Osteoclasts in Tumor Biology: Metastasis and Epithelial-Mesenchymal-Myeloid Transition

Abstract

Osteoclast is a specialized cell that originates from monocytic lineage, communicates closely with osteoblasts under physiological conditions, participates in bone modeling and re-modeling, contributes to calcium homeostasis and osteoimmunity. In pathological conditions, it is involved in many tumors such as giant cell bone tumor (osteoclastoma), aneurysmal bone cyst, osteosarcoma, and metastatic cancers, and it usually causes local spread and progression of the tumor, working against the host. Since osteoclasts play an active role in primary bone tumors and bone metastases, the use of anti-osteoclastic agents significantly reduces the mortality and morbidity rates of patients by preventing the progression and local spread of tumors. Osteoclasts also accompany undifferentiated carcinomas of many organs, especially pancreas, thyroid, bladder and ovary. Undifferentiated carcinomas rich in osteoclasts have osteoclastoma-like histology. In these organs, osteoclastoma-like histology may accompany epithelial carcinomas, and de novo, benign and borderline tumors. Mature and immature myeloid cells, including osteoclasts, play an active role in the tumor progression in primary and metastatic tumor microenvironment, in epithelial-mesenchymal transition (EMT), mesenchymal-epithelial-transition (MET), and cancer stem cell formation. Additionally, they are the most suitable candidates for cancer cells in cell fusion due to their evolutionary fusion capabilities. Myeloid features and markers (CD163, CD33, CD68 etc.) can be seen in metastatic cancer cells. Consequently, they provide metastatic cancer cells with motility, margination, transmigration, chemotaxis, phagocytosis, angiogenesis, matrix degradation, and resistance to chemotherapy. For these reasons, we think that the concept of Epithelial-Mesencyhmal-Myeloid-Transition (EMMT) will be more accurate than EMT for cancer cells with myeloid properties.

Clinicopathological value of the upregulation of cyclin-dependent kinases regulatory subunit 2 in osteosarcoma

“…Therefore, including CKS2 in the diagnosis of OS will increase the chance of patients receiving effective diagnosis and treatment. Secondly, the high incidence of hematogenous metastasis and rapid progress of OS seriously threatened the lives of patients [ 32 ]. Therefore, it is urgent to find molecular markers that can reliably reflect the risk of metastasis in OS patients.…”

Characterization of osteosarcoma subtypes mediated by macrophage-related genes and creation and validation of a risk score system to quantitatively assess the prognosis of osteosarcoma and reflect the tumor microenvironment

“…Monocytes, macrophages are specialized phagocytes ( 25 ). Anti-osteoclast drugs have been reported to significantly reduce patient mortality and morbidity by preventing tumor progression and local spread ( 26 ). Macrophages represent the main immune components in the microenvironment of osteosarcoma, and the therapy focused on targeting TAM has become a hot topic of immunotherapy ( 13 ).…”

The dynamic microenvironment associated with metastatic bone disease: Current concepts

“…Unregulated osteoclastic activity then results in lytic bone lesions with weakened biomechanical strength. The clinical sequelae elicit an increased risk of fracture with even physiologic loads at the sites of disease in bone 28 . In contrast to the formation of lytic lesions, pancreatic carcinoma bone metastases and sometimes breast carcinoma metastases are associated with the development of blastic bone lesions.…”

“…The clinical sequelae elicit an increased risk of fracture with even physiologic loads at the sites of disease in bone. 28 In contrast to T A B L E 1 Average 5-year survival estimates after diagnosis of metastatic disease by primary cancer type. 8 Primary cancer type 5-year survival (%) F I G U R E 1 Outline of key anatomical and physiological functions of bones along the pathway of metastatic mechanisms of cancer cells that lead to metastatic bone disease.…”