Sox2 maintains self renewal of tumor-initiating cells in osteosarcomas

Abstract

Tumors are thought to be sustained by a reservoir of self-renewing cells, termed tumor initiating cells or cancer stem cells. Osteosarcomas are high-grade sarcomas derived from osteoblast progenitor cells and are the most common pediatric bone malignancy. In this report we show that the stem cell transcription factor Sox2 is highly expressed in human and murine osteosarcoma cell lines as well as in tumor samples. Osteosarcoma cells have increased ability to grow in suspension as osteospheres, that are greatly enriched in expression of Sox2 and the stem cell marker, Sca-1. Depletion of Sox2 by shRNAs in independent murine osteosarcoma-derived cells drastically reduces their transformed properties in vitro and their ability to form tumors. Sox2-depleted osteosarcoma cells can no longer form osteospheres, and differentiate into mature osteoblasts. Concomitantly, they exhibit decreased Sca-1 expression and upregulation of the Wnt signaling pathway. Thus, despite other mutations, these tumor cells maintain a proliferative requirement for Sox2. Our data indicate that Sox2 is required for osteosarcoma cell self-renewal, and that Sox2 antagonizes the pro-differentiation Wnt pathway, that can in turn reduce Sox2 expression. These studies define Sox2 as a survival factor and a novel biomarker of self-renewal in osteosarcomas, and support a tumor suppressive role for the Wnt pathway in tumors of mesenchymal origin. Our findings could provide the basis for novel therapeutic strategies based on inhibiting Sox2 or enhancing Wnt signaling for the treatment of osteosarcomas.

Sox2 Is Required to Maintain Cancer Stem Cells in a Mouse Model of High-Grade Oligodendroglioma

“…In contrast, Sox2 is expressed in many tumor types, both in the brain and in other organs (mammary gland, lung, esophagus, bone; refs. [31][32][33].…”

“…These include tumors of the osteoblast lineage, as shown in osteosarcoma cell lines (32); here, Sox2 is required also in the normal tissue stem cell counterpart, osteoblast stem/progenitor cells (10), as seen with neural cells. CSC from mammary tumors cultured as tumorigenic "mammospheres" express Sox2 and Sox2 knockdown impairs mammosphere formation and delays tumor formation following transplantation (33).…”

Dihydromyricetin Activates AMP-Activated Protein Kinase and P38MAPK Exerting Antitumor Potential in Osteosarcoma

“…Sox2, as a transcription factor, marked and maintained a distinct cell population in osteosarcomas that had stem cell-like properties and was responsible for their tumorigenic potential. A recent study reported overexpression of Sox2 in sphere-forming cells from human sarcomas, and Sox2 downregulation decreased the stem-cell population in murine and human osteosarcomas (27,47). Our previous work also demonstrated that overexpressed Sox2 could increase the capability of sphere formation in osteosarcoma cells (20).…”

“…4A, U2OS, U2OS/ MTX, and 143B cells treated with dihydromyricetin as indicated have reduced ability to form osteospheres. Sox2 is a transcription factor of the high-mobility group (HMG) domain family that has a critical role in embryonic development and in maintaining pluripotency and self-renewal of osteosarcoma stem cells (20,27). Therefore, we investigated whether dihydromyricetin could affect the expression of Sox2.…”

Kanserde yeni bir hedef haline gelen çok yönlü Sox2 geni

“…İnsanda glioblastomadan türetilen tümör başlatıcı hücrelerde Sox2'nin etkisizleştirilmesi, hücre çoğalmasının inhibisyonuna ve bağışıklık sistemi eksik farelerde tümörijenik oluşumun kaybolmasına yol açması, Sox2'nin tümör başlatan hücrelerde kendiniyenileme yeteneğinin sürdürülmesinde rol oynadığını ve glioblastoma tedavisinde hedef olabileceğini göstermek-tedir (48). Aynı şekilde osteosarkomda Sox2 bir sağkalım faktörüdür ve kendini yenilemede yeni bir biyobelirteç olabileceği önerilmektedir (49). Öte yandan, insan baş-boyun kanser örneklerinde azalmış Sox2 ifadesi vimentin proteinini upregüle ederek, tümör hücre göçünü arttırmıştır (50).…”