Osteosarcoma is a "Differentiation Disease"

Under the direction of T.-C. He, M.D., Ph.D., Rex C. Haydon, M.D., Ph.D., and Hue H. Luu, M.D. the Molecular Oncology Laboratory has focused on the molecular aspects of bone and soft tissue tumors through collaborations with Drs. Michael A. Simon, and Anthony Montag. They previously found that b-catenin signaling is activated in approximately 70% of human osteosarcoma samples, suggesting that deregulation of b-catenin may play a role in the development of human osteosarcoma.  They examined the expression of the S100A6 in human osteosarcoma, and found that approximately 84% of the analyzed osteosarcoma specimens stained positive for S100A6.  Thus, their findings suggest that S100A6 may be associated with the pathogenesis of osteosarcoma (International Journal of Cancer 102:338-342; Clin Orthop Relat Res 466: 2060-2070, and Cancer Letters  229: 135-148).  

More recently, Drs. Haydon, Luu and He found that, while in mesenchymal stem cells BMP-2 and BMP-9 induce osteogenic differentiation, osteosarcoma cells are refractory to BMP-induced bone formation with increased cell proliferation, suggesting that blocks to normal BMP-induced differentiation must exist. Downstream targets of the osteogenic BMPs include several key inhibitors of differentiation that are commonly expressed in human tumors. They hypothesize that that osteosarcoma may represent a “disease of differentiation”, possibly caused by the defects in the terminal differentiation pathway of pre-osteoblast and/or osteoblasts (Laboratory Investigation  88:1264-1277; Clinical Orthopaedics and Related Research 466: 2114–2130; Clinical Orthopaedics and Related Research  454: 237-246; Clinical Cancer Research16; 2235–2245, Clinical Cancer Research  8: 1288-1294). They are attempting to reconstruct osteosarcoma-like cells from mesenchymal stem cells by disrupting the differentiation pathway and enhancing proliferation activity of the progenitors. Consistent with “disease of differentiation” model, generic differentiation agents, such as PPARg agonists and retinoic acids were shown to promote osteogenic differentiation and inhibit osteosarcoma tumor growth (Clinical Cancer Research 16; 2235–2245; PPAR Research 2010: 956427; PLoS ONE 5: e11917).

Drs. He, Haydon and Luu developed a novel orthotopic tumor model for osteosarcoma progression and pulmonary metastasis (Clin Exp Metastasis. 22: 319-329).  This model highlights different stages of primary bone tumor progression and the eventual development of pulmonary metastasis. They are currently using this model to investigate several genes for their role in controlling bone tumorigenesis and metastasis. Meanwhile, they have conducted gene profiling analysis of gene expression patterns between non-metastatic and highly metastatic osteosarcoma cells, and have identified several promising candidate genes associated with pulmonary metastasis of osteosarcoma. Further functional characterization of these target genes is currently ongoing (Clinical & Experimental Metastasis 26:599–610). They have recently reported that insulin-like growth factor binding protein 5 (IGFBP5) suppresses tumor growth and metastasis of human osteosarcoma (Oncogene 30(37):3907-17).

Effects of natural products and herbal extracts on cancer cells and stem cell differentiation: As natural products and herbs represent a great deal of resources for drug discovery, we have collaborated with Dr. Chun-Su Yuan of the Tang Center for Herbal Medicine Research and investigated the effect of several herbal products, such as Berberine and ginseng extracts, on cancer growth and proliferation, as well as on stem cell differentiation. Dr. He was one of the PIs on a P01 grant from the NIH to study the role of herbal products in cancer (International Journal of Oncology  32: 975-983; Oncol Rep 22: 943-952; Biol Pharm Bull  32: 1552-1558; Cancer Lett 289: 62-70; Mol Pharmacol  79(2):211-9).