Cancer-associated stroma significantly contributes to the mesenchymal subtype signature of serous ovarian cancer

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2 Citations (Scopus)

Abstract

Objective: Mesenchymal (MES) subtype of high-grade serous ovarian cancer (HGSOC) is associated with worse outcomes including survival and resectability compared with other molecular subtypes. Molecular subtypes have historically been derived from ‘tumor’ consisting of both cancer and stromal cells. We sought to determine the origins of multiple MES subtype gene signatures in HGSOC. Methods: Fifteen patients with MES subtype of HGSOC diagnosed between 2010 and 2013 were identified. Formalin-fixed paraffin-embedded (FFPE) blocks from primary surgery were sectioned for immunohistochemistry (IHC) staining of relevant proteins. Eight genes (ACTA2, COL5A1, COL11A1, FAP, POSTN, VCAN, ZEB1 and p-SMAD2) were selected for IHC staining based on their differential expression in MES vs. non-MES subtypes of HGSOC. Slides were scored for intensity and localization and simple statistics were used to compare expression results in cancer vs. stroma and between primary and metastatic sites. Results: COL5A1, VCAN, FAP, and ZEB1 proteins were almost exclusively expressed by stroma as opposed to cancer cells. In addition, stromal expression was dominant for ACTA2, COL11A1, POSTN and p-SMAD2. In general there were minimal differences in expression of proteins between primary and metastatic sites, exceptions being COL5A1 (reduced in metastases) and COL11A1 (increased in metastases). Nuclear p-SMAD2 expression was more common in metastatic stroma. Conclusions: The existing molecular classification of HGSOC MES subtype reflects a significant stromal contribution, suggesting an important role in HGSOC behavior and thus stroma may be a relevant therapeutic target. Specific patterns of expression indicate that collagens and TGF-β signaling are involved in the metastatic process.

Original languageEnglish (US)
JournalGynecologic Oncology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Ovarian Neoplasms
Neoplasms
Immunohistochemistry
Staining and Labeling
Neoplasm Metastasis
Proteins
Stromal Cells
Paraffin
Formaldehyde
Genes
Collagen
Survival

Keywords

  • High-grade serous ovarian cancer (HGSOC)
  • Mesenchymal (MES)
  • Metastatic
  • Primary
  • Stroma

ASJC Scopus subject areas

  • Oncology
  • Obstetrics and Gynecology

Cite this

@article{24394eb3dd3242b9bcce6f0de657d5c9,
title = "Cancer-associated stroma significantly contributes to the mesenchymal subtype signature of serous ovarian cancer",
abstract = "Objective: Mesenchymal (MES) subtype of high-grade serous ovarian cancer (HGSOC) is associated with worse outcomes including survival and resectability compared with other molecular subtypes. Molecular subtypes have historically been derived from ‘tumor’ consisting of both cancer and stromal cells. We sought to determine the origins of multiple MES subtype gene signatures in HGSOC. Methods: Fifteen patients with MES subtype of HGSOC diagnosed between 2010 and 2013 were identified. Formalin-fixed paraffin-embedded (FFPE) blocks from primary surgery were sectioned for immunohistochemistry (IHC) staining of relevant proteins. Eight genes (ACTA2, COL5A1, COL11A1, FAP, POSTN, VCAN, ZEB1 and p-SMAD2) were selected for IHC staining based on their differential expression in MES vs. non-MES subtypes of HGSOC. Slides were scored for intensity and localization and simple statistics were used to compare expression results in cancer vs. stroma and between primary and metastatic sites. Results: COL5A1, VCAN, FAP, and ZEB1 proteins were almost exclusively expressed by stroma as opposed to cancer cells. In addition, stromal expression was dominant for ACTA2, COL11A1, POSTN and p-SMAD2. In general there were minimal differences in expression of proteins between primary and metastatic sites, exceptions being COL5A1 (reduced in metastases) and COL11A1 (increased in metastases). Nuclear p-SMAD2 expression was more common in metastatic stroma. Conclusions: The existing molecular classification of HGSOC MES subtype reflects a significant stromal contribution, suggesting an important role in HGSOC behavior and thus stroma may be a relevant therapeutic target. Specific patterns of expression indicate that collagens and TGF-β signaling are involved in the metastatic process.",
keywords = "High-grade serous ovarian cancer (HGSOC), Mesenchymal (MES), Metastatic, Primary, Stroma",
author = "Qing Zhang and Chen Wang and Cliby, {William Arthur}",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.ygyno.2018.11.014",
language = "English (US)",
journal = "Gynecologic Oncology",
issn = "0090-8258",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - Cancer-associated stroma significantly contributes to the mesenchymal subtype signature of serous ovarian cancer

