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Adipose-derived stem cells promote tumor initiation and accelerate tumor growth by interleukin-6 production.

Wei HJ, Zeng R, Lu JH, Lai WF, Chen WH, Liu HY, Chang YT, Deng WP - Oncotarget (2015)

Bottom Line: Here, we show that ADSCs enhance sphere formation and in vivo tumor initiation of breast and colon cancer cells.ADSCs also accelerated tumor growth.We suggest that ADSCs may enhance tumor initiation and promotion.

View Article: PubMed Central - PubMed

Affiliation: Graduate Institute of Biomedical Materials and Engineering, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan.

ABSTRACT
Adipose-derived stem cells (ADSCs) are multipotent cells that have attracted much recent attention. Here, we show that ADSCs enhance sphere formation and in vivo tumor initiation of breast and colon cancer cells. In co-culture, ADSCs induced several stem cell markers in cancer cells. ADSCs also accelerated tumor growth. Interaction of ADSCs and cancer cells stimulated secretion of interlukin-6 in ADSCs, which in turn acted in a paracrine manner on cancer cells to enhance their malignant properties. Interleukin-6 regulated stem cell-related genes and activated JAK2/STAT3 in cancer cells. We suggest that ADSCs may enhance tumor initiation and promotion.

No MeSH data available.


Related in: MedlinePlus

Enhanced tumor-initiating properties of breast and colon cancer cells by ADSC stimulation(A) Representative phase-contrast and fluorescence images and (B) quantitation of spheres generated by 4T1, 4T1 plus ADSCs, CT26, and CT26 plus ADSCs; scale bars indicate 100 μm. Values are means + SEM; *, P<0.05; ***P<0.001 in unpaired t test with Welch's correction. (C) mRNA expression of CSC markers SOX2, NANOG, ALDH1A1, and ABCG2 were evaluated by RT-PCR; GAPDH served as loading control. (D) Representative bioluminescence images and (E) tumour volume measurements (means ± SEM) from syngeneic tumor models. Results were taken 0, 7, 14, and 21 days after subcutaneous injection of 4T1 or CT26 cells with or without ADSCs; *, P<0.05; ***, P<0.001 using two-way ANOVA. (F) Quantitation of tumor formation by 4T1 and CT26 cells with or without ADSCs in mice. Animals were implanted with indicated cell amounts subcutaneously, and the number of mice with tumors after 60 days is indicated.
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Figure 2: Enhanced tumor-initiating properties of breast and colon cancer cells by ADSC stimulation(A) Representative phase-contrast and fluorescence images and (B) quantitation of spheres generated by 4T1, 4T1 plus ADSCs, CT26, and CT26 plus ADSCs; scale bars indicate 100 μm. Values are means + SEM; *, P<0.05; ***P<0.001 in unpaired t test with Welch's correction. (C) mRNA expression of CSC markers SOX2, NANOG, ALDH1A1, and ABCG2 were evaluated by RT-PCR; GAPDH served as loading control. (D) Representative bioluminescence images and (E) tumour volume measurements (means ± SEM) from syngeneic tumor models. Results were taken 0, 7, 14, and 21 days after subcutaneous injection of 4T1 or CT26 cells with or without ADSCs; *, P<0.05; ***, P<0.001 using two-way ANOVA. (F) Quantitation of tumor formation by 4T1 and CT26 cells with or without ADSCs in mice. Animals were implanted with indicated cell amounts subcutaneously, and the number of mice with tumors after 60 days is indicated.

Mentions: Tumor development is thought to be a multistage progress, including tumor initiation, promotion, and progression. Cancer stem cells (CSCs) are a small population of cancer cells with stem-like properties. CSCs perform a critical role during tumor development, especially in tumor initiation. Thus, the properties of CSCs are highly associated with cancer incidence and poor prognosis of patients. Sphere formation assay has been extensively utilized to retrospectively recognize CSCs based on their reported ability to evaluate self-renewal at the single-cell level in vitro [26]. To investigate whether the tumor-initiating ability of breast and colon cancer cells was affected by ADSCs, we first performed tumor sphere assay. We utilized cancer cells transduced with mCherry fluorescent protein and ADSCs isolated from green fluorescent protein (GFP)-transgenic mice. We found that breast or colon cancer cells cultured alone were able to form 3-dimensional tumor spheres and, as expected, ADSCs alone showed no sphere generation. In co-culture, representative images showed that ADSCs could survive and integrate into breast or colon cancer spheres (Figure 2A). We found that the sphere-forming efficiency of breast or colon cancer cells was significantly increased while directly co-cultured with ADSCs (Figure 2B). RT-PCR analysis further revealed that cancer cells upregulate several CSC markers upon co-culture with ADSCs, including SOX2, NANOG, ALDH1A1, and ABCG2 (Figure 2C). To evaluate whether in vivo tumor initiation of cancer cells was influenced by ADSCs, we subcutaneously inoculated 4T1 or CT26 cells with or without ADSCs into BALB/c mice. We then monitored tumor formation in mice by using non-invasive bioluminescent imaging. Representative images are shown in Figure 2D, and quantitative results are shown in Figure 2E and 2F. We found that ADSCs can markedly induce the formation of 4T1 and CT26 tumors, while cancer cells or ADSCs alone formed no tumors in mice. Above results indicate that ADSCs enhance the tumor-initiating properties of breast and colon cancer cells.


