Growth of xenografted squamous cell carcinoma of the head and neck ‐ possible correlation with patient survival

Zätterström, Ulf; Braakhuis, Boudewijn J.M.; Wennerberg, Johan; Dongen, Guus A.M.S. van; Attewell, Robyn; Nauta, J. J. P.; Laarman, D.; Ask, Anders

doi:10.1111/j.1699-0463.1992.tb04028.x

Cited by 8 publications

(3 citation statements)

References 15 publications

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“…In that model, poorly differentiated tumors, larger tumors, recurrent tumors, and tumors from lymph node metastases were more likely to form xenografts [30,33]. Additional PDX models of HNSCC have been developed but have not been well characterized at the molecular level and most also demonstrated low engraftment rates [34-40]. In our study, tumors that were poorly differentiated and node positive were significantly more likely to engraft.…”

Section: Discussionmentioning

confidence: 61%

Tumor grafts derived from patients with head and neck squamous carcinoma authentically maintain the molecular and histologic characteristics of human cancers

et al. 2013

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BackgroundThe patient-derived xenograft (PDX) model is likely to reflect human tumor biology more accurately than cultured cell lines because human tumors are implanted directly into animals; maintained in an in vivo, three-dimensional environment; and never cultured on plastic. PDX models of head and neck squamous cell carcinoma (HNSCC) have been developed previously but were not well characterized at the molecular level. HNSCC is a deadly and disfiguring disease for which better systemic therapy is desperately needed. The development of new therapies and the understanding of HNSCC biology both depend upon clinically relevant animal models. We developed and characterized the patient-derived xenograft (PDX) model because it is likely to recapitulate human tumor biology.MethodsWe transplanted 30 primary tumors directly into mice. The histology and stromal components were analyzed by immunohistochemistry. Gene expression analysis was conducted on patient tumors and on PDXs and cell lines derived from one PDX and from independent, human tumors.ResultsFive of 30 (17%) transplanted tumors could be serially passaged. Engraftment was more frequent among HNSCC with poor differentiation and nodal disease. The tumors maintained the histologic characteristics of the parent tumor, although human stromal components were lost upon engraftment. The degree of difference in gene expression between the PDX and its parent tumor varied widely but was stable up to the tenth generation in one PDX. For genes whose expression differed between parent tumors and cell lines in culture, the PDX expression pattern was very similar to that of the parent tumor. There were also significant expression differences between the human tumors that subsequently grew in mice and those that did not, suggesting that this model enriches for cancers with distinct biological features. The PDX model was used successfully to test targeted drugs in vivo.ConclusionThe PDX model for HNSCC is feasible, recapitulates the histology of the original tumor, and generates stable gene expression patterns. Gene expression patterns and histology suggested that the PDX more closely recapitulated the parental tumor than did cells in culture. Thus, the PDX is a robust model in which to evaluate tumor biology and novel therapeutics.

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Section: Discussionmentioning

confidence: 61%

Tumor grafts derived from patients with head and neck squamous carcinoma authentically maintain the molecular and histologic characteristics of human cancers

et al. 2013

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“…The implantation of HNSCC samples in vivo is feasible with engraftment rates between 29% and 44% (Chen et al., 1996; Hennessey et al., 2011; Kimple et al., 2013; Prince et al., 2007; Wennerberg et al., 1983; Zatterstrom et al., 1992). No differences in tumor biology or clinical findings, including survival, were observed in patients with engraftment (Chen et al., 1996), regardless of mouse background (Prince et al., 2007).…”

Section: Introductionmentioning

confidence: 99%

A patient tumor transplant model of squamous cell cancer identifies PI3K inhibitors as candidate therapeutics in defined molecular bins

et al. 2013

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Targeted therapy development in head and neck squamous cell carcinoma (HNSCC) is challenging given the rarity of activating mutations. Additionally, HNSCC incidence is increasing related to human papillomavirus (HPV). We sought to develop an in vivo model derived from patients reflecting the evolving HNSCC epidemiologic landscape, and use it to identify new therapies. Primary and relapsed tumors from HNSCC patients, both HPV+ and HPV−, were implanted on mice, giving rise to 25 strains. Resulting xenografts were characterized by detecting key mutations, measuring protein expression by IHC and gene expression/pathway analysis by mRNA-sequencing. Drug efficacy studies were run with representative xenografts using the approved drug cetuximab as well as the new PI3K inhibitor PX-866. Tumors maintained their original morphology, genetic profiles and drug susceptibilities through serial passaging. The genetic makeup of these tumors was consistent with known frequencies of TP53, PI3KCA, NOTCH1 and NOTCH2 mutations. Because the EGFR inhibitor cetuximab is a standard HNSCC therapy, we tested its efficacy and observed a wide spectrum of efficacy. Cetuximab-resistant strains had higher PI3K/Akt pathway gene expression and protein activation than cetuximab-sensitive strains. