Three frequently used human esophageal adenocarcinoma cell lines used for research were confirmed as being from other tumor types, according to a brief communication published online January 14 in the Journal of the National Cancer Institute. Two of the cell lines have been used in 11 U.S. patents and more than 100 published studies.
The 13 established esophageal adenocarcinoma cell lines are important because of the limited availability of patient samples and animal models.
To determine the authenticity of all the available cell lines, Winand N.M. Dinjens, Ph.D., Department of Pathology, Erasmus MC, University Medical Center, in Rotterdam, the Netherlands, and colleagues used data from pathology archives and genotyping assays in collaboration with the primary investigators who established the cell lines.
Cell lines SEG-1, BIC-1, and SK-GT-5 were proven to be cell lines from other tumor types, including lung carcinoma, colorectal adenocarcinoma, and gastric fundus carcinoma, respectively.
"Experimental results based on these contaminated cell lines have led to ongoing clinical trials recruiting [esophageal adenocarcinoma] patients, to more than 100 scientific publications, and to at least three National Institutes of Health cancer research grants and 11 U.S. patents, which emphasizes the importance of our findings," the authors write. "Widespread use of contaminated cell lines threatens the development of treatment strategies for [esophageal adenocarcinoma]."
The cell lines whose authenticity was verified will be placed in public repositories to promote future research, according to the brief communication.
The researchers also suggest that the clinical trial involving Barrett-related esophageal adenocarcinoma patients on the drug sorafenib should be reconsidered since the wrong cell line was used. They say there is now scant evidence for inhibition of the mitogen-activated protein kinase pathway by the drug in this cancer.
In an accompanying editorial, Robert Shoemaker, Ph.D., of the National Cancer Institute at Frederick in Maryland, questions this suggestion, pointing out that tissue of origin may not be important for all research studies. "…Given the knowledge that cancer is a heterogeneous disease," he writes, "one might question the rationale for any therapeutic maneuver that is based on studies conducted on a single cell line."
Shoemaker suggests that a study conducted with the correct cell lines (esophageal adenocarcinomas) would probably provide the same rationale for sorafenib because alterations in mitogen-activated protein kinase pathways are common in many tumor types.
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Journal of the National Cancer Institute: http://jncicancerspectrum.oupjournals.org
Thanks to Journal of the National Cancer Institute for this article.
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This is a huge problem that keeps cropping up year after year but nothing really ever seems to get done about it. I found a shocking statistic from a study looking into cross-contamination of cell lines a few years ago that indicated that about 36% of cell lines are incorrectly designated. When labs have multiple cell lines and lines are being shared from lab to lab it's easy for these kinds of things to happen. It totally undermines research and, as we can see from the data above, can even bring clinical trial data into question. I found a white paper written by a researcher a few years ago trying to drum up support to do something about this but it seems like nothing ever really seems to actually get done about it. I'm not sure what the answer would be anyway, except maybe ensuring that all lines are verified prior to moving things into clinical trial stages or even prior to publication?
"…Given the knowledge that cancer is a heterogeneous disease," he writes, "one might question the rationale for any therapeutic maneuver that is based on studies conducted on a single cell line."
Shoemaker makes an excellent point, but it applies just as well to the opposite side of the argument. Are drugs being approved for clinical trials on the basis of results in a single cell line in culture or xenograft models? If so, why? Many drugs fail because they're not effective in trials. Perhaps there should be a burden to establish efficacy in multiple cell lines derived from similar tumor types, because the drug may not be equally effective across all lines. Although it is more work in the preclinical stage, it opens up the possibility of discovering tumor genotypes against which the drug is most effective.
Janede, that is a disturbing statistic. I understand that many people want to ignore it, sweep it under the rug, because they've published, patented, or written grants using their favorite cell line. But this is research, after all--we should be striving for accuracy. Besides, if there's something wonky with a transgenic or knockout mouse or a knockdown or overexpressing cell line, we'd go back and genotype or something to make sure we have what we think we have, so why not do the same with cell lines? Perhaps one issue is having an established method that can be run by any lab to determine whether the cell line is what we think.
This is why we have STR fingerprinting damnit. People just need to use it.
Good point, GRM. It would save a lot of time and heartache in the end!
And some journals are starting to require verification of cell lines now, so my belief is that this will become a normal thing in the future.
I think that would be great. Although a lot of times we decide what cell lines to use out of older journals, so I don't think the problem will completely go away for a while.
Let's hope so, it just seems like it has always been an issue and every now and then a big controversy surfaces over it and then it all dies down and everyone forgets about it. I agree that a common method is definitely the way forward. I didn't realise that some journals were already starting to require verification, perhaps you're right GR and this will start to become a thing of the past now. It seems completely crazy, as BB says we should be striving for better accuracy.