Abstract
Osteosarcoma is a high-grade malignant bone tumor that manifests ingravescent clinical behavior. The intrinsic events that confer malignant properties on osteosarcoma cells have remained unclear, however. We previously established two lines of mouse osteosarcoma cells: AX cells, which are able to form tumors in syngeneic mice, and AXT cells, which were derived from such tumors and acquired an increased tumorigenic capacity during tumor development. We have now identified Igf2 mRNA-binding protein3 (Imp3) as a key molecule responsible for this increased tumorigenicity of AXT cells in vivo. Imp3 is consistently up-regulated in tumors formed by AX cells, and its expression in these cells was found to confer malignant properties such as anchorage-independent growth, loss of contact inhibition, and escape from anoikis in vitro. The expression level of Imp3 also appeared directly related to tumorigenic ability in vivo which is the critical determination for tumor-initiating cells. The effect of Imp3 on tumorigenicity of osteosarcoma cells did not appear to be mediated through Igf2-dependent mechanism. Our results implicate Imp3 as a key regulator of stem-like tumorigenic characteristics in osteosarcoma cells and as a potential therapeutic target for this malignancy.
Highlights
Malignant tumors are derived from transformed normal cells
These findings suggested that AXT cells acquired properties of anchorage-independent growth and anoikis resistance, and that these properties might contribute to their increased tumorigenicity in vivo
We found that Igf2 mRNA-binding protein3 (Imp3) meets all these criteria, as shown below
Summary
As the disease course progresses, tumor cells acquire various malignant biological properties such as deregulated cell proliferation, anchorage-independent growth, increased invasiveness, as well as the potential to induce neovascularization and to undergo metastasis, the combination of all of which eventually becomes life threatening [1,2]. Subcutaneous injection of AX cells into syngeneic mice resulted in the formation of lethal osteosarcoma tumors that underwent metastasis, mimicking the pathology of human osteosarcoma [3]. We further established tumor-initiating cells, designated AXT, from such AX cell-derived subcutaneous tumors. Injection of AXT cells resulted in the generation of tumors that were identical histologically to those formed by AX cells but with a greatly shortened disease course, suggesting that tumorigenic capability of AXT cells increased during initial tumor formation in vivo. Further investigation revealed that AXT cells showed enhanced anchorage-independent growth and anoikis resistance compared with AX cells
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