Abstract
BackgroundHuman cancer cells can transfer signaling molecules to neighboring and distant cells predisposing them to malignant transformation. This process might contribute to tumor progression and invasion through delivery of oncogenes or inhibitors of tumor suppressor genes, derived from the primary tumor cells, to susceptible target cells. The oncogenic potential of human cancer serum has been described in immortalized mouse fibroblasts but has not been shown yet in human cells. The objective of this study was to determine whether metastatic cancer patient sera have the ability to induce neoplastic transformation in immortalized human embryonic kidney (HEK293) cells, human embryonic stem cells (hESCs), human mesenchymal stem cells (hMSCs) and human adult liver fibroblasts (hALFs).MethodsEarly passage HEK293 cells, hESCs, hMSCs and hALFs were exposed to cancer patient serum, or cancer cells-derived condition medium for 3 weeks. Treated cells were analyzed for cell proliferation and transformation both in vitro and in vivo.ResultsHEK293 cells exposed to cancer serum increased their proliferative capability and displayed characteristics of transformed cells, as evaluated by in vitro anchorage-independent growth assay and in vivo tumorigenesis in immunodeficient mice. The same phenotypes were acquired when these cells were cultured in cancer cell line conditioned medium suggesting that the putative oncogenic factors present in the serum might derive directly from the primary tumor. Histopathological analyses revealed that the tumors arising from cancer patient serum and conditioned medium-treated HEK293 cells were poorly differentiated and displayed a high proliferative index. In contrast, neither of these phenomena was observed in treated hMSCs and hALFs. Intriguingly enough, hESC-treated cells maintained their self-renewal and differentiation potentials, as shown by in vitro sphere formation assay and in vivo development of teratomas in immunodeficient mice.ConclusionOur results indicate that cancer patients serum is able to induce oncogenic transformation of HEK293 cells and maintain the self-renewal of hESCs. To our knowledge, this is the first study that demonstrates the oncogenic transformation potential of cancer patient serum on human cells. In depth characterization of this process and the molecular pathways involved are needed to confirm its validity and determine its potential use in cancer therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-014-0086-5) contains supplementary material, which is available to authorized users.
Highlights
Human cancer cells can transfer signaling molecules to neighboring and distant cells predisposing them to malignant transformation
Recent experimental and clinical data suggest that metastases might occur via transfer of biologically active plasma circulating oncogenes or inhibitors of tumor suppressor genes from the primary tumor to susceptible target cells located in distant organs [6,7]
Cancer patient sera increased Human embryonic kidney 293 cells (HEK293) cells proliferation Previous studies had shown that plasma or serum from cancer patients increased the proliferation and induced the transformation of mouse immortalized fibroblast NIH3T3 cells [19], they were not able to transform human adipose-derived stem cells, a primary nonimmortalized cell line
Summary
Human cancer cells can transfer signaling molecules to neighboring and distant cells predisposing them to malignant transformation. Recent experimental and clinical data suggest that metastases might occur via transfer of biologically active plasma circulating oncogenes or inhibitors of tumor suppressor genes from the primary tumor to susceptible target cells located in distant organs [6,7] Under both physiological and pathological conditions, different cell types release microvesicles into their microenvironment [8,9]. Several types of human cancer cells have been shown to shed in their surrounding extracellular space and into body fluids cargo entities, named oncosomes They permit lateral transfer of their cargo to neighboring normal cells that promote the activation of survival and mitogenic signaling pathways, allowing them to acquire cancer cell characteristics [7,18]. Mutation of a single gene is not sufficient to trigger neoplastic transformation in human cells [21]
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