Retinoic acid induced chordomas as a model of differential therapy.

C originating from the remnants of notochord during embryogenesis, is one of the major challenging tumor types of all bone sarcomas with slow growing potential and high recurrence rate. Studies indicated that brachyury, the expressed gene in early stages of mesodermal development in cells with high potential of differentiation; is specific to almost all chordomas. Differentiation therapy is a promising method with less toxicity for tumor types originating from stem cells. we hypothesize that the differentiation therapy will be a novel technique for curing chordomas. The fight against cancer has been a major challenge for decades and scientists have been struggling to find new treatment models depending on the tumor type, its grade, and location. To date it is shown that the most common treatment methods are chemotherapy and radiotherapy, which are not real solutions for the treatment of cancer due to recurrence, metastasis, and drug resistance, supposedly caused by cancer stem cells.1 This is also true in the case of chordomas, which are rare primary tumors of bone originating from the remnants of notochordal primitive mesenchymal cells, during embryogenesis. They are traditionally considered as slow growing, and locally invasive neoplasms with little tendency to metastasize and have highly potential recurrence rate after surgery. The previous studies showed that brachyury, a significant marker expressed in early stages of mesoderm formation,2 is expressed in chordomas. It has been also demonstrated that brachyury gene plays a key role in notochord differentiation in chordates during embryonal development. It is well-known that brachyury is no longer expressed after late differentiation of mesoderm. All of these findings suggested that brachyury is the crucial factor for the differentiation of late mesodermal development. Cells expressing brachyury are more likely to differentiate into other late mesodermal lineages (for example bone, cartilage, and so forth) when induced with differentiation factors. One study reported that brachyury expression was elevated when FgFR3 was introduced as an inducer into mesenchymal stem cell line, differentiating these cells into the chondrogenic lineage successfully in vitro and in vivo transplantations.3 Our preliminary results showed that expression of brachyury and some of the transcriptional factor genes such as Oct4, Klf4, Nanog, which all are expressed in cancer stem cells and stem cells, were also expressed in chordoma cell line, UCH-1, and primary chordoma tissues. Therefore, chordoma cells have a promising potential to be the appropriate targets for the differentiation therapy owing to the expression of these markers. Differentiation therapy is a promising method that makes cancer cells continue to maturate and eventually