Mechanisms, Diagnosis and Treatment of Bone Metastases

Abstract

Bone and bone marrow are among the most frequent metastatic sites of cancer. The occurrence of bone metastasis is frequently associated with a dismal disease outcome. The prevention and therapy of bone metastases is a priority in the treatment of cancer patients. However, current therapeutic options for patients with bone metastatic disease are limited in efficacy and associated with increased morbidity. Therefore, most current therapies are mainly palliative in nature. A better understanding of the underlying molecular pathways of the bone metastatic process is warranted to develop novel, well-tolerated and more successful treatments for a significant improvement of patients’ quality of life and disease outcome. In this review, we provide comparative mechanistic insights into the bone metastatic process of various solid tumors, including pediatric cancers. We also highlight current and innovative approaches to biologically targeted therapy and immunotherapy. In particular, we discuss the role of the bone marrow microenvironment in the attraction, homing, dormancy and outgrowth of metastatic tumor cells and the ensuing therapeutic implications. Multiple signaling pathways have been described to contribute to metastatic spread to the bone of specific cancer entities, with most knowledge derived from the study of breast and prostate cancer. However, it is likely that similar mechanisms are involved in different types of cancer, including multiple myeloma, primary bone sarcomas and neuroblastoma. The metastatic rate-limiting interaction of tumor cells with the various cellular and noncellular components of the bone-marrow niche provides attractive therapeutic targets, which are already partially exploited by novel promising immunotherapies.

Bone Disease in Multiple Myeloma: Biologic and Clinical Implications

“…Uncontrolled malignancies are the cause of most cancer-related mortalities [ 18 ]. Bone, specifically in the spine and ribs, is a common site for metastasis in breast, prostate, lung, kidney, and hematological cancers, which together account for around 350,000 deaths per year [ 18 ].…”

“…Bone, specifically in the spine and ribs, is a common site for metastasis in breast, prostate, lung, kidney, and hematological cancers, which together account for around 350,000 deaths per year [ 18 ]. Due to increased vascularity, abundant growth factor, and prostaglandin production, the bone marrow microenvironment is an attractive space for the colonization of tumor cells [ 18 ]. In MM specifically, bone-disease-related lesions are the second-most-prevalent CRAB feature [ 19 ].…”

Mini-Review: Can the Metastatic Cascade Be Inhibited by Targeting CD147/EMMPRIN to Prevent Tumor Recurrence?

“…This induced the JAK2/STAT6/GATA3 signaling, initiated their MET process and enhanced their colonization ( 82 ). In bone metastases, secreted pro-inflammatory cytokines including Parathyroid hormone-releasing peptide (PTHrP) stimulate osteoclasts to secrete RANK-L to promote bone degradation, and this releases dormant cells from the control of the bone microenvironment and promotes their proliferation and escape from dormancy ( 83 ). However, not all pro-inflammatory signals induce metastatic outgrowth.…”

Role of Interleukin-1 family in bone metastasis of prostate cancer

“…Pro-inflammatory cytokines and other immune agents including chemokines and selectins, as the key components of tumor microenvironment, exert a vital role in the survival, proliferation and metastasis of tumor ( 19 , 20 ). The microenvironment determines the metastatic place by supporting the formation of a pre-metastatic niche and bone colonization, metastatic dormancy and reactivation ( 21 ). The process of metastasis begins with cancer cells invading adjacent tissue and the formation of EMT.…”