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Hepatoma SK Hep-1 cells exhibit characteristics of oncogenic mesenchymal stem cells with highly metastatic capacity.

Eun JR, Jung YJ, Zhang Y, Zhang Y, Tschudy-Seney B, Ramsamooj R, Wan YJ, Theise ND, Zern MA, Duan Y - PLoS ONE (2014)

Bottom Line: We found that classical mesenchymal stem cell (MSC) markers were presented on SK cells, but endothelial marker CD31, hematopoietic markers CD34 and CD45 were negative.SK cells presented greater in vitro invasive capacity than those of Ad-MSC and BM-MSC.Thus, it represents a novel mechanism of tumor initiation, development and metastasis by CSCs of non-epithelial and endothelia origin.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, University of California Davis Medical Center, Sacramento, California, United States of America; Institute for Regenerative Cures, University of California Davis Medical Center, Sacramento, California, United States of America; Department of Internal Medicine, Yeungnam University College Medicine, Daegu, Korea.

ABSTRACT

Background: SK Hep-1 cells (SK cells) derived from a patient with liver adenocarcinoma have been considered a human hepatoma cell line with mesenchymal origin characteristics, however, SK cells do not express liver genes and exhibit liver function, thus, we hypothesized whether mesenchymal cells might contribute to human liver primary cancers. Here, we characterized SK cells and its tumourigenicity.

Methods and principal findings: We found that classical mesenchymal stem cell (MSC) markers were presented on SK cells, but endothelial marker CD31, hematopoietic markers CD34 and CD45 were negative. SK cells are capable of differentiate into adipocytes and osteoblasts as adipose-derived MSC (Ad-MSC) and bone marrow-derived MSC (BM-MSC) do. Importantly, a single SK cell exhibited a substantial tumourigenicity and metastatic capacity in immunodefficient mice. Metastasis not only occurred in circulating organs such as lung, liver, and kidneys, but also in muscle, outer abdomen, and skin. SK cells presented greater in vitro invasive capacity than those of Ad-MSC and BM-MSC. The xenograft cells from subcutaneous and metastatic tumors exhibited a similar tumourigenicity and metastatic capacity, and showed the same relatively homogenous population with MSC characteristics when compared to parental SK cells. SK cells could unlimitedly expand in vitro without losing MSC characteristics, its tumuorigenicity and metastatic capacity, indicating that SK cells are oncogenic MSC with enhanced self-renewal capacity. We believe that this is the first report that human MSC appear to be transformed into cancer stem cells (CSC), and that their derivatives also function as CSCs.

Conclusion: Our findings demonstrate that SK cells represent a transformation mechanism of normal MSC into an enhanced self-renewal CSC with metastasis capacity, SK cells and their xenografts represent a same relative homogeneity of CSC with substantial metastatic capacity. Thus, it represents a novel mechanism of tumor initiation, development and metastasis by CSCs of non-epithelial and endothelia origin.

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Characterization of isolates from primary tumors and metastatic tumors.A–D, parental SK cells (A), re-culture of subcutaneous primary tumors (B), re-culture of metastatic tumors in liver (C) and lung (D). E, classical mesenchymal stem cell (MSC) markers were detected and measured in three isolates employing flow cytometry. F, expression of MSC markers, vimentin (a mesodermal origin marker), and alpha smooth muscle actin (α-SMA) was measured by quantitative PCR in three isolates. Abbreviations: HLA ABC, major histocompatibility complex (MHC) class I antigen; HLA DR, MHC class II antigen; ALP, Alkaline phosphatase. Magnifications: 100X
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pone-0110744-g006: Characterization of isolates from primary tumors and metastatic tumors.A–D, parental SK cells (A), re-culture of subcutaneous primary tumors (B), re-culture of metastatic tumors in liver (C) and lung (D). E, classical mesenchymal stem cell (MSC) markers were detected and measured in three isolates employing flow cytometry. F, expression of MSC markers, vimentin (a mesodermal origin marker), and alpha smooth muscle actin (α-SMA) was measured by quantitative PCR in three isolates. Abbreviations: HLA ABC, major histocompatibility complex (MHC) class I antigen; HLA DR, MHC class II antigen; ALP, Alkaline phosphatase. Magnifications: 100X

Mentions: The primary tumors produced by the subcutaneous injection, and metastatic tumors in lung and liver were collected and the cells from these tumors were isolated and re-cultured. The morphology of these cells was the same as those of parental SK cells (Figure 6A–D), and flow cytomery results showed that the percentage of classic MSC surface markers in these isolates are very similar to those in parental SK cells (Figure 6E, Figure 6S), but HLA DR were slightly decreased in isolates of livers and lungs. Expression of major MSC markers were not significantly changed (Figure 6F). These isolates from SK xenografts (primary and metastatic tumors) were subcutaneously injected into mice, and subcutaneous tumor formation and metastases occurred as similar to the parental SK cells (Table 1).


