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    Contents lists available at ScienceDirect
    Gynecologic Oncology
    Cancer-associated stroma significantly contributes to the mesenchymal subtype signature of serous ovarian cancer
    Qing Zhang a, Chen Wang b, William A. Cliby a,
    a Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN 55905, USA
    b Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
    • Stroma significantly contributes to the molecular classification of MES subtype of HGSOC.
    • Collagen expression is associated with metastases of MES subtype of HGSOC but with different roles.
    • Activated TGF-β signaling is associated with metastases of MES subtype of HGSOC.
    Article history:
    High-grade serous ovarian cancer (HGSOC)
    Mesenchymal (MES)
    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 immunohistochemis-try (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 contri-bution, 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.
    1. Introduction
    In the United States high-grade serous ovarian cancer (HGSOC) ac-counts for 70% of ovarian cancer cases, most of these are advanced stages [1]. Typical first-line treatment includes cytoreductive surgery followed by chemotherapy. The majority of patients experience recur-rence and the 5-year survival rate is b50% illustrating the need for novel therapies [1,2].
    Corresponding author.
    E-mail address: [email protected] (W.A. Cliby).
    Molecular subtypes of HGSOC have been defined by using tumor mRNA profiling to classify, and hopefully better understand, the biologic basis of tumor behavior [3–5]. Such developments should lead to more personalized therapeutic strategies instead of a ‘one size fits all’ approach. Tothill et al. initially clustered high-grade serous and endometrioid OC samples into 4 molecular subtypes: C1, C2, C4, and C5 [3]. The 4 molecular subtypes were subsequently validated by The Cancer Genome Atlas (TCGA) network and termed: mesenchymal (MES), immunoreactive (IMM), differentiated (DIF), and proliferative (PRO) subtypes L-α-Hydroxyglutaric Acid [4].