Genetically transforming human osteoblasts to sarcoma: development of an osteosarcoma model
Yi Yang1,6, Rui Yang2, Michael Roth1, Sajida Piperdi1, Wendong Zhang1, Howard Dorfman2,3, Pulivarthi Rao4, Amy Park1, Sandeep Tripathi1, Carrie Freeman1, Yunjia Zhang1, Rebecca Sowers1, Jeremy Rosenblum1, David Geller2, Bang Hoang2, Jonathan Gill1, and Richard Gorlick1,5,7
1 Department of Pediatrics, Children’s Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA
2 Department of Orthopaedic Surgery, Albert Einstein College of Medicine of Yeshiva University and Montefiore Medical Center, Bronx, NY, USA
3 Department of Pathology, Albert Einstein College of Medicine of Yeshiva University and Montefiore Medical Center, Bronx, NY, USA
4 Department of Pediatrics, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX, USA
5 Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
6 Current affiliations: Department of Orthopaedic Surgery, Musculoskeletal Tumor Center, People’s Hospital, Peking University, Beijing, China
7 Current affiliations: Pediatrics Administration, The University of Texas MD Anderson Cancer Center, Children’s Cancer Hospital, Houston, TX, USA
Correspondence:
Richard Gorlick, email:
Keywords: osteosarcoma, mesenchymal stem cells, osteoblast
Received: October 27, 2016 Accepted: February 25, 2016 Published: March 02, 2017
Abstract
Osteosarcoma is the most common primary malignant bone tumor in children and young adults. Although histologically defined by the presence of malignant osteoid, the tumor possesses lineage multipotency suggesting it could be derived from a cell anywhere on the differentiation pathway between a mesenchymal stem cell (MSC) and a mature osteoblast. To determine if preosteoblasts (pOB) could be the cell of origin differentiated MSCs were transformed with defined genetic elements. MSCs and pOB differentiated from the same MSCs were serially transformed with the oncogenes hTERT, SV40 large T antigen and H-Ras. Assays were performed to determine their tumorigenic properties, differentiation capacity and histologic appearance. When subcutaneously implanted in immunocompromised mice, cell lines derived from transformed MSC and pOB formed tumors in 4 weeks. In contrast to the transformed MSC, the pOB tumors demonstrated a histological appearance characteristic of osteosarcoma. The cell lines derived from the transformed pOB only had osteogenic and chondrogenic differentiation potential, but not adipogenic ones. However, the transformed MSC cells and standard osteosarcoma cell lines maintained their tri-lineage differentiation capacity. The inability of the transformed pOB cell line to undergo adipogenic differentiation, may suggest that osteosarcoma is derived from a cell intermediate in differentiation between an MSC and a pOB, with partial commitment to the osteoblastic lineage.
