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Hypoxic 3D in vitro culture models reveal distinct resistance processes to TKIs in renal cancer cells

Overview of attention for article published in Cell & Bioscience, December 2017
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Title
Hypoxic 3D in vitro culture models reveal distinct resistance processes to TKIs in renal cancer cells
Published in
Cell & Bioscience, December 2017
DOI 10.1186/s13578-017-0197-8
Pubmed ID
Authors

Zofia F. Bielecka, Agata Malinowska, Klaudia K. Brodaczewska, Aleksandra Klemba, Claudine Kieda, Paweł Krasowski, Elżbieta Grzesiuk, Jan Piwowarski, Anna M. Czarnecka, Cezary Szczylik

Abstract

The aim of this study is to determine the effect of hypoxia on axitinib and sorafenib-treated renal cell carcinoma (RCC) cells. Hypoxia is a crucial factor influencing transcription process via protein modulation, which was shown i.e. in pancreatic cancer. Until now, hypoxia has been defined as associated with poorer outcome and inducing chemotherapy resistance in solid tumors. The unique phenomenon of pseudo-hypoxia connected with vhl mutation was observed in clear-cell, but not in papillary RCC, and the treatment of this subtype of cancer is still challenging. Despite the introduction of new antiangiogenic targeted therapies (inter alia tyrosine kinase inhibitors, TKIs), patients still develop both primary and acquired resistance. Overcoming resistance to TKIs, also in papillary RCC, may be possible by finding significantly modified protein expression. To do this, hypoxic 3D in vitro models must be developed to mimic both molecular pathways typical for low oxygen tension and cell-cell dynamics in tumor-like spatial structures. Clear-cell and papillary renal cell carcinoma (cc and pRCC) cell lines were used in the study to determine the impact of hypoxia on primary drug resistance phenomenon previously observed in papillary, but not in ccRCC. Resistance was confirmed in monolayer culture and in 3D models in soft agar and suspension culture. Human papillary kidney cancer stem-like cells (HKCSCs) cultured in hypoxia developed resistance to sorafenib, while when cultured in normoxia resistance to axitinib has developed. Flow cytometry revealed that hypoxia decreased proliferation rates in all investigated RCC cells. In HKCSCs, there was an increase of quiescent cells (Ki67-) and percentage of cells arrested in S phase. It also appeared that map2k1 and eif4b protein expression is altered in papillary RCC resistant to tested drugs at different oxygen tensions. Also, HKCSCs did not express vegfr-1, braf nor c-kit, TKIs target receptors, which were present in ccRCC cells sensitive to TKI treatment. The results confirm that low oxygen tension affects RCC cells. Hypoxia facilitates induction of sorafenib resistance in pRCC and induces map2k1 overexpression, while normoxic axitinib-resistant cells up-regulated eif4b. Further studies may determine if map2k1 or eif4b proteins play a role in pRCC resistance to TKIs. It is also of interest to establish if other than vegfr-1, braf, c-kit receptors can serve as potential molecular targets for more effective anti-RCC strategies.

Twitter Demographics

The data shown below were collected from the profile of 1 tweeter who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 23 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 23 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 7 30%
Researcher 7 30%
Student > Master 3 13%
Unknown 6 26%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 6 26%
Agricultural and Biological Sciences 6 26%
Neuroscience 2 9%
Immunology and Microbiology 1 4%
Engineering 1 4%
Other 0 0%
Unknown 7 30%

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 24 December 2017.
All research outputs
#11,821,859
of 13,324,776 outputs
Outputs from Cell & Bioscience
#278
of 315 outputs
Outputs of similar age
#325,494
of 385,423 outputs
Outputs of similar age from Cell & Bioscience
#15
of 25 outputs
Altmetric has tracked 13,324,776 research outputs across all sources so far. This one is in the 1st percentile – i.e., 1% of other outputs scored the same or lower than it.
So far Altmetric has tracked 315 research outputs from this source. They receive a mean Attention Score of 2.0. This one is in the 1st percentile – i.e., 1% of its peers scored the same or lower than it.
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We're also able to compare this research output to 25 others from the same source and published within six weeks on either side of this one. This one is in the 1st percentile – i.e., 1% of its contemporaries scored the same or lower than it.