Limits...
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.

Show MeSH

Related in: MedlinePlus

Gene expression patterns in differentiated SK cells, MSC-ad and MSC-BM.A and B, expression levels of adipocyte genes, C/EBPα, C/EBPβ, PPAR-γ, and FABP4 (A), osteoblast genes, RBC32 and COL1 (B), and MSC genes, CD73, CD90, and CD105 (A and B) were measured by quantitative PCR in differentiated SK cells, MSC-ad and MSC-BM at day 15 after differentiation. Abbreviations: SK, SK Hep-1 cells; MSC-ad, adipocyte-derived MSC; MSC-BM, bone marrow-derived MSC; FABP4, fatty acid binding protein 4; RBC32, response gene to complement 32; COL1, collage 1A1.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4206444&req=5

pone-0110744-g003: Gene expression patterns in differentiated SK cells, MSC-ad and MSC-BM.A and B, expression levels of adipocyte genes, C/EBPα, C/EBPβ, PPAR-γ, and FABP4 (A), osteoblast genes, RBC32 and COL1 (B), and MSC genes, CD73, CD90, and CD105 (A and B) were measured by quantitative PCR in differentiated SK cells, MSC-ad and MSC-BM at day 15 after differentiation. Abbreviations: SK, SK Hep-1 cells; MSC-ad, adipocyte-derived MSC; MSC-BM, bone marrow-derived MSC; FABP4, fatty acid binding protein 4; RBC32, response gene to complement 32; COL1, collage 1A1.

Mentions: After culturing with adipogenic or osteogenic differentiation medium for 2 weeks, SK cells were differentiated into adipocytes and osteoblasts, with a similar differentiation pattern as MSC-ad and MSC-BM do, thereby confirming its MSC-like characteristics. Adipogenic differentiation was evidenced by Red oil R staining, whereas Alizarin red S staining confirmed the accumulation of calcium deposits, a characteristic of osteogenic cells, in differentiated SK cells, MSC-ad and MSC-BM (Figure 2). ALP, an osteogenic marker, was also expressed by these three cell types under osteogenic differentiation medium for 2 weeks, as determined by NBT/BICP staining (Figure 2). Expression of four adipogenic genes, C/EBP α, C/EBP β, PPAR-γ, and fatty acid binding protein 4 (FABP4), were up-regulated in these three cell types under adipogenic differentiation medium (Figure 3A), and two osteogenic genes, response gene to complement 32 (RGC32) and collagen 1A1, were highly expressed under osteogenic differentiation condition (Figure 3B). On the other hand, the expression of three major MSC markers, CD73, CD90, and CD105, was decreased in all three cell types under both differentiation conditions (Figure 3A and B).


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)

Gene expression patterns in differentiated SK cells, MSC-ad and MSC-BM.A and B, expression levels of adipocyte genes, C/EBPα, C/EBPβ, PPAR-γ, and FABP4 (A), osteoblast genes, RBC32 and COL1 (B), and MSC genes, CD73, CD90, and CD105 (A and B) were measured by quantitative PCR in differentiated SK cells, MSC-ad and MSC-BM at day 15 after differentiation. Abbreviations: SK, SK Hep-1 cells; MSC-ad, adipocyte-derived MSC; MSC-BM, bone marrow-derived MSC; FABP4, fatty acid binding protein 4; RBC32, response gene to complement 32; COL1, collage 1A1.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0110744-g003: Gene expression patterns in differentiated SK cells, MSC-ad and MSC-BM.A and B, expression levels of adipocyte genes, C/EBPα, C/EBPβ, PPAR-γ, and FABP4 (A), osteoblast genes, RBC32 and COL1 (B), and MSC genes, CD73, CD90, and CD105 (A and B) were measured by quantitative PCR in differentiated SK cells, MSC-ad and MSC-BM at day 15 after differentiation. Abbreviations: SK, SK Hep-1 cells; MSC-ad, adipocyte-derived MSC; MSC-BM, bone marrow-derived MSC; FABP4, fatty acid binding protein 4; RBC32, response gene to complement 32; COL1, collage 1A1.
Mentions: After culturing with adipogenic or osteogenic differentiation medium for 2 weeks, SK cells were differentiated into adipocytes and osteoblasts, with a similar differentiation pattern as MSC-ad and MSC-BM do, thereby confirming its MSC-like characteristics. Adipogenic differentiation was evidenced by Red oil R staining, whereas Alizarin red S staining confirmed the accumulation of calcium deposits, a characteristic of osteogenic cells, in differentiated SK cells, MSC-ad and MSC-BM (Figure 2). ALP, an osteogenic marker, was also expressed by these three cell types under osteogenic differentiation medium for 2 weeks, as determined by NBT/BICP staining (Figure 2). Expression of four adipogenic genes, C/EBP α, C/EBP β, PPAR-γ, and fatty acid binding protein 4 (FABP4), were up-regulated in these three cell types under adipogenic differentiation medium (Figure 3A), and two osteogenic genes, response gene to complement 32 (RGC32) and collagen 1A1, were highly expressed under osteogenic differentiation condition (Figure 3B). On the other hand, the expression of three major MSC markers, CD73, CD90, and CD105, was decreased in all three cell types under both differentiation conditions (Figure 3A and B).

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