TY - JOUR
T1 - Adipose tissue derived stem cells differentiate into carcinoma-associated fibroblast-like cells under the influence of tumor derived factors
AU - Jotzu, Constantin
AU - Alt, Eckhard
AU - Welte, Gabriel
AU - Li, Jie
AU - Hennessy, Bryan T.
AU - Devarajan, Eswaran
AU - Krishnappa, Srinivasalu
AU - Pinilla, Severin
AU - Droll, Lilly
AU - Song, Yao Hua
N1 - Funding Information:
This research was supported in part by the Department of Defense Breast Cancer Research Program W81XWH-08-1-0523 01 (to YHS) and by the Alliance of Cardiovascular Researchers (to EA).We thank Feras J Abdul Khalek and Christoph Beckmann for their technical assistance. The authors are also grateful to Dr. Sendurai Mani for helpful comments on this study.
PY - 2011/2
Y1 - 2011/2
N2 - Background Carcinoma-associated fibroblasts (CAF) are considered to contribute to tumor growth, invasion and metastasis. However, the cell type of origin remains unknown. Since human adipose tissue derived stem cells (hASCs) are locally adjacent to breast cancer cells and might directly interact with tumor cells, we investigated whether CAFs may originate from hASCs. Methods hASCs cultured under different conditions were quantified for the expression of alpha smooth muscle actin. ELISAwas performed using the human TGFβ1, SDF-1α and CCL5 Quantikine Kit. The invasion potential ofMDAMB231 cancer cells was evaluated using a Boyden chamber with filter inserts coated with Matrigel in 24-well dishes. Results We demonstrated that a significant percentage of hASCs differentiated into a CAF-like myofibroblastic phenotype (e.g. expression of alpha smooth muscle actin and tenascin-C) when exposed to conditioned medium from the human breast cancer lines MDAMB231 and MCF7. The conditioned medium from MDAMB231 and MCF7 contains significant amounts of transforming growth factorbeta 1 (TGFβ1) and the differentiation of hASCs towards CAFs is dependent on TGFβ1 signaling via Smad3 in hASCs. The induction of CAFs can be abolished using a neutralizing antibody to TGFβ1 as well as by pretreatment of the hASCs with SB431542, a TGFβ1 receptor kinase inhibitor. Additionally, we found that these hASC-derived CAF-like cells exhibit functional properties of CAFs, including the ability to promote tumor cell invasion in an in vitro invasion assay, as well as increased expression of stromal-cell derived factor 1 (SDF-1) and CCL5. Conclusion Our data suggest that hASCs are a source of CAFs which play an important role in the tumor invasion.
AB - Background Carcinoma-associated fibroblasts (CAF) are considered to contribute to tumor growth, invasion and metastasis. However, the cell type of origin remains unknown. Since human adipose tissue derived stem cells (hASCs) are locally adjacent to breast cancer cells and might directly interact with tumor cells, we investigated whether CAFs may originate from hASCs. Methods hASCs cultured under different conditions were quantified for the expression of alpha smooth muscle actin. ELISAwas performed using the human TGFβ1, SDF-1α and CCL5 Quantikine Kit. The invasion potential ofMDAMB231 cancer cells was evaluated using a Boyden chamber with filter inserts coated with Matrigel in 24-well dishes. Results We demonstrated that a significant percentage of hASCs differentiated into a CAF-like myofibroblastic phenotype (e.g. expression of alpha smooth muscle actin and tenascin-C) when exposed to conditioned medium from the human breast cancer lines MDAMB231 and MCF7. The conditioned medium from MDAMB231 and MCF7 contains significant amounts of transforming growth factorbeta 1 (TGFβ1) and the differentiation of hASCs towards CAFs is dependent on TGFβ1 signaling via Smad3 in hASCs. The induction of CAFs can be abolished using a neutralizing antibody to TGFβ1 as well as by pretreatment of the hASCs with SB431542, a TGFβ1 receptor kinase inhibitor. Additionally, we found that these hASC-derived CAF-like cells exhibit functional properties of CAFs, including the ability to promote tumor cell invasion in an in vitro invasion assay, as well as increased expression of stromal-cell derived factor 1 (SDF-1) and CCL5. Conclusion Our data suggest that hASCs are a source of CAFs which play an important role in the tumor invasion.
KW - Breast cancer
KW - Carcinoma-associated fibroblasts
KW - Invasion
KW - Mesenchymal stem cells
KW - Transforming growth factor-beta 1
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U2 - 10.1007/s13402-011-0012-1
DO - 10.1007/s13402-011-0012-1
M3 - Article
C2 - 21327615
AN - SCOPUS:80052537717
SN - 2211-3428
VL - 34
SP - 55
EP - 67
JO - Cellular Oncology
JF - Cellular Oncology
IS - 1
ER -