AU - Zhang, Qing

AU - Wang, Chen

AU - Cliby, William Arthur

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Objective: Mesenchymal (MES) subtype of high-grade serous ovarian cancer (HGSOC) is associated with worse outcomes including survival and resectability compared with other molecular subtypes. Molecular subtypes have historically been derived from ‘tumor’ consisting of both cancer and stromal cells. We sought to determine the origins of multiple MES subtype gene signatures in HGSOC. Methods: Fifteen patients with MES subtype of HGSOC diagnosed between 2010 and 2013 were identified. Formalin-fixed paraffin-embedded (FFPE) blocks from primary surgery were sectioned for immunohistochemistry (IHC) staining of relevant proteins. Eight genes (ACTA2, COL5A1, COL11A1, FAP, POSTN, VCAN, ZEB1 and p-SMAD2) were selected for IHC staining based on their differential expression in MES vs. non-MES subtypes of HGSOC. Slides were scored for intensity and localization and simple statistics were used to compare expression results in cancer vs. stroma and between primary and metastatic sites. Results: COL5A1, VCAN, FAP, and ZEB1 proteins were almost exclusively expressed by stroma as opposed to cancer cells. In addition, stromal expression was dominant for ACTA2, COL11A1, POSTN and p-SMAD2. In general there were minimal differences in expression of proteins between primary and metastatic sites, exceptions being COL5A1 (reduced in metastases) and COL11A1 (increased in metastases). Nuclear p-SMAD2 expression was more common in metastatic stroma. Conclusions: The existing molecular classification of HGSOC MES subtype reflects a significant stromal contribution, suggesting an important role in HGSOC behavior and thus stroma may be a relevant therapeutic target. Specific patterns of expression indicate that collagens and TGF-β signaling are involved in the metastatic process.

AB - Objective: Mesenchymal (MES) subtype of high-grade serous ovarian cancer (HGSOC) is associated with worse outcomes including survival and resectability compared with other molecular subtypes. Molecular subtypes have historically been derived from ‘tumor’ consisting of both cancer and stromal cells. We sought to determine the origins of multiple MES subtype gene signatures in HGSOC. Methods: Fifteen patients with MES subtype of HGSOC diagnosed between 2010 and 2013 were identified. Formalin-fixed paraffin-embedded (FFPE) blocks from primary surgery were sectioned for immunohistochemistry (IHC) staining of relevant proteins. Eight genes (ACTA2, COL5A1, COL11A1, FAP, POSTN, VCAN, ZEB1 and p-SMAD2) were selected for IHC staining based on their differential expression in MES vs. non-MES subtypes of HGSOC. Slides were scored for intensity and localization and simple statistics were used to compare expression results in cancer vs. stroma and between primary and metastatic sites. Results: COL5A1, VCAN, FAP, and ZEB1 proteins were almost exclusively expressed by stroma as opposed to cancer cells. In addition, stromal expression was dominant for ACTA2, COL11A1, POSTN and p-SMAD2. In general there were minimal differences in expression of proteins between primary and metastatic sites, exceptions being COL5A1 (reduced in metastases) and COL11A1 (increased in metastases). Nuclear p-SMAD2 expression was more common in metastatic stroma. Conclusions: The existing molecular classification of HGSOC MES subtype reflects a significant stromal contribution, suggesting an important role in HGSOC behavior and thus stroma may be a relevant therapeutic target. Specific patterns of expression indicate that collagens and TGF-β signaling are involved in the metastatic process.

KW - High-grade serous ovarian cancer (HGSOC)

KW - Mesenchymal (MES)

KW - Metastatic

KW - Primary

KW - Stroma

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U2 - 10.1016/j.ygyno.2018.11.014

DO - 10.1016/j.ygyno.2018.11.014

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JO - Gynecologic Oncology

JF - Gynecologic Oncology

SN - 0090-8258

ER -