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. 2013 Feb 15;19(4):855-64.
doi: 10.1158/1078-0432.CCR-12-2746. Epub 2012 Dec 18.

Development and characterization of HPV-positive and HPV-negative head and neck squamous cell carcinoma tumorgrafts

Randall J Kimple  1 , Paul M Harari, Alexandra D Torres, Robert Z Yang, Benjamin J Soriano, Menggang Yu, Eric A Armstrong, Grace C Blitzer, Molly A Smith, Laurel D Lorenz, Denis Lee, David T Yang, Timothy M McCulloch, Gregory K Hartig, Paul F Lambert
Affiliations

Development and characterization of HPV-positive and HPV-negative head and neck squamous cell carcinoma tumorgrafts

Randall J Kimple et al. Clin Cancer Res. .

Abstract

Purpose: To develop a clinically relevant model system to study head and neck squamous cell carcinoma (HNSCC), we have established and characterized a direct-from-patient tumorgraft model of human papillomavirus (HPV)-positive and HPV-negative cancers. VSports手机版.

Experimental design: Patients with newly diagnosed or recurrent HNSCC were consented for donation of tumor specimens. Surgically obtained tissue was implanted subcutaneously into immunodeficient mice V体育安卓版. During subsequent passages, both formalin-fixed/paraffin-embedded as well as flash-frozen tissues were harvested. Tumors were analyzed for a variety of relevant tumor markers. Tumor growth rates and response to radiation, cisplatin, or cetuximab were assessed and early passage cell strains were developed for rapid testing of drug sensitivity. .

Results: Tumorgrafts have been established in 22 of 26 patients to date. Significant diversity in tumorgraft tumor differentiation was observed with good agreement in degree of differentiation between patient tumor and tumorgraft (Kappa 0. 72). Six tumorgrafts were HPV-positive on the basis of p16 staining V体育ios版. A strong inverse correlation between tumorgraft p16 and p53 or Rb was identified (Spearman correlations P = 0. 085 and P = 0. 002, respectively). Significant growth inhibition of representative tumorgrafts was shown with cisplatin, cetuximab, or radiation treatment delivered over a two-week period. Early passage cell strains showed high consistency in response to cancer therapy between tumorgraft and cell strain. .

Conclusions: We have established a robust human tumorgraft model system for investigating HPV-positive and HPV-negative HNSCC VSports最新版本. These tumorgrafts show strong correlation with the original tumor specimens and provide a powerful resource for investigating mechanisms of therapeutic response as well as preclinical testing. .

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Conflict of interest statement

Conflicts of Interest: none

Figures

Figure 1
Figure 1
Histopathologic features of three patient tumors and corresponding tumorgrafts. UW-SCC6 (A), UW-SCC14N (B), and UW-SCC22 (C). Shown are photomicrografts of primary tumor H&E and p16 IHC top two rows in addition to tumorgraft passage 1 H&E, p16 IHC, Trichrome, Rb, and p53. Overall a strong correlation between Rb and p53 staining was observed (Spearman correlation p=0.04). Images at 200×.
Figure 2
Figure 2
A) Well differentiated primary tumor along with consistency between passages. B) Overall correlation between patient and tumorgraft differentiation showing good agreement (unweighted Kappa = 0.72, Std error = 0.13). C) Scatterplot depicting time from implantation to passage for the initial implantation (P0) and the second (P1), and third (P2) passages. One-way ANOVA, p=0.28. D) qRT-PCR with primers specific for HPV-16 E6 and HPV-16 E7 RNA showed high correlation in Cq values between E6 and E7 (HPV-negative, circles; HPV+, triangles), Pearson r=0.96, p<0.0001.
Figure 3
Figure 3
Effects of radiation, cetuximab, and cisplatin in three tumorgrafts: UW-SCC6 (A), UW-SCC14N (B), and UW-SCC22 (C). Treatments, started when subcutaneously growing tumors reached a volume of approximately 200 mm3, were administered twice weekly for two weeks as described in the methods. Growth curves plotting the mean (+/− SEM) tumor volume over time are shown. For each group, n=8–10 mice with dual tumors began treatment. *p<0.01, #p=not significant. D) Early passage cell strains developed from UW-SCC24 and UW-SCC14N were assessed for proliferative potential in the presence of indicated drugs. Cell number was estimated by CCK8 assay and standardized to the maximum relative value of vehicle control.
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