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Prostate cancer is one of the most frequent malignancies and the second-leading cause of cancer mortality in males in Western countries. Although prostate cancer is often an indolent disease, 25-30% of the tumours behave aggressively resulting in poor prognosis and eventually in the death of the patients. The present stage of knowledge often does not permit a decision which tumour, when diagnosed, will proceed to an aggressive cancer, and there is an urgent need to better understand the biology and biochemistry of prostate cancer in order to establish new prognostic markers on the one hand and to detect cellular functions suitable for therapeutic interference on the other hand.

IGF axis proteins

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Disruptions in the balance of the insulin-like growth factor (IGF) axis, that is the ligands IGF-I and IGF-II, six IGF-binding proteins, type I and type II IGF receptors, and downstream signaling proteins, have been attributed a critical role in the establishment and maintenance of the transformed phenotype in prostate cancer.

IGF-I receptor, IRS-1, Akt/PKB, and the two ligands IGF-I and IGF-II, but not the inhibitory IGF-binding protein-3 (IGFBP3), were significantly upregulated in epithelial prostate cancer cells compared to benign tissue. These observations suggest a misbalance in free and bound IGFs in favour of free IGFs, and enhanced IGF signaling in prostate cancer. Further, a strong correlation of IGF-I, IGF-II and IRS-1 expression with tumor progression is observed. This suggests both significant alterations in the IGF system as prostate cancer develops, and the association of high levels of growth stimulating components of the IGF system with the malignant phenotype and with more aggressive tumor behavior.

S100A8/A9 proteins

The calcium-modulated proteins S100A8 (calgranulin A) and S100A9 (calgranulin B), that act as heterodimer under physiological conditions, were expressed at high levels in primary prostate cancer, preferentially in high-grade adenocarcinomas, whereas benign tissue was negative or showed only weak expression. Expression was particularly strong in tumor areas close to the invaded stroma of the prostate suggesting a role in tumor invasion.
S100A8 and S100A9 co-localized with the receptor for advanced glycation end products (RAGE) which has been suggested as S100 receptor.

Preliminary analysis of S100A8 and S100A9 function revealed activation of the MAP kinase and NFkappaB pathways by the two proteins, pathways that are also activated by RAGE. Furthermore, the two proteins stimulated migration of epithelial prostate cells in vitro.

S100A9 serum levels are similar in healthy men and in patients with benign prostatic hyperplasia (BPH). Levels were significantly higher in cancer patients. The results suggest that S100A9 may be a useful serum marker to discriminate between BPH and tumor in patients who display PSA levels <10 ng/ml. This finding could become of clinical relevance.