High stromal hyaluronan level is associated with poor differentiation and metastasis in prostate cancer

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Abstract

Several epithelial tumours accumulate hyaluronan (HA) which promotes cancer cell invasion and metastasis. We analysed the expression of HA and its receptor CD44 and their prognostic value in 166 prostate cancer patients followed up for a mean of 13 years; standard deviation (S.D.) 2.7; range 8.7–21.4 years. HA was detected with a specific biotinylated probe prepared from cartilage aggrecan and link protein, and CD44 with an antibody recognising all forms of CD44. The peri- and intratumoral stroma from half of the patients strongly expressed immunohistochemically detectable HA in ⩽15% of the stromal area; the tumours in the remaining half expressed HA in >15% of the area. The staining of cancer cells for HA was scored positive or negative, and for CD44 the median value of 80% of positive tumour cells was used as a cut-off point. The expression of HA in cancer cells was weakly associated with perineural infiltration of the tumour (P=0.03) and high Gleason score (P=0.002). There was also a significant inverse relationship between the expression of HA and CD44 in cancer cells (P<0.001). The high level of HA in the peri-and intratumoral stroma was related to metastasis, high T-category, high Gleason score, perineural infiltration and high mitotic activity of the tumour (for all P<0.001). There was a significant inverse relationship between the expression of CD44 in cancer cells and high level of strong expression of HA in the tumour stroma (P<0.001). A low fraction of CD44-positive cells was related to a high TM-category, high Gleason score and rapid cell proliferation (for all P<0.0001; M/V P value=0.0013). In the univariate survival analysis, the high level of strong expression of HA in tumour stroma predicted an unfavourable outcome in the entire series (P=0.003) and also in the M0 tumours (P=0.07), while in T1–2 M0 tumours the prognostic value did not reach the level of statistical significance (P=0.1). A low fraction of CD44-positive cells predicted a poor outcome in the entire series (P<0.001) and also in M0 tumours (P=0.003). Cancer cell-associated HA expression had no prognostic value in any tumour categories. In the multivariate analysis of prognostic factors, HA expression in the cancer cells or in the tumour stroma had no additional value to the standard prognostic factors TM-classification, Gleason score and CD44 expression. Our results show that stromal HA accumulation is related to several malignant features and adverse clinical outcome in prostate cancer. However, further studies based on uniformly treated patient cohorts are needed to establish the clinical significance of these findings in current clinical practice.

Introduction

Prostate cancer is the most common malignancy in men in the western world. The prognostic evaluation and the decisions on treatment strategy are mainly based on the histological differentiation [1] and the extent of the tumour [2] at diagnosis. These prognostic parameters perform in an acceptable way in tumours which have progressed beyond the prostate capsule, while in local tumours these factors can not predict accurately the clinical outcome in all cases. The role of tumour supressor genes [3], cell proliferation [4], angiogenesis [5] and cell adhesion molecules [6] has been extensively studied in prostate cancer to find out new accurate prognostic tools.

Studies from several epithelial neoplasms show that the extracellular matrix polysaccharide hyaluronan (HA) [7] has a significant role in tumour progression and metastasis 8, 9, 10, 11. HA controls cell migration, differentiation and cell proliferation, which all are important in tumour growth 5, 12, 13, 14, 15. Increased HA concentrations may help invasion by providing a less dense matrix for cancer cells, stimulating cancer cell motility and forming an immunoprotective coat for cancer cells 16, 17, 18. In addition, the cell surface receptor of HA, cell determinant (CD)44, has been shown to be important in cancer cell adhesion, cell migration and tumour neovascularisation 19, 20. Alterations in CD44 expression with prognostic significance have also been shown in prostate cancer 21, 22.

Although there are many previous studies of CD44 in prostate cancer 21, 22, the content of HA, its major ligand, has received no attention. Therefore, we evaluated the expression of HA in a series of 166 cases of prostate cancer. The results of HA histochemistry were compared with standard prognostic factors, CD44 expression and prognosis during a long-term follow-up.

Section snippets

Patients

The current study comprised 166 patients with prostate cancer diagnosed and treated at the Department of Urology, Kuopio University Hospital, between 1973 and 1992. The mean observation period was 13 years standard deviation (S.D.) 2.7, range 8.7–21.4 years) and the mean age of patients at presentation was 71 years (S.D. 7, range 40–89 years). The cohort was not entirely consecutive, since sufficient tumour specimens for histochemistry were not available in all cases. Tumour-

Results

The expression of HA in the cancer cell epithelium was weakly associated with the perineural infiltration of the tumour and a high Gleason score, but inversely related to CD44 expression (Table 1). The high level of strong expression of HA in the tumour stroma was significantly related to the TM-classification, Gleason score, perineural infiltration of the tumours and high proliferation rate of the cancer cells (Table 2). There was an inverse relationship between stromal HA expression and the

Discussion

Several malignant tumours contain elevated levels of HA 8, 9, 10, 11, which may be caused by increased HA production by the tumour cells themselves or by interactions between the tumour cells and surrounding stromal cells that induce increased HA production by the latter.

Experimental analyses show that HA and HA receptors are important in tumour growth and metastasis 20, 27. The intracellular HA receptor RHAMM/IHABP interacts with microtubules and actin filaments in interphase and in dividing

Acknowledgments

This study was financially supported by a research grant (EVO funding) from the Kuopio University Hospital. The technical assistance of Mr Kari Kotikumpu, Ms Eija Rahunen and Ms Aija Parkkinen is gratefully acknowledged.

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