Stem-Like Cells in Bone Sarcomas: Implications for Tumorigenesis

Abstract

Bone sarcomas are a clinically and molecularly heterogeneous group of malignancies characterized by varying degrees of mesenchymal differentiation. Despite advances in medical and surgical management, survival rates for high-grade tumors have remained static at 50% to 70%. Tumor stem cells have been recently implicated in the pathogenesis of other heterogeneous, highly malignant tumors. We demonstrate here the existence of a small subpopulation of self-renewing bone sarcoma cells that are capable of forming suspended spherical, clonal colonies, also called "sarcospheres," in anchorage-independent, serum-starved conditions. These bone sarcoma cells as well as tissue specimens express activated STAT3 and the marker genes of pluripotent embryonic stem (ES) cells, Oct 3/4 and Nanog. Expression levels of Oct 3/4 and Nanog are greater in sarcospheres than in adherent cultures. A subset of bone sarcoma cells displays several surface markers of mesenchymal stem cells (Stro-1, CD105, and CD44) as well as attributes of mesodermal, ectodermal, and endodermal differentiation. Although previously documented in brain and breast tumors, our results support the extension of the cancer stem cell hypothesis to include tumors of mesenchymal lineage. Furthermore, they suggest the participation of ES cell homeobox proteins in non-germ cell tumorigenesis.

Immunotherapy targeting HER2 with genetically modified T cells eliminates tumor-initiating cells in osteosarcoma

“…[4][5][6][7]13 Their enhanced capacity to form sarcospheres is a surrogate of their self-renewal property regardless of the method used to characterize and isolate this cell subpopulation from Targeting tumor-initiating cells in osteosarcoma N Rainusso et al the tumor bulk. Sarcospheres have previously been shown to be resistant to doxorubicin, cisplatin and vincristine, 8,9 and we now show they are also resistant to methotrexate.…”

“…7,13,14 To test the effect of methotrexate on OS TICs, single-cell suspensions of ZsGreenexpressing 143B and MNNG/HOS cells were exposed to methotrexate for 4 h at increasing concentrations (0.0001-1 mMl À1 ) and cultured in 'sarcosphere medium'. Subsequently, sarcospheres were trypsinized and viable cells were sorted for the expression of ZsGreen.…”

“…3 TICs have been identified in OS by the expression of certain surface markers or as a 'side population' through the exclusion of the vital dye Hoechst 33342. [4][5][6] In addition, OS TICs can be grown in culture as sphere-like structures (sarcospheres) under serum starvation, 7 a property that allows functional testing of different anti-neoplastic agents against this tumor cell compartment. Furthermore, OS TICs have been reported to be resistant to chemotherapy.…”

Controversial issue: Is it safe to employ mesenchymal stem cells in cell-based therapies?

“…In a breast cancer xenograft model, though having no effect on tumor growth per se, MSC greatly increased the metastasis rate through secretion of CCL5 (also called RANTES) (Karnoub et al, 2007). It has also been shown that highly malignant bone sarcomas contain selfrenewing stem cells, which express stem cell markers such as Oct3/4 and Nanog, in parallel with the surface markers Stro-1, CD105 and CD44, a phenotype similar to MSC (Gibbs et al, 2005).…”

Cancer stem cells as targets for cancer therapy: selected cancers as examples

“…Although a multitude of potential therapeutic approaches have been identified, many can be broadly classified as either differentiation or elimination therapy in which CSCs are coaxed to differentiate or are themselves eliminated, respectively [15,108,187]. Molecules that have been implicated in playing a role in CSC signaling spanning several tissue types, and may subsequently serve as potential targets for the development of novel therapies, include CD133 [166] and components of the hedgehog/patched (HH/PTCH) [101], Wnt [84], and Notch signaling cascades [84,108] as well as signal transducer and activator of transcription 3 (STAT3) [58] and telomerase [67]. Regulating various components of the CSC microenvironment and niche, such as the intracellular reactive oxygen species (ROS) levels [166] and tumor vasculature [166,180], have also been suggested as a potential means of therapy.…”