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.

Keywords: EMMT; breast carcinoma metastasis; epithelial-mesenchymal-myeloid transition; giant cell tumor of bone; metastasis; osteoclast; tumor biology.

FIGURE 1

(A): Giant-cell tumor of bone showing the characteristic giant cells and mononuclear cells (H&E stain). (B): Giant-cell tumor of bone showing vascular invasion (H&E stain). (C): Metastatic breast carcinoma cells and osteoclast-like cells in bone tissue (H&E stain). (D): İntraductal polypoid growth of osteoclast-rich undifferentiated carcinoma in pancreas (H&E stain). (E, F): Cells of thyroid undifferentiated carcinoma in osteoclastic cells (phagocytosis? or fusion?).

FIGURE 2

(A): PanIN in the duct adjacent to undifferentiated carcinoma rich in osteoclasts in the pancreas (H&E stain). (B): Loss of e-cadherin in undifferentiated carcinoma in immunohistochemical study (C): Positivity of vimentin in osteoclast-rich undifferentiated carcinoma cells in immunohistochemical study (D): CD68 positivity is remarkable in osteoclastic cells and undifferentiated carcinoma cells (E): CD163 positivity is remarkable in undifferentiated carcinoma cells (F): Reactivity with CD33 in osteoclastic cells (long arrow) and tumor cells (short arrow) in pancreatic osteoclast-rich undifferentiated carcinoma.

FIGURE 3

A case of breast carcinoma metastasized to the lymph node (A–D). (A): Epithelioid cancer cells and spindle-pleomorphic cells are intertwined (H&E stain). (B): Estrogen positivity in epithelioid cells in immunohistochemical study (C): Remarkable CD33 positivity in cells with pleomorphism and atypical mitosis in immunohistochemical study (D): Remarkable CD163 positivity in pleomorphic cells, negativity in epithelioid cells (arrow) in immunohistochemical study (E): Diffuse osteoclastic cells in a case of invasive breast carcinoma (H&E stain). (F): CD33 reactivity in osteoclasts (long arrow) and cancer cells (short arrow) in immunohistochemical study.