Oncology
The central dogma of cancer harbors a "cell of origin" tenet for oncogenesis. In sarcoma, the prescient concept is that mesodermal tissue spawns the cancers that afflict and threaten our patients. But strictly speaking, must this be the case? For certain translocation-associated sarcomas, the genesis of a molecular chimera is THE critical step in onco-initiation that might belie the importance of the host cell. Over the past decade and a half, investigators at our institution have dedicated much of their academic careers to better understanding these deadly onco-driving hybrid genetic aberrancies. From synovial and Ewing's sarcoma to now clear cell sarcoma (CCS), perhaps the nascent cell phenotypic origin is less, or certainly not solely, responsible for the development of these deadly cancers. Whether it be SS18-SSX1,2,4, EWS-ETS or EWS-ATF1 that drives sarcoma formation, might not it be the translocation itself that unbridles cancer formation as much if not more than the cell type in which the translocation arises? Prior work by several of us collaborating with Nobel Laureate Mario Capecchi demonstrated that certain cell type specific drivers could unleash the full potential of synovial sarcoma when the human derived cDNA was introduced into immunocompetent mice. ...
But perhaps it may be an even more complicated relationship. Recently, this same lab elegantly demonstrated that when EWS-ATF1 is conditionally expressed in select cell types in varying degrees of differentiation, the resulting cancer phenotype can exhibit differing degrees of CCS versus melanoma, a differential diagnosis with substantial clinical relevance. This begs the question that perhaps if the cell type of origin does have influence, then the stage of cell line differentiation when the translocation is realized matters as much in terms of cancer phenotype. Recently, our team has begun to look at mesenchymal stem cells and the influence of the degree of differentiation when EWS-Fli1 is turned on. So, moving forward, we sarcomatologists should be sensitive to the varying influence of the environment (cell type at a given stage of development/differentiation) that serves as "host" to an onco-apogee of translocation initiation. The seed/soil hypothesis resonates into the molecular era.
R. Lor Randall, MD, FACS, The LB & Olive S. Young Endowed Chair for Cancer Research, Director, Sarcoma Services & Chief, SARC Lab, Medical Director, HCI Surgical Services, Professor of Orthopaedics, Huntsman Cancer Institute & Primary Children's Medical Center, The University of Utah, USA
May 2013
