Molecular biology and cellular physiology of refractoriness to androgen ablation therapy in advanced prostate cancer

We review the extensive body of data on the molecular aetiology of hormone refractory disease in metastatic prostate cancer patients. Particular empha sis is placed on the crucial role of the bone micro-environment, especially the intercellular interactions of metastatic prostate cancer cells and ost eoblasts in promoting the establishment of hormone refractory disease. Resi stance of tumour cells to anticancer therapies is generally viewed as a phe nomenon almost exclusively determined by chromosomal defects and/or gene mu tations. However, it is now well-documented that the local milieu of the bo ne metastases can also protect tumour cells from anticancer therapy-induced apoptosis, either independently or synergistically with resistance-related genetic alterations. A key determinant of this protection is the urokinase /plasmin cascade which modulates the local concentration of survival factor s, such as insulin-like growth factor (IGF-1). The molecular pathways where by this major growth and survival factor for prostate cancer cells exerts i ts anti-apoptotic effect on prostate cancer cells are discussed.