Abstract
Malignant mesothelioma (MM) is an aggressive serosal tumor associated with asbestos exposure. We previously demonstrated that mesothelial cells differentiate into cells of different mesenchymal lineages and hypothesize that osseous tissue observed in a subset of MM patients is due to local differentiation of MM cells. In this study, the capacity of human and mouse MM cells to differentiate into osteoblast-like cells was determined in vitro using a functional model of bone nodule formation and in vivo using an established model of MM. Human and murine MM cell lines cultured in osteogenic medium expressed alkaline phosphatase and formed mineralized bone-like nodules. Several human and mouse MM cell lines also expressed a number of osteoblast phenotype markers, including runt-related transcription factor 2 (RUNX2), osteopontin, osteonectin and bone sialoprotein mRNA and protein. Histological analysis of murine MM tumors identified areas of ossification within the tumor, similar to those observed in human MM biopsies. These data demonstrate the ability of MM to differentiate into another mesenchymal cell type and suggest that MM cells may contribute to the formation of the heterologous elements observed in MM tumors.
Highlights
Malignant mesothelioma (MM) is a rare but aggressive primary tumor of the serosa associated with past exposure to asbestos[1]
Higher magnification showed that the spindle shaped cells located within the osteoid area had morphological malignant characteristics that closely resembled cells in the adjacent sarcomatoid mesothelioma tissue (Fig. 1b), supporting the notion that these cells originate from a common precursor
We have previously demonstrated that normal mesothelial cells can differentiate to an osteogenic phenotype[4] and hypothesize that all cells of mesothelial origin, including MM, are responsible for the observed osseous differentiation and mineralized bone formation in MM tumors
Summary
Malignant mesothelioma (MM) is a rare but aggressive primary tumor of the serosa associated with past exposure to asbestos[1]. It has been proposed that the mesenchymal components (osseous and cartilaginous) and the variability of the histological subtypes of MM are due to the capacity of mesothelial-derived cells to differentiate into multiple cell lineages of the embryonic mesoderm (termed multipotent)[7]. In the early 19th century, Durante and Conheim presented the embryonal rest theory of cancer, which stated that remnants of embryonic tissue remain in adult organs and that a change in the surrounding environment would allow the embryonic tissue to proliferate and produce masses of cells that resemble fetal tissues[8]. This is known as the stem cell theory of cancer. Given the evidence of osteoid elements within MM biopsy samples, we hypothesize that MM cells have plasticity and are capable of differentiating into osteoblast-like cells and may be responsible for the elements of differentiated bone tissue observed in a subset of MM patients
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