Steps in prostate cancer progression that lead to bone metastasis

Abstract

Prostate cancer is a complex disease in which metastasis to the bone is the main cause of death. Initial stages of metastasis are generally similar to those for most solid tumors; however, the mechanisms that underlie the homing of prostate tumor cells to the bone are not completely understood. Prostate cancer bone metastasis is also a microenvironment-driven disease, involving bidirectional interactions between the tumor and the bone microenvironment. In this review, we discuss the current understanding of the biologic processes and regulatory factors involved in the metastasis of prostate cancer cells, and their specific properties that promote growth in bone. Although many of these processes still need to be fully elucidated, a better understanding of the complex tumor/microenvironment interplay is slowly leading to more effective therapies for patients with prostate cancer bone metastases.

Figure 1. Src stimulation of migration and invasion through the E-cadherin/β-catenin complex

Following engagement, activated Src phosphorylates E-cadherin/β-catenin complexes, with several results including recruitment of PI3K to this complex, activating downstream signaling pathways that lead to unbranching of actin filaments, eventual dissociation of β-catenin from the complex and functional loss of E-cadherin, all processes that promote tumor cell invasion. Src also promotes migration/invasion through focal adhesion kinase, as described in the text.

Figure 2. Homing and growth of prostate tumor cells in the bone

As described in the text, the specific mechanisms by which tumor cells home to the bone remain unknown, but are thought to occur through factors produced or expressed in both bone and tumor. Integrin β1 has been implicated in attachment of prostate cancer cells to the bone epithelium. Cadherin-11 (osteoblast-cadherin) is highly expressed in bone metastases and its knockdown decreases bone homing. Chemotactic factors such as SDF-1 released from the bone are implicated in bone homing of tumor cells. Once Tumor cells reach the bone, the classic vicious cycle occurs, whereby factors from the tumor lead to bone destruction and bone formation, and factors from the bone released in this process promote tumor growth.