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Immunohistochemical Level of Unsulfated Chondroitin Disaccharides in the Cancer Stroma Is an Independent Predictor of Prostate Cancer Relapse

¹ Discipline of Obstetrics and Gynecology, Research Centre for Reproductive Health, University of Adelaide; ² Dame Roma Mitchell Cancer Research Laboratories, Hanson Institute, University of Adelaide; ³ Matrix Biology Unit, Department of Genetic Medicine, Children, Youth and Women's Health Service; ⁴ Paediatrics Department, University of Adelaide; ⁵ Department of Pathology, University of Adelaide; ⁶ Adelaide Pathology Partners, Mile End, South Australia, Australia; ⁷ Cancer Research Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia; ⁸ Department of Tissue Pathology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, New South Wales, Australia; ⁹ Sydney Cancer Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia; ¹⁰ Department of Urology, St Vincent's Hospital, Darlinghurst, New South Wales, Australia; and ¹¹ Surgical and Specialty Services, Royal Adelaide Hospital, Adelaide, South Australia, Australia

Requests for reprints: Carmela Ricciardelli, Discipline of Obstetrics and Gynaecology, University of Adelaide, Frome Road, Adelaide, SA 5005, Australia. Phone: 61-8-8303-8255; Fax: 61-8-8303-4099. E-mail: carmela.ricciardelli{at}adelaide.edu.au

The glycosaminoglycan chondroitin sulfate is significantly increased in the peritumoral stroma of prostate tumors compared with normal stroma and is an independent predictor of prostate-specific antigen (PSA) relapse following radical prostatectomy. In this study, we determined whether specific alterations in the sulfation pattern of glycosaminoglycan chains in clinically organ-confined prostate cancer are associated with PSA relapse. Immunoreactivity to distinct glycosaminoglycan disaccharide epitopes was assessed by manually scoring the staining intensity in prostate tissues from patients with benign prostatic hyperplasia (n = 19), early-stage cancer (cohort 1, n = 55 and cohort 2, n = 275), and advanced-stage cancer (n = 20). Alterations to glycosaminoglycans in benign and malignant prostate tissues were determined by cellulose acetate chromatography and high-pressure liquid chromatography. Glycosaminoglycan disaccharide epitopes were localized to the peritumoral stroma of clinically localized prostate cancer. The level of immunostaining for unsulfated disaccharides (C0S) in the peritumoral stroma, but not for 4-sulfated (C4S) or 6-sulfated disaccharides (C6S), was significantly associated with the rate of PSA relapse following radical prostatectomy. High levels of C0S immunostaining were determined to be an independent predictor of PSA relapse (1.6-fold, P = 0.020). Advanced-stage prostate cancer tissues exhibited reduced electrophoretic mobility for chondroitin sulfate and increased unsulfated disaccharides when compared with benign prostatic hyperplasia tissues, whereas the sulfated disaccharide levels were unaffected. The level of C0S immunostaining in the peritumoral stroma is an independent determinant of PSA failure in clinically localized prostate cancer. Specific alterations to chondroitin sulfate side chains occurring during tumor development may be a crucial step for disease progression in prostate cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2488–97)