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 emphasis is placed on the crucial role of the bone micro-environment, especially the intercellular interactions of metastatic prostate cancer cells and osteoblasts in promoting the establishment of hormone refractory disease. Resistance of tumour cells to anticancer therapies is generally viewed as a phenomenon almost exclusively determined by chromosomal defects and/or gene mutations. However, it is now well-documented that the local milieu of the bone 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 factors, such as insulin-like growth factor (IGF-1). The molecular pathways whereby this major growth and survival factor for prostate cancer cells exerts its anti-apoptotic effect on prostate cancer cells are discussed.
Mitsiades
C S
CS
Department of Experimental Physiology, Medical School, University of Athens, 75 Micras Asias, Goudi 11527, Athens, Greece.
Koutsilieris
M
M
D000726:Androgen Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D059002:Androgen Receptor Antagonists; D000728:Androgens / Q000378:metabolism*; D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000728:Androgens; D011944:Receptors, Androgen; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1