Theories

Theories about the origins of osteosarcoma (OS), the most common primary bone tumor, focus on its genetic, cellular, and environmental aspects. Here is a summary of key insights from research:

Evidence:

• Mesenchymal Stem Cells (MSCs) as Origin:
  • OS is believed to arise from mesenchymal stem cells (MSCs), which undergo aneuploidization and genetic mutations, such as loss of CDKN2A/p16, leading to malignancy (Mohseny et al., 2009).
  • Experimental models demonstrate that transformations of MSCs by genetic modifications like Rb silencing and c-Myc overexpression can induce OS-like tumors (Wang et al., 2016).
• Cancer Stem Cells and Differentiation:
  • OS is characterized by cancer stem cell (CSC) populations that may originate from normal cells in the osteogenic lineage acquiring cancer-promoting mutations (Abarrategi et al., 2016).
  • Epigenetic disruptions, such as DNA methylation and histone modifications, also contribute to the transformation of normal osteoblasts into malignant cells (Veríssimo de Azevedo et al., 2019).

• Genetic Mutations and Syndromic Associations:
  • Specific genetic mutations, such as alterations in TP53, RB, and other tumor suppressor genes, are implicated in OS pathogenesis. Germline mutations associated with syndromes like Li-Fraumeni and retinoblastoma also predispose individuals to OS (Czarnecka et al., 2020).
• Role of Osteoblasts and Osteocytes:
  • Osteoblasts, derived from MSCs, and osteocytes, terminally differentiated osteoblasts, are proposed as potential progenitor cells of OS. Tumor growth from osteocytes in experimental models provides evidence for this theory (Sottnik et al., 2014).
• Environmental and Developmental Influences:
  • OS frequently occurs during periods of rapid bone growth, suggesting environmental and developmental factors like cellular turnover and hormonal influences may contribute (Lindsey et al., 2016).

Conclusion:

Osteosarcoma is thought to originate from mesenchymal stem cells or osteogenic lineage cells through genetic mutations, epigenetic dysregulation, and influences of rapid bone development. These findings provide a framework for understanding its pathogenesis and targeting its origins for therapeutic interventions.