Osteosarcoma development and stem cell differentiation

Abstract

Osteosarcoma is the most common nonhematologic malignancy of bone in children and adults. The peak incidence occurs in the second decade of life, with a smaller peak after age 50. Osteosarcoma typically arises around the growth plate of long bones. Most osteosarcoma tumors are of high grade and tend to develop pulmonary metastases. Despite clinical improvements, patients with metastatic or recurrent diseases have a poor prognosis. Here, we reviewed the current understanding of human osteosarcoma, with an emphasis on potential links between defective osteogenic differentiation and bone tumorigenesis. Existing data indicate osteosarcoma tumors display a broad range of genetic and molecular alterations, including the gains, losses, or arrangements of chromosomal regions, inactivation of tumor suppressor genes, and the deregulation of major signaling pathways. However, except for p53 and/or RB mutations, most alterations are not constantly detected in the majority of osteosarcoma tumors. With a rapid expansion of our knowledge about stem cell biology, emerging evidence suggests osteosarcoma should be regarded as a differentiation disease caused by genetic and epigenetic changes that interrupt osteoblast differentiation from mesenchymal stem cells. Understanding the molecular pathogenesis of human osteosarcoma could ultimately lead to the development of diagnostic and prognostic markers, as well as targeted therapeutics for osteosarcoma patients.

Fig. 1A–B

(A) Osteogenic differentiation is a well-coordinated process. Mesenchymal stem cells (MSCs) can give rise to several lineages, such as myocytes, adipocytes, chondrocytes, and osteocytes, with appropriate stimuli, presumably by activating proper lineage-specific regulators, eg, MyoD, PPARγ, Sox9, or Runx2/Osterix. Osteogenic differentiation is a tightly controlled process, which can be monitored by using alkaline phosphatase as an early marker and osteocalcin and osteopontin as late markers. (B) Disruption of osteogenic differentiation may lead to OS development. The defects caused by genetic (eg, activation of oncogenes or inactivation of p53 and RB tumor suppressor genes) and epigenetic alterations may occur at different stages of osteogenic differentiation. It is conceivable defects at the early stages may lead to the development of more aggressive and undifferentiated OS, or vice versa. The cells filled with black color indicate cancer-initiating cells.