Upregulation of periostin and reactive stroma is associated with primary chemoresistance and predicts clinical outcomes in epithelial ovarian cancer

Lisa Ryner, Yinghui Guan, Ron Firestein, Yuanyuan Xiao, Younjeong Choi, Christina Rabe, Shan Lu, Eloisa Fuentes, Ling-Yuh Huw, Mark R. Lackner, Ling Fu, Lukas C. Amler, Carlos Bais, Yulei Wang

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Abstract

Purpose: Up to one third of ovarian cancer patients are intrinsically resistant to platinum-based treatment. However, predictive and therapeutic strategies are lacking due to a poor understanding of the underlying molecular mechanisms. This study aimed to identify key molecular characteristics that are associated with primary chemoresistance in epithelial ovarian cancers. Experimental Design: Gene expression profiling was performed on a discovery set of 85 ovarian tumors with clinically well-defined response to chemotherapies as well as on an independent validation dataset containing 138 ovarian patients from the chemotreatment arm of the ICON7 trial. Results: We identified a distinct "reactive stroma" gene signature that is specifically associated with primary chemoresistant tumors and was further upregulated in posttreatment recurrent tumors. Immunohistochemistry (IHC) and RNA in situ hybridization (RNA ISH) analyses on three of the highest-ranked signature genes (POSTN, LOX, and FAP) confirmed that modulation of the reactive stroma signature genes within the peritumoral stromal compartments was specifically associated with the clinical chemoresistance. Consistent with these findings, chemosensitive ovarian cells grown in the presence of recombinant POSTN promoted resistance to carboplatin and paclitaxel treatment in vitro. Finally, we validated the reactive stroma signature in an independent dataset and demonstrated that a high POSTN expression level predicts shorter progression-free survival following first-line chemotherapy. Conclusions: Our findings highlight the important interplay between cancer and the tumor microenvironment in ovarian cancer biology and treatment. The identified reactive stromal components in this study provide a molecular basis to the further development of novel diagnostic and therapeutic strategies for overcoming chemoresistance in ovarian cancer.

Original languageEnglish
Pages (from-to)2941-2951
Number of pages11
JournalClinical Cancer Research
Volume21
Issue number13
DOIs
Publication statusPublished - Jul 2015
Externally publishedYes

Cite this

Ryner, Lisa ; Guan, Yinghui ; Firestein, Ron ; Xiao, Yuanyuan ; Choi, Younjeong ; Rabe, Christina ; Lu, Shan ; Fuentes, Eloisa ; Huw, Ling-Yuh ; Lackner, Mark R. ; Fu, Ling ; Amler, Lukas C. ; Bais, Carlos ; Wang, Yulei. / Upregulation of periostin and reactive stroma is associated with primary chemoresistance and predicts clinical outcomes in epithelial ovarian cancer. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 13. pp. 2941-2951.
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title = "Upregulation of periostin and reactive stroma is associated with primary chemoresistance and predicts clinical outcomes in epithelial ovarian cancer",
abstract = "Purpose: Up to one third of ovarian cancer patients are intrinsically resistant to platinum-based treatment. However, predictive and therapeutic strategies are lacking due to a poor understanding of the underlying molecular mechanisms. This study aimed to identify key molecular characteristics that are associated with primary chemoresistance in epithelial ovarian cancers. Experimental Design: Gene expression profiling was performed on a discovery set of 85 ovarian tumors with clinically well-defined response to chemotherapies as well as on an independent validation dataset containing 138 ovarian patients from the chemotreatment arm of the ICON7 trial. Results: We identified a distinct {"}reactive stroma{"} gene signature that is specifically associated with primary chemoresistant tumors and was further upregulated in posttreatment recurrent tumors. Immunohistochemistry (IHC) and RNA in situ hybridization (RNA ISH) analyses on three of the highest-ranked signature genes (POSTN, LOX, and FAP) confirmed that modulation of the reactive stroma signature genes within the peritumoral stromal compartments was specifically associated with the clinical chemoresistance. Consistent with these findings, chemosensitive ovarian cells grown in the presence of recombinant POSTN promoted resistance to carboplatin and paclitaxel treatment in vitro. Finally, we validated the reactive stroma signature in an independent dataset and demonstrated that a high POSTN expression level predicts shorter progression-free survival following first-line chemotherapy. Conclusions: Our findings highlight the important interplay between cancer and the tumor microenvironment in ovarian cancer biology and treatment. The identified reactive stromal components in this study provide a molecular basis to the further development of novel diagnostic and therapeutic strategies for overcoming chemoresistance in ovarian cancer.",
author = "Lisa Ryner and Yinghui Guan and Ron Firestein and Yuanyuan Xiao and Younjeong Choi and Christina Rabe and Shan Lu and Eloisa Fuentes and Ling-Yuh Huw and Lackner, {Mark R.} and Ling Fu and Amler, {Lukas C.} and Carlos Bais and Yulei Wang",
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doi = "10.1158/1078-0432.CCR-14-3111",
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Ryner, L, Guan, Y, Firestein, R, Xiao, Y, Choi, Y, Rabe, C, Lu, S, Fuentes, E, Huw, L-Y, Lackner, MR, Fu, L, Amler, LC, Bais, C & Wang, Y 2015, 'Upregulation of periostin and reactive stroma is associated with primary chemoresistance and predicts clinical outcomes in epithelial ovarian cancer', Clinical Cancer Research, vol. 21, no. 13, pp. 2941-2951. https://doi.org/10.1158/1078-0432.CCR-14-3111