Adipose-derived stem cells promote tumor initiation and accelerate tumor growth by interleukin-6 production.

Wei HJ, Zeng R, Lu JH, Lai WF, Chen WH, Liu HY, Chang YT, Deng WP - Oncotarget (2015)

Enhanced tumor-initiating properties of breast and colon cancer cells by ADSC stimulation(A) Representative phase-contrast and fluorescence images and (B) quantitation of spheres generated by 4T1, 4T1 plus ADSCs, CT26, and CT26 plus ADSCs; scale bars indicate 100 μm. Values are means + SEM; *, P<0.05; ***P<0.001 in unpaired t test with Welch's correction. (C) mRNA expression of CSC markers SOX2, NANOG, ALDH1A1, and ABCG2 were evaluated by RT-PCR; GAPDH served as loading control. (D) Representative bioluminescence images and (E) tumour volume measurements (means ± SEM) from syngeneic tumor models. Results were taken 0, 7, 14, and 21 days after subcutaneous injection of 4T1 or CT26 cells with or without ADSCs; *, P<0.05; ***, P<0.001 using two-way ANOVA. (F) Quantitation of tumor formation by 4T1 and CT26 cells with or without ADSCs in mice. Animals were implanted with indicated cell amounts subcutaneously, and the number of mice with tumors after 60 days is indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480711&req=5

Figure 2: Enhanced tumor-initiating properties of breast and colon cancer cells by ADSC stimulation(A) Representative phase-contrast and fluorescence images and (B) quantitation of spheres generated by 4T1, 4T1 plus ADSCs, CT26, and CT26 plus ADSCs; scale bars indicate 100 μm. Values are means + SEM; *, P<0.05; ***P<0.001 in unpaired t test with Welch's correction. (C) mRNA expression of CSC markers SOX2, NANOG, ALDH1A1, and ABCG2 were evaluated by RT-PCR; GAPDH served as loading control. (D) Representative bioluminescence images and (E) tumour volume measurements (means ± SEM) from syngeneic tumor models. Results were taken 0, 7, 14, and 21 days after subcutaneous injection of 4T1 or CT26 cells with or without ADSCs; *, P<0.05; ***, P<0.001 using two-way ANOVA. (F) Quantitation of tumor formation by 4T1 and CT26 cells with or without ADSCs in mice. Animals were implanted with indicated cell amounts subcutaneously, and the number of mice with tumors after 60 days is indicated.
Mentions: Tumor development is thought to be a multistage progress, including tumor initiation, promotion, and progression. Cancer stem cells (CSCs) are a small population of cancer cells with stem-like properties. CSCs perform a critical role during tumor development, especially in tumor initiation. Thus, the properties of CSCs are highly associated with cancer incidence and poor prognosis of patients. Sphere formation assay has been extensively utilized to retrospectively recognize CSCs based on their reported ability to evaluate self-renewal at the single-cell level in vitro [26]. To investigate whether the tumor-initiating ability of breast and colon cancer cells was affected by ADSCs, we first performed tumor sphere assay. We utilized cancer cells transduced with mCherry fluorescent protein and ADSCs isolated from green fluorescent protein (GFP)-transgenic mice. We found that breast or colon cancer cells cultured alone were able to form 3-dimensional tumor spheres and, as expected, ADSCs alone showed no sphere generation. In co-culture, representative images showed that ADSCs could survive and integrate into breast or colon cancer spheres (Figure 2A). We found that the sphere-forming efficiency of breast or colon cancer cells was significantly increased while directly co-cultured with ADSCs (Figure 2B). RT-PCR analysis further revealed that cancer cells upregulate several CSC markers upon co-culture with ADSCs, including SOX2, NANOG, ALDH1A1, and ABCG2 (Figure 2C). To evaluate whether in vivo tumor initiation of cancer cells was influenced by ADSCs, we subcutaneously inoculated 4T1 or CT26 cells with or without ADSCs into BALB/c mice. We then monitored tumor formation in mice by using non-invasive bioluminescent imaging. Representative images are shown in Figure 2D, and quantitative results are shown in Figure 2E and 2F. We found that ADSCs can markedly induce the formation of 4T1 and CT26 tumors, while cancer cells or ADSCs alone formed no tumors in mice. Above results indicate that ADSCs enhance the tumor-initiating properties of breast and colon cancer cells.

Bottom Line: Here, we show that ADSCs enhance sphere formation and in vivo tumor initiation of breast and colon cancer cells.ADSCs also accelerated tumor growth.We suggest that ADSCs may enhance tumor initiation and promotion.

View Article: PubMed Central - PubMed

Affiliation: Graduate Institute of Biomedical Materials and Engineering, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan.

ABSTRACT
Adipose-derived stem cells (ADSCs) are multipotent cells that have attracted much recent attention. Here, we show that ADSCs enhance sphere formation and in vivo tumor initiation of breast and colon cancer cells. In co-culture, ADSCs induced several stem cell markers in cancer cells. ADSCs also accelerated tumor growth. Interaction of ADSCs and cancer cells stimulated secretion of interlukin-6 in ADSCs, which in turn acted in a paracrine manner on cancer cells to enhance their malignant properties. Interleukin-6 regulated stem cell-related genes and activated JAK2/STAT3 in cancer cells. We suggest that ADSCs may enhance tumor initiation and promotion.

No MeSH data available.


Related in: MedlinePlus