International Congress on Hormonal Steroids and Hormones and Cancer Endocrine/paracrine/autocrine survival factor activity of bone microenvironment participates in the development of androgen ablation and chemotherapy refractoriness of prostate cancer metastasis in skeleton

Bone is the most frequent site of metastases of prostate cancer andis almost always the first and frequently the only site of metastases where disease will progress to stage D3. In addition, the number of skeletal metastatic foci is the most powerful independent prognostic factor of limited response to hormone ablation therapy andpoor survival of patients with ad vancedprostate cancer. Furthermore, disease progression frequently occurs in the osteoblastic metastases, even though androgen ablation therapy still provides adequate and sustained control of disease at the primary site. Notably, the management of metastatic disease onto bones has traditionally relied on therapeutic modalities, which almost exclusively aim at directly inducing cancer cell death. However, accumulating pieces of evidence, from both the clinical and the basic research front, point to major limitations of this conventional approach. The in vivo response of malignant cells to anticancer therapies is directly influenced by the local microenvironment in which they metastasize. In particular, organ sites frequently involvedin metastatic d iseases, such as the bones, appear to confer to metastatic cells protection from anticancer drug-induced apoptosis. This protection is mediated by soluble growth factors andcytokines releasedby the normal cellular constituents of the host tissue microenvironment. The characterization of bone microenvironment-relatedsurvival factors has ledto the development of a novel hormone manipulation which can re-introduce clinical responses in patients with stage D3 prostate cancer. Endocrine-Related Cancer (2003) 10 279–289