Upregulation of periostin and reactive stroma is associated with primary chemoresistance and predicts clinical outcomes in epithelial ovarian cancer. / Ryner, Lisa; Guan, Yinghui; Firestein, Ron; Xiao, Yuanyuan; Choi, Younjeong; Rabe, Christina; Lu, Shan; Fuentes, Eloisa; Huw, Ling-Yuh; Lackner, Mark R.; Fu, Ling; Amler, Lukas C.; Bais, Carlos; Wang, Yulei.

In: Clinical Cancer Research, Vol. 21, No. 13, 07.2015, p. 2941-2951.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Upregulation of periostin and reactive stroma is associated with primary chemoresistance and predicts clinical outcomes in epithelial ovarian cancer

AU - Ryner, Lisa

AU - Guan, Yinghui

AU - Firestein, Ron

AU - Xiao, Yuanyuan

AU - Choi, Younjeong

AU - Rabe, Christina

AU - Lu, Shan

AU - Fuentes, Eloisa

AU - Huw, Ling-Yuh

AU - Lackner, Mark R.

AU - Fu, Ling

AU - Amler, Lukas C.

AU - Bais, Carlos

AU - Wang, Yulei

PY - 2015/7

Y1 - 2015/7

N2 - Purpose: Up to one third of ovarian cancer patients are intrinsically resistant to platinum-based treatment. However, predictive and therapeutic strategies are lacking due to a poor understanding of the underlying molecular mechanisms. This study aimed to identify key molecular characteristics that are associated with primary chemoresistance in epithelial ovarian cancers. Experimental Design: Gene expression profiling was performed on a discovery set of 85 ovarian tumors with clinically well-defined response to chemotherapies as well as on an independent validation dataset containing 138 ovarian patients from the chemotreatment arm of the ICON7 trial. Results: We identified a distinct "reactive stroma" gene signature that is specifically associated with primary chemoresistant tumors and was further upregulated in posttreatment recurrent tumors. Immunohistochemistry (IHC) and RNA in situ hybridization (RNA ISH) analyses on three of the highest-ranked signature genes (POSTN, LOX, and FAP) confirmed that modulation of the reactive stroma signature genes within the peritumoral stromal compartments was specifically associated with the clinical chemoresistance. Consistent with these findings, chemosensitive ovarian cells grown in the presence of recombinant POSTN promoted resistance to carboplatin and paclitaxel treatment in vitro. Finally, we validated the reactive stroma signature in an independent dataset and demonstrated that a high POSTN expression level predicts shorter progression-free survival following first-line chemotherapy. Conclusions: Our findings highlight the important interplay between cancer and the tumor microenvironment in ovarian cancer biology and treatment. The identified reactive stromal components in this study provide a molecular basis to the further development of novel diagnostic and therapeutic strategies for overcoming chemoresistance in ovarian cancer.

AB - Purpose: Up to one third of ovarian cancer patients are intrinsically resistant to platinum-based treatment. However, predictive and therapeutic strategies are lacking due to a poor understanding of the underlying molecular mechanisms. This study aimed to identify key molecular characteristics that are associated with primary chemoresistance in epithelial ovarian cancers. Experimental Design: Gene expression profiling was performed on a discovery set of 85 ovarian tumors with clinically well-defined response to chemotherapies as well as on an independent validation dataset containing 138 ovarian patients from the chemotreatment arm of the ICON7 trial. Results: We identified a distinct "reactive stroma" gene signature that is specifically associated with primary chemoresistant tumors and was further upregulated in posttreatment recurrent tumors. Immunohistochemistry (IHC) and RNA in situ hybridization (RNA ISH) analyses on three of the highest-ranked signature genes (POSTN, LOX, and FAP) confirmed that modulation of the reactive stroma signature genes within the peritumoral stromal compartments was specifically associated with the clinical chemoresistance. Consistent with these findings, chemosensitive ovarian cells grown in the presence of recombinant POSTN promoted resistance to carboplatin and paclitaxel treatment in vitro. Finally, we validated the reactive stroma signature in an independent dataset and demonstrated that a high POSTN expression level predicts shorter progression-free survival following first-line chemotherapy. Conclusions: Our findings highlight the important interplay between cancer and the tumor microenvironment in ovarian cancer biology and treatment. The identified reactive stromal components in this study provide a molecular basis to the further development of novel diagnostic and therapeutic strategies for overcoming chemoresistance in ovarian cancer.

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