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Appropriateness of using patient-derived xenograft models for pharmacologic evaluation of novel therapies for esophageal/gastro-esophageal junction cancers.

Dodbiba L, Teichman J, Fleet A, Thai H, Starmans MH, Navab R, Chen Z, Girgis H, Eng L, Espin-Garcia O, Shen X, Bandarchi B, Schwock J, Tsao MS, El-Zimaity H, Der SD, Xu W, Bristow RG, Darling GE, Boutros PC, Ailles LE, Liu G - PLoS ONE (2015)

Bottom Line: Tumors that were implanted (n=55) in NOD/SCID mice had features suggestive of more aggressive biology than tumors that were never implanted (n=32).Of those implanted, 21/55 engrafted; engraftment was associated with poorly differentiated tumors (p=0.04) and older patients (p=0.01).Because of their ability to recapitulate primary tumor characteristics during engraftment and across serial passaging, PTXGs can be useful clinical systems for assessment of drug sensitivity of human E/GEJ cancers.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Wayne State University, School of Medicine, Detroit, Michigan, United States of America.

ABSTRACT
The high morbidity and mortality of patients with esophageal (E) and gastro-esophageal junction (GEJ) cancers, warrants new pre-clinical models for drug testing. The utility of primary tumor xenografts (PTXGs) as pre-clinical models was assessed. Clinicopathological, immunohistochemical markers (p53, p16, Ki-67, Her-2/neu and EGFR), and global mRNA abundance profiles were evaluated to determine selection biases of samples implanted or engrafted, compared with the underlying population. Nine primary E/GEJ adenocarcinoma xenograft lines were further characterized for the spectrum and stability of gene/protein expression over passages. Seven primary esophageal adenocarcinoma xenograft lines were treated with individual or combination chemotherapy. Tumors that were implanted (n=55) in NOD/SCID mice had features suggestive of more aggressive biology than tumors that were never implanted (n=32). Of those implanted, 21/55 engrafted; engraftment was associated with poorly differentiated tumors (p=0.04) and older patients (p=0.01). Expression of immunohistochemical markers were similar between patient sample and corresponding xenograft. mRNA differences observed between patient tumors and first passage xenografts were largely due to loss of human stroma in xenografts. mRNA patterns of early vs late passage xenografts and of small vs large tumors of the same passage were similar. Complete resistance was present in 2/7 xenografts while the remaining tumors showed varying degrees of sensitivity, that remained constant across passages. Because of their ability to recapitulate primary tumor characteristics during engraftment and across serial passaging, PTXGs can be useful clinical systems for assessment of drug sensitivity of human E/GEJ cancers.

No MeSH data available.


Related in: MedlinePlus

Scatterplot showing mRNA abundance comparisons for each established adenocarcinoma line.Comparisons were made between P1 xenograft vs patient tumor (left column), Platestvs Pearly xenograft (middle column) and Large vs Small xenograft tumors (right column). Normalized expression levels for individual genes were used to plot the comparison. R2 values are included for each comparison. mRNA for lines F and I could not be extracted for all comparisons since mRNA degradation in the frozen tissue had occurred. Both samples had intact mRNA for the patient tumor but Line I did not have a matching later passage xenograft while Line F did not have a matching first passage xenograft. Both lines were included in statistical comparisons where the data was present.
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pone.0121872.g003: Scatterplot showing mRNA abundance comparisons for each established adenocarcinoma line.Comparisons were made between P1 xenograft vs patient tumor (left column), Platestvs Pearly xenograft (middle column) and Large vs Small xenograft tumors (right column). Normalized expression levels for individual genes were used to plot the comparison. R2 values are included for each comparison. mRNA for lines F and I could not be extracted for all comparisons since mRNA degradation in the frozen tissue had occurred. Both samples had intact mRNA for the patient tumor but Line I did not have a matching later passage xenograft while Line F did not have a matching first passage xenograft. Both lines were included in statistical comparisons where the data was present.

Mentions: In the mRNA abundance analysis of primary patient tissue vs first passage xenografts, we found good concordance (Fig 3, first column) with R2 values ranging from 0.52–0.88. Unsupervised hierarchical clustering showed that xenografts clustered together while patient tumors clustered with other patient tumors (S1 Fig). 2164 genes were differentially expressed between P0 and P1 tumors (false discovery rate <5%).


