Osteocytes: New Kids on the Block for Cancer in Bone Therapy

Abstract

The tumor microenvironment plays a central role in the onset and progression of cancer in the bone. Cancer cells, either from tumors originating in the bone or from metastatic cancer cells from other body systems, are located in specialized niches where they interact with different cells of the bone marrow. These interactions transform the bone into an ideal niche for cancer cell migration, proliferation, and survival and cause an imbalance in bone homeostasis that severely affects the integrity of the skeleton. During the last decade, preclinical studies have identified new cellular mechanisms responsible for the dependency between cancer cells and bone cells. In this review, we focus on osteocytes, long-lived cells residing in the mineral matrix that have recently been identified as key players in the spread of cancer in bone. We highlight the most recent discoveries on how osteocytes support tumor growth and promote bone disease. Additionally, we discuss how the reciprocal crosstalk between osteocytes and cancer cells provides the opportunity to develop new therapeutic strategies to treat cancer in the bone.

Bridging the Gap in Understanding Bone Metastasis: A Multifaceted Perspective

“…A study was conducted to investigate the impact of mechanically stimulated osteocytes on the migratory and epithelial–mesenchymal transition (EMT) characteristics of breast cancer cells. However, the findings of this study have been conflicting [ 122 ]. In several reports, certain factors released by stimulated osteocytes, specifically CXCL1 and CXCL2 cytokines, have been found to enhance the migration of cancer cells [ 123 ].…”

Role of the osteocyte in bone metastasis – The importance of networking

“…Understanding the complexities of osteocyte-cancer cell interactions opens avenues for developing targeted therapies to disrupt this relationship and inhibit bone metastasis. Various additional therapeutic approaches to those mentioned here, including targeting specific signalling pathways, immune modulation, and bone-targeted therapies, have been explored elsewhere [1] , [5] , [6] . Additionally, a number of recent studies have suggested that many of the findings elucidated through mechanical loading studies discussed in Section 3 , e.g.…”

“…Long neglected in the field of bone oncology, recent endeavours by researchers have demonstrated multiple crosstalk mechanisms through which they may regulate the tumour microenvironment. A number of excellent reviews of have delved into the detail of the osteocyte’s interactions in the microenvironment of various metastatic cancers affecting bone [5] , [6] , as well as its potential role in the cellular origins of osteosarcoma [1] . These in-depth reviews are listed for further reading in Table 1 , alongside a number of other articles that explain what is known about the vicious cycle [1] , [5] , [6] , [7] , osteocyte biology and mechanobiology [2] , [3] , [4] , the role of osteoblasts and osteoclasts in metastasis [8] , [9] , [10] , [11] , and the bone remodelling cycle [12] .…”

“…A number of excellent reviews of have delved into the detail of the osteocyte’s interactions in the microenvironment of various metastatic cancers affecting bone [5] , [6] , as well as its potential role in the cellular origins of osteosarcoma [1] . These in-depth reviews are listed for further reading in Table 1 , alongside a number of other articles that explain what is known about the vicious cycle [1] , [5] , [6] , [7] , osteocyte biology and mechanobiology [2] , [3] , [4] , the role of osteoblasts and osteoclasts in metastasis [8] , [9] , [10] , [11] , and the bone remodelling cycle [12] . This perspective instead shines a spotlight on key recent findings in the last 5 years that underline emerging role of the osteocyte as the central cell in a complex network of signalling crosstalk in the metastatic microenvironment.…”

Decoding the Impact of Tumor Microenvironment in Osteosarcoma Progression and Metastasis

“…Osteocytes communicate with OS cells by secreting several soluble factors, including GDF15, TGFβ, CXCL1/2, and VEGFA, as well as through physical interactions (e.g., NOTCH3 signaling). Osteocytes also produce RANKL, CSF1, HMGB1, and IL-11 to stimulate osteoclastogenesis and bone resorption [45]. Osteocytes activate the CXCL12-CXCR4 signaling axis in OS by producing CXCL12, favoring tumor metastasis.…”