Bone Metastasis Microenvironment Participates in the Development of Androgen Ablation Refractoriness and Chemotherapy Resistance of Prostate Cancer Cells Residing in the Skeleton: Clinical Implications

The development of resistance to anti-cancer therapies is a major hurdle preventing long-lasting clinical responses to conventional or investigational therapies in hormone refractory prostate cancer. Herein, we analyze the molecular evidence which show that bone metastasis microenvironment survival factors, mainly paracrine, growth hormone (GH)-independent, urokinase-type plasminogen activator (uPA)-mediated production of insulin-like growth factor 1 (IGF-1) and endocrine, GH-dependent production of IGF-1 (mainly liver-derived IGF-1), produce an epigenetic form of cancer cells resistance to pro-apoptotic therapies. In addition, we review the conceptual framework of a novel hormone manipulation for hormone refractory metastatic prostate cancer (combination of dexamethasone and somatostatin analog (SM-A)), which yielded durable objective responses and major improvement of bone pain and performance status in stage D3 prostate cancer patients.