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Changes in the Extracellular Matrix Are Associated With the Development of Serous Tubal Intraepithelial Carcinoma Into High-Grade Serous Carcinoma
  1. Sophieke C.H.A. van der Steen, MD*,,
  2. Johan Bulten, MD, PhD,
  3. Koen K. Van de Vijver, MD, PhD§,
  4. Toin H. van Kuppevelt, PhD and
  5. Leon F.A.G. Massuger, MD, PhD*
  1. * Department of Obstetrics and Gynaecology, Radboud University Medical Center;
  2. Department of Biochemistry, Radboud Institute for Molecular Life Sciences;
  3. Department of Pathology, Radboud University Medical Center, Nijmegen; and
  4. § Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
  1. Address correspondence and reprint requests to Sophieke C.H.A. van der Steen, MD, Department of Obstetrics and Gynaecology, Post 791, Radboud University Medical Center, Nijmegen, the Netherlands, PO Box 9101, 6500 HB Nijmegen, the Netherlands. E-mail: Sophieke.vandersteen{at}


Objective The identification of a marker for early progression of preinvasive lesions into invasive pelvic high-grade serous carcinoma (HGSC) may provide novel handles for innovative screening and prevention strategies. The interplay between cancer cells and the extracellular matrix (ECM) is one of the main principles in cancer development and growth, but has been largely neglected in preinvasive lesions. This is the first study addressing the involvement of the ECM in the “step-by-step” transition of normal fallopian tube epithelium into preinvasive lesions, and eventually the progression of preinvasive lesions into invasive HGSC.

Methods The expression of highly sulfated chondroitin sulfate (CS-E), a characteristic glycosaminoglycan of the cancer-associated ECM, was assessed by immunohistochemistry in a large cohort of precursor lesions of the full spectrum of HGSC development, including 97 serous tubal intraepithelial carcinomas (STICs), 27 serous tubal intraepithelial lesions, and 24 p53 signatures. In addition, the immunological reactivity in the microenvironment was evaluated.

Results Increased stromal expression of highly sulfated CS-E was observed in 3.7%, 57.7%, and 90.6% of serous tubal intraepithelial lesions, STICs, and invasive HGSCs, respectively (P < 0.001). No or limited expression was found in p53 signatures and normal tubal epithelium (compared with STIC, P < 0.001). A gradual increase in the amount of CS-E expression between STIC and paired HGSC was demonstrated. Intense stromal CS-E expression in STIC was significantly associated with an immune infiltrate (P < 0.001).

Conclusions Our study showed that increased stromal CS-E expression is related to the degree of the tubal epithelium abnormality. Specific alterations in the ECM (ie, CS-E expression) occur early in pelvic HGSC development and may represent a novel biomarker of early cancer progression, useful for the identification of novel clinical strategies.

  • Glycosaminoglycan
  • Chondroitin sulfate
  • Serous tubal intraepithelial carcinoma
  • Ovarian cancer
  • Biomarker

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  • The authors declare no conflicts of interest.