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Open AccessArticle

SOX2 Expression and Transcriptional Activity Identifies a Subpopulation of Cancer Stem Cells in Sarcoma with Prognostic Implications

1
Instituto de Investigación Sanitaria del Principado de Asturias (ISPA)—Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
2
Instituto Universitario de Oncología del Principado de Asturias, 33006 Oviedo, Spain
3
CIBER en oncología (CIBERONC), 28029 Madrid, Spain
4
Departamento de Cirugía, Universidad de Oviedo, 33006 Oviedo, Spain
5
Cellular Biotechnology Unit, Instituto de Salud Carlos III, Majadahonda, 28220 Madrid, Spain
6
Servicio de Anatomía Patológica of the Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
7
Servicio de Oncología Médica of the Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
*
Author to whom correspondence should be addressed.
These authors contributed equally to the manuscript.
Cancers 2020, 12(4), 964; https://doi.org/10.3390/cancers12040964
Received: 14 February 2020 / Revised: 7 April 2020 / Accepted: 10 April 2020 / Published: 13 April 2020
(This article belongs to the Special Issue Cancer Stem Cells and Therapy Resistance)
Stemness in sarcomas is coordinated by the expression of pluripotency factors, like SOX2, in cancer stem cells (CSC). The role of SOX2 in tumor initiation and progression has been well characterized in osteosarcoma. However, the pro-tumorigenic features of SOX2 have been scarcely investigated in other sarcoma subtypes. Here, we show that SOX2 depletion dramatically reduced the ability of undifferentiated pleomorphic sarcoma (UPS) cells to form tumorspheres and to initiate tumor growth. Conversely, SOX2 overexpression resulted in increased in vivo tumorigenicity. Moreover, using a reporter system (SORE6) which allows to monitor viable cells expressing SOX2 and/or OCT4, we found that SORE6+ cells were significantly more tumorigenic than the SORE6- subpopulation. In agreement with this findings, SOX2 expression in sarcoma patients was associated to tumor grade, differentiation, invasive potential and lower patient survival. Finally, we studied the effect of a panel of anti-tumor drugs on the SORE6+ cells of the UPS model and patient-derived chondrosarcoma lines. We found that the mithramycin analogue EC-8042 was the most efficient in reducing SORE6+ cells in vitro and in vivo. Overall, this study demonstrates that SOX2 is a pro-tumorigenic factor with prognostic potential in sarcoma. Moreover, SORE6 transcriptional activity is a bona fide CSC marker in sarcoma and constitutes an excellent biomarker for evaluating the efficacy of anti-tumor treatments on CSC subpopulations. View Full-Text
Keywords: sarcoma; undifferentiated pleomorphic sarcoma; chondrosarcoma; SOX2; cancer stem cells; EC-8042 sarcoma; undifferentiated pleomorphic sarcoma; chondrosarcoma; SOX2; cancer stem cells; EC-8042
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MDPI and ACS Style

Menendez, S.T.; Rey, V.; Martinez-Cruzado, L.; Gonzalez, M.V.; Morales-Molina, A.; Santos, L.; Blanco, V.; Alvarez, C.; Estupiñan, O.; Allonca, E.; Rodrigo, J.P.; García-Castro, J.; Garcia-Pedrero, J.M.; Rodriguez, R. SOX2 Expression and Transcriptional Activity Identifies a Subpopulation of Cancer Stem Cells in Sarcoma with Prognostic Implications. Cancers 2020, 12, 964. https://doi.org/10.3390/cancers12040964

AMA Style

Menendez ST, Rey V, Martinez-Cruzado L, Gonzalez MV, Morales-Molina A, Santos L, Blanco V, Alvarez C, Estupiñan O, Allonca E, Rodrigo JP, García-Castro J, Garcia-Pedrero JM, Rodriguez R. SOX2 Expression and Transcriptional Activity Identifies a Subpopulation of Cancer Stem Cells in Sarcoma with Prognostic Implications. Cancers. 2020; 12(4):964. https://doi.org/10.3390/cancers12040964

Chicago/Turabian Style

Menendez, Sofia T.; Rey, Veronica; Martinez-Cruzado, Lucia; Gonzalez, M. V.; Morales-Molina, Alvaro; Santos, Laura; Blanco, Verónica; Alvarez, Carlos; Estupiñan, Oscar; Allonca, Eva; Rodrigo, Juan P.; García-Castro, Javier; Garcia-Pedrero, Juana M.; Rodriguez, Rene. 2020. "SOX2 Expression and Transcriptional Activity Identifies a Subpopulation of Cancer Stem Cells in Sarcoma with Prognostic Implications" Cancers 12, no. 4: 964. https://doi.org/10.3390/cancers12040964

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