Hepatoma SK Hep-1 cells exhibit characteristics of oncogenic mesenchymal stem cells with highly metastatic capacity.

Eun JR, Jung YJ, Zhang Y, Zhang Y, Tschudy-Seney B, Ramsamooj R, Wan YJ, Theise ND, Zern MA, Duan Y - PLoS ONE (2014)

Characterization of isolates from primary tumors and metastatic tumors.A–D, parental SK cells (A), re-culture of subcutaneous primary tumors (B), re-culture of metastatic tumors in liver (C) and lung (D). E, classical mesenchymal stem cell (MSC) markers were detected and measured in three isolates employing flow cytometry. F, expression of MSC markers, vimentin (a mesodermal origin marker), and alpha smooth muscle actin (α-SMA) was measured by quantitative PCR in three isolates. Abbreviations: HLA ABC, major histocompatibility complex (MHC) class I antigen; HLA DR, MHC class II antigen; ALP, Alkaline phosphatase. Magnifications: 100X
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4206444&req=5

pone-0110744-g006: Characterization of isolates from primary tumors and metastatic tumors.A–D, parental SK cells (A), re-culture of subcutaneous primary tumors (B), re-culture of metastatic tumors in liver (C) and lung (D). E, classical mesenchymal stem cell (MSC) markers were detected and measured in three isolates employing flow cytometry. F, expression of MSC markers, vimentin (a mesodermal origin marker), and alpha smooth muscle actin (α-SMA) was measured by quantitative PCR in three isolates. Abbreviations: HLA ABC, major histocompatibility complex (MHC) class I antigen; HLA DR, MHC class II antigen; ALP, Alkaline phosphatase. Magnifications: 100X
Mentions: The primary tumors produced by the subcutaneous injection, and metastatic tumors in lung and liver were collected and the cells from these tumors were isolated and re-cultured. The morphology of these cells was the same as those of parental SK cells (Figure 6A–D), and flow cytomery results showed that the percentage of classic MSC surface markers in these isolates are very similar to those in parental SK cells (Figure 6E, Figure 6S), but HLA DR were slightly decreased in isolates of livers and lungs. Expression of major MSC markers were not significantly changed (Figure 6F). These isolates from SK xenografts (primary and metastatic tumors) were subcutaneously injected into mice, and subcutaneous tumor formation and metastases occurred as similar to the parental SK cells (Table 1).

Bottom Line: We found that classical mesenchymal stem cell (MSC) markers were presented on SK cells, but endothelial marker CD31, hematopoietic markers CD34 and CD45 were negative.SK cells presented greater in vitro invasive capacity than those of Ad-MSC and BM-MSC.Thus, it represents a novel mechanism of tumor initiation, development and metastasis by CSCs of non-epithelial and endothelia origin.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, University of California Davis Medical Center, Sacramento, California, United States of America; Institute for Regenerative Cures, University of California Davis Medical Center, Sacramento, California, United States of America; Department of Internal Medicine, Yeungnam University College Medicine, Daegu, Korea.

ABSTRACT

Background: SK Hep-1 cells (SK cells) derived from a patient with liver adenocarcinoma have been considered a human hepatoma cell line with mesenchymal origin characteristics, however, SK cells do not express liver genes and exhibit liver function, thus, we hypothesized whether mesenchymal cells might contribute to human liver primary cancers. Here, we characterized SK cells and its tumourigenicity.

Methods and principal findings: We found that classical mesenchymal stem cell (MSC) markers were presented on SK cells, but endothelial marker CD31, hematopoietic markers CD34 and CD45 were negative. SK cells are capable of differentiate into adipocytes and osteoblasts as adipose-derived MSC (Ad-MSC) and bone marrow-derived MSC (BM-MSC) do. Importantly, a single SK cell exhibited a substantial tumourigenicity and metastatic capacity in immunodefficient mice. Metastasis not only occurred in circulating organs such as lung, liver, and kidneys, but also in muscle, outer abdomen, and skin. SK cells presented greater in vitro invasive capacity than those of Ad-MSC and BM-MSC. The xenograft cells from subcutaneous and metastatic tumors exhibited a similar tumourigenicity and metastatic capacity, and showed the same relatively homogenous population with MSC characteristics when compared to parental SK cells. SK cells could unlimitedly expand in vitro without losing MSC characteristics, its tumuorigenicity and metastatic capacity, indicating that SK cells are oncogenic MSC with enhanced self-renewal capacity. We believe that this is the first report that human MSC appear to be transformed into cancer stem cells (CSC), and that their derivatives also function as CSCs.

Conclusion: Our findings demonstrate that SK cells represent a transformation mechanism of normal MSC into an enhanced self-renewal CSC with metastasis capacity, SK cells and their xenografts represent a same relative homogeneity of CSC with substantial metastatic capacity. Thus, it represents a novel mechanism of tumor initiation, development and metastasis by CSCs of non-epithelial and endothelia origin.

Show MeSH
Related in: MedlinePlus