Appropriateness of using patient-derived xenograft models for pharmacologic evaluation of novel therapies for esophageal/gastro-esophageal junction cancers.

Dodbiba L, Teichman J, Fleet A, Thai H, Starmans MH, Navab R, Chen Z, Girgis H, Eng L, Espin-Garcia O, Shen X, Bandarchi B, Schwock J, Tsao MS, El-Zimaity H, Der SD, Xu W, Bristow RG, Darling GE, Boutros PC, Ailles LE, Liu G - PLoS ONE (2015)

Scatterplot showing mRNA abundance comparisons for each established adenocarcinoma line.Comparisons were made between P1 xenograft vs patient tumor (left column), Platestvs Pearly xenograft (middle column) and Large vs Small xenograft tumors (right column). Normalized expression levels for individual genes were used to plot the comparison. R2 values are included for each comparison. mRNA for lines F and I could not be extracted for all comparisons since mRNA degradation in the frozen tissue had occurred. Both samples had intact mRNA for the patient tumor but Line I did not have a matching later passage xenograft while Line F did not have a matching first passage xenograft. Both lines were included in statistical comparisons where the data was present.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4380353&req=5

pone.0121872.g003: Scatterplot showing mRNA abundance comparisons for each established adenocarcinoma line.Comparisons were made between P1 xenograft vs patient tumor (left column), Platestvs Pearly xenograft (middle column) and Large vs Small xenograft tumors (right column). Normalized expression levels for individual genes were used to plot the comparison. R2 values are included for each comparison. mRNA for lines F and I could not be extracted for all comparisons since mRNA degradation in the frozen tissue had occurred. Both samples had intact mRNA for the patient tumor but Line I did not have a matching later passage xenograft while Line F did not have a matching first passage xenograft. Both lines were included in statistical comparisons where the data was present.
Mentions: In the mRNA abundance analysis of primary patient tissue vs first passage xenografts, we found good concordance (Fig 3, first column) with R2 values ranging from 0.52–0.88. Unsupervised hierarchical clustering showed that xenografts clustered together while patient tumors clustered with other patient tumors (S1 Fig). 2164 genes were differentially expressed between P0 and P1 tumors (false discovery rate <5%).

Bottom Line: Tumors that were implanted (n=55) in NOD/SCID mice had features suggestive of more aggressive biology than tumors that were never implanted (n=32).Of those implanted, 21/55 engrafted; engraftment was associated with poorly differentiated tumors (p=0.04) and older patients (p=0.01).Because of their ability to recapitulate primary tumor characteristics during engraftment and across serial passaging, PTXGs can be useful clinical systems for assessment of drug sensitivity of human E/GEJ cancers.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Wayne State University, School of Medicine, Detroit, Michigan, United States of America.

ABSTRACT
The high morbidity and mortality of patients with esophageal (E) and gastro-esophageal junction (GEJ) cancers, warrants new pre-clinical models for drug testing. The utility of primary tumor xenografts (PTXGs) as pre-clinical models was assessed. Clinicopathological, immunohistochemical markers (p53, p16, Ki-67, Her-2/neu and EGFR), and global mRNA abundance profiles were evaluated to determine selection biases of samples implanted or engrafted, compared with the underlying population. Nine primary E/GEJ adenocarcinoma xenograft lines were further characterized for the spectrum and stability of gene/protein expression over passages. Seven primary esophageal adenocarcinoma xenograft lines were treated with individual or combination chemotherapy. Tumors that were implanted (n=55) in NOD/SCID mice had features suggestive of more aggressive biology than tumors that were never implanted (n=32). Of those implanted, 21/55 engrafted; engraftment was associated with poorly differentiated tumors (p=0.04) and older patients (p=0.01). Expression of immunohistochemical markers were similar between patient sample and corresponding xenograft. mRNA differences observed between patient tumors and first passage xenografts were largely due to loss of human stroma in xenografts. mRNA patterns of early vs late passage xenografts and of small vs large tumors of the same passage were similar. Complete resistance was present in 2/7 xenografts while the remaining tumors showed varying degrees of sensitivity, that remained constant across passages. Because of their ability to recapitulate primary tumor characteristics during engraftment and across serial passaging, PTXGs can be useful clinical systems for assessment of drug sensitivity of human E/GEJ cancers.

No MeSH data available.


Related in: MedlinePlus