therapeutic strategies. 2018-09-05T02:54:17Z 2018-09-05T02:54:17Z 2016-01-01 Journal 10970215 00207136 2-s2.0-84955705245 10.1002/ijc.29804 https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84955705245&origin=inward http://cmuir.cmu.ac.th/jspui/handle/6653943832/55312
institution Chiang Mai University
building Chiang Mai University Library
country Thailand
collection CMU Intellectual Repository
topic Biochemistry, Genetics and Molecular Biology
Medicine
spellingShingle Biochemistry, Genetics and Molecular Biology
Medicine
Kanda Fanhchaksai
Futoshi Okada
Naoko Nagai
Peraphan Pothacharoen
Prachya Kongtawelert
Sonoko Hatano
Shinji Makino
Tomoyuki Nakamura
Hideto Watanabe
Host stromal versican is essential for cancer-associated fibroblast function to inhibit cancer growth
description © 2015 UICC. The stroma provides a microenvironment that regulates tumor cell behavior. The extracellular matrix (ECM) has long been recognized to be important in tumor cell behavior, and previous studies have revealed the impact of individual matrix molecules on tumor progression. Although several reports have highlighted some central roles of tumor cell-expressed versican, the role of host stromal versican is not yet understood. In this study, we demonstrate that versican is an important molecule in the functional ECM structure and maintaining cancer-associated fibroblasts, using versican-negative QRsP11 fibrosarcoma cells. By their subcutaneous injection with cre-expressing adenoviruses to versican-floxed mice, we demonstrate that loss of host stromal versican facilitates tumor cell proliferation, and following angiogenesis, decreases cancer-associated fibroblasts, diminishes collagen fibers and alters hyaluronan distribution, concomitant with upregulation of hyaluronan, TGFβ and VEGF-mediated signaling. When the versican V3 variant consisting of G1 and G3 domains was expressed in tumor cells, it was integrated into the ECM, regained collagen fibers and cancer-associated fibroblasts and resulted in successful recovery of tumor growth inhibition, indicating that whatever cells produce, the G1 and G3 domains are adequate for versican function. Collectively, our results indicate a dynamic function of versican in the ECM that regulates tumor cell behavior. A greater understanding of the regulation of versican expression may contribute to the development of cancer therapies. What's new? The dynamic behavior of tumor cells is closely tied to the extracellular matrix (ECM) and changes in its composition and regulation that occur during tumorigenesis. In this study, loss of the stromal protein versican in mice was found to facilitate changes in the ECM that are conducive to tumor growth. Specifically, versican ablation led to declines in cancer-associated fibroblasts and collagen fibers and to changes in hyaluronan regulation. It also facilitated angiogenesis via elevated VEGF signaling. Further understanding of the factors that control versican expression could provide important insight for the development of novel therapeutic strategies.
format Journal
author Kanda Fanhchaksai
Futoshi Okada
Naoko Nagai
Peraphan Pothacharoen
Prachya Kongtawelert
Sonoko Hatano
Shinji Makino
Tomoyuki Nakamura
Hideto Watanabe
author_facet Kanda Fanhchaksai
Futoshi Okada
Naoko Nagai
Peraphan Pothacharoen
Prachya Kongtawelert
Sonoko Hatano
Shinji Makino
Tomoyuki Nakamura
Hideto Watanabe
author_sort Kanda Fanhchaksai
title Host stromal versican is essential for cancer-associated fibroblast function to inhibit cancer growth
title_short Host stromal versican is essential for cancer-associated fibroblast function to inhibit cancer growth
title_full Host stromal versican is essential for cancer-associated fibroblast function to inhibit cancer growth
title_fullStr Host stromal versican is essential for cancer-associated fibroblast function to inhibit cancer growth
title_full_unstemmed Host stromal versican is essential for cancer-associated fibroblast function to inhibit cancer growth
title_sort host stromal versican is essential for cancer-associated fibroblast function to inhibit cancer growth
publishDate 2018
url https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84955705245&origin=inward
http://cmuir.cmu.ac.th/jspui/handle/6653943832/55312
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