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Open Access Highly Accessed Research article

Protein markers of cancer-associated fibroblasts and tumor-initiating cells reveal subpopulations in freshly isolated ovarian cancer ascites

My Wintzell1, Elisabet Hjerpe2, Elisabeth Åvall Lundqvist2 and Maria Shoshan1*

Author affiliations

1 Department of Oncology-Pathology, Cancer Center Karolinska CCK R8:03 Karolinska Institutet, Stockholm, S-171 76, Sweden

2 Department of Gynecologic Oncology, Karolinska University Hospital, Stockholm, S-171 76, Sweden

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Citation and License

BMC Cancer 2012, 12:359  doi:10.1186/1471-2407-12-359

Published: 18 August 2012

Abstract

Background

In ovarian cancer, massive intraperitoneal dissemination is due to exfoliated tumor cells in ascites. Tumor-initiating cells (TICs or cancer stem cells) and cells showing epithelial-mesenchymal-transition (EMT) are particularly implicated. Spontaneous spherical cell aggregates are sometimes observed, but although similar to those formed by TICs in vitro, their significance is unclear.

Methods

Cells freshly isolated from malignant ascites were separated into sphere samples (S-type samples, n=9) and monolayer-forming single-cell suspensions (M-type, n=18). Using western blot, these were then compared for expression of protein markers of EMT, TIC, and of cancer-associated fibroblasts (CAFs).

Results

S-type cells differed significantly from M-type by expressing high levels of E-cadherin and no or little vimentin, integrin-β3 or stem cell transcription factor Oct-4A. By contrast, M-type samples were enriched for CD44, Oct-4A and for CAF markers. Independently of M- and S-type, there was a strong correlation between TIC markers Nanog and EpCAM. The CAF marker α-SMA correlated with clinical stage IV. This is the first report on CAF markers in malignant ascites and on SUMOylation of Oct-4A in ovarian cancer.

Conclusions

In addition to demonstrating potentially high levels of TICs in ascites, the results suggest that the S-type population is the less tumorigenic one. Nanoghigh/EpCAMhigh samples represent a TIC subset which may be either M- or S-type, and which is separate from the CD44high/Oct-4Ahigh subset observed only in M-type samples. This demonstrates a heterogeneity in TIC populations in vivo which has practical implications for TIC isolation based on cell sorting. The biological heterogeneity will need to be addressed in future therapeutical strategies.

Keywords:
Ovarian carcinoma; Dissemination ascites; Cancer-associated fibroblasts; Tumor-initiating cells; EMT