The role of tumor microenvironment in prostate cancer bone metastasis

Abstract

Prostate cancer (PCa) epithelial cells require a number of factors to facilitate their establishment and growth at a distant site of metastasis. Their ability to adapt to their microenvironment, proliferate and recruit an underlying stroma is integral to the survival and growth of the metastasis. PCa predominantly metastasizes to the bone, and bone metastases are the main cause of morbidity. The bone marrow provides a permissive environment for the formation of a metastasis. In some cases, the cells may remain dormant for some time, eventually proliferating in response to an unknown "trigger." The marrow is rich in progenitor cells that differentiate into numerous cell types, producing new blood vessels, supporting fibroblasts, and an underlying extracellular matrix (ECM) that form the reactive stroma. By secreting a number of cytokines, growth factors and proteases they recruit auxiliary cells required to produce a functional stroma. These components are involved in a reciprocal interaction between the stroma and the PCa cells, allowing for the growth and survival of the tumor. Left unchecked, once a PCa tumor has established itself in the bone marrow it will eventually replace the marrow, interrupting bone homeostasis and typically promoting an osteoblastic response in the bone including osteoclastic events. The abundant deposition of new woven bone results in nerve compression, bone pain and an increase in fractures in patients with PCa bone metastases. This review will examine the tumor microenvironment, its role in facilitating tumor dissemination, growth and the resultant pathologies associated with PCa bone metastasis.

Presence of prostate cells in bone marrow biopsies as a sign of micrometastasis in cancer patients

“…Conversely, patients with negative bone marrow aspirate may have cancer cells attached to the endosteal surface that later may develop into metastasis. This may explain in part the lack of correlation between positive aspirates and prognosis in some studies (16,17). Results of this study are consistent with this theory.…”

Frequent Gene Products and Molecular Pathways Altered in Prostate Cancer- and Metastasis-Initiating Cells and Their Progenies and Novel Promising Multitargeted Therapies

“…Numerous gene expression profiling analyses have allowed researchers to identify specific molecular signatures that may be associated with a high potential of PC cells detected at primary tumors to undergo metastatic spread and establish their homing at specific distant tissues as well as the molecular changes that may occur at the predestinated metastatic sites (23,153,154). In particular, a loss of PTEN, p53 and breast cancer type 1 (BRCA1) combined with an upregulation of EGFR, hedgehog, TGF-β/TGF-βR receptor, ECM components/integrins and SDF-1/ CXCR4 and downstream effectors such as PI3K/Akt, small GTPase Rac-1, mitogenactivated protein kinases, NF-κB, MIC-1 and Rho are often detected in metastatic PC cells (11,135,153,(155)(156)(157)(158)(159)(160)(161)(162)(163)(164)(165)(166). It has also been shown that the migration and engraftment of metastatic PC cells in bones, the most common site of PC metastasis, as well as other distant tissues may be mediated in part through the formation of chemoattractant gradients such as SDF-1 released by host endothelial cells and fibroblasts at distant tissues that specifically attract the metastatic PC cells overexpressing CXCR4 (Figure 1) (23,122,(167)(168)(169).…”

Nuclear androgen receptor staining in bone metastases is related to a poor outcome in prostate cancer patients

“…This therapy initially reduces symptoms and metastases growth, but after some time, the metastases relapse to castration-resistant growth (Denmeade & Isaacs 2002). The mechanisms regulating growth of PC bone metastases as well as the mechanisms behind the early treatment response and the later relapse in androgen ablated patients are not fully established (Chen et al 2004, Morrissey & Vessella 2007, Wikstrom et al 2009, Bonkhoff & Berges 2010. Notably, most of our current knowledge about PC is based on studies of primary tumours or soft tissue metastases, and not on studies of bone metastases.…”