title: Adipose tissue derived stem cells differentiate into carcinoma-associated fibroblast-like cells under the influence of tumor derived factors.
abstract: 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. ELISA was performed using the human TGFβ1, SDF-1α and CCL5 Quantikine Kit. The invasion potential of MDAMB231 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 factor-beta 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.
  
  
  CONCLUSIONS
  Our data suggest that hASCs are a source of CAFs which play an important role in the tumor invasion.
authors.affiliation: Department of Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Constantin
authors.initials: C
authors.lastname: Jotzu
authors.forename: Eckhard
authors.initials: E
authors.lastname: Alt
authors.forename: Gabriel
authors.initials: G
authors.lastname: Welte
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Hennessy
authors.forename: Eswaran
authors.initials: E
authors.lastname: Devarajan
authors.forename: Srinivasalu
authors.initials: S
authors.lastname: Krishnappa
authors.forename: Severin
authors.initials: S
authors.lastname: Pinilla
authors.forename: Lilly
authors.initials: L
authors.lastname: Droll
authors.forename: Yao-Hua
authors.initials: YH
authors.lastname: Song
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D015415:Biomarkers / Q000378:metabolism; D001943:Breast Neoplasms / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D018946:Chemokine CCL5 / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D010641:Phenotype; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D019063:Tenascin / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D015415:Biomarkers; C483024:CCL5 protein, human; D018946:Chemokine CCL5; D054377:Chemokine CXCL12; D017077:Culture Media, Conditioned; D019063:Tenascin; D053773:Transforming Growth Factor beta1