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Dasatinib reverses Cancer-associated Fibroblasts (CAFs) from primary Lung Carcinomas to a Phenotype comparable to that of normal Fibroblasts

Overview of attention for article published in Molecular Cancer, June 2010
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Title
Dasatinib reverses Cancer-associated Fibroblasts (CAFs) from primary Lung Carcinomas to a Phenotype comparable to that of normal Fibroblasts
Published in
Molecular Cancer, June 2010
DOI 10.1186/1476-4598-9-168
Pubmed ID
Authors

Silke Haubeiss, Jens O Schmid, Thomas E Mürdter, Maike Sonnenberg, Godehard Friedel, Heiko van der Kuip, Walter E Aulitzky

Abstract

Cancer associated fibroblasts (CAFs) play a critical role for growth, invasion, and metastasis of cancer. Therefore, targeting CAFs with small molecule inhibitors may be an attractive anti-tumor strategy. The current study aims to identify small molecule kinase inhibitors affecting CAF's growth and to characterize the biological effects of active compounds on primary CAFs from lung cancer. We screened two individual CAF strains for their sensitivity to a panel of 160 kinase inhibitors. Five kinase inhibitors were identified inhibiting more than 50% of the growth of both cell lines. Three of them were inhibitors of PDGFR at nanomolar concentrations. Therefore, we further tested the FDA approved PDGFR inhibitors Dasatinib, Nilotinib, Sorafenib, and Imatinib. All 37 CAF strains investigated were highly sensitive to Dasatinib at clinically relevant concentrations. Imatinib was slightly less effective, whereas the inhibitory effects of Nilotinib and Sorafenib were significantly less pronounced.We investigated the effect of Dasatinib on the CAF transcriptome by microarray analysis of 9 individual CAF strains. 492 genes were identified whose expression was changed at least twofold. 104 of these encoded cell cycle related proteins with 97 of them being downregulated by Dasatinib. The majority of regulated genes, however, were of diverse biological functions not directly related to proliferation. We compared this Dasatinib expression signature to previously described differential signatures of normal tissue associated fibroblasts (NAFs) and CAFs and to a signature of fibroblast serum response. There was a significant overlap between genes regulated by Dasatinib and serum repression genes. More importantly, of the 313 genes downregulated by Dasatinib 64 were also reduced in NAFs compared to CAFs. Furthermore, 26 of 179 genes identified as upregulated by Dasatinib were also found to be elevated in NAFs compared to CAFs. These data demonstrate that Dasatinib partially reverses the phenotype of CAFs to a normal fibroblast like phenotype. This is further supported by the finding that incubation of tumor cells with conditioned medium from CAFs pre-incubated with Dasatinib significantly reduced tumor cell proliferation, suggesting that Dasatinib partially reverses the CAF mediated tumor promoting effect. Therefore, targeting CAFs with Dasatinib represents a promising therapeutic principle.

Mendeley readers

The data shown below were compiled from readership statistics for 71 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
India 1 1%
Germany 1 1%
Norway 1 1%
Saudi Arabia 1 1%
Unknown 67 94%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 20 28%
Researcher 13 18%
Student > Master 8 11%
Student > Doctoral Student 6 8%
Professor 5 7%
Other 9 13%
Unknown 10 14%
Readers by discipline Count As %
Agricultural and Biological Sciences 22 31%
Medicine and Dentistry 14 20%
Biochemistry, Genetics and Molecular Biology 7 10%
Pharmacology, Toxicology and Pharmaceutical Science 2 3%
Immunology and Microbiology 2 3%
Other 4 6%
Unknown 20 28%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 28 March 2011.
All research outputs
#2,017,258
of 3,628,445 outputs
Outputs from Molecular Cancer
#252
of 439 outputs
Outputs of similar age
#22,134
of 51,724 outputs
Outputs of similar age from Molecular Cancer
#5
of 7 outputs
Altmetric has tracked 3,628,445 research outputs across all sources so far. This one is in the 25th percentile – i.e., 25% of other outputs scored the same or lower than it.
So far Altmetric has tracked 439 research outputs from this source. They receive a mean Attention Score of 3.4. This one is in the 23rd percentile – i.e., 23% of its peers scored the same or lower than it.
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We're also able to compare this research output to 7 others from the same source and published within six weeks on either side of this one. This one has scored higher than 2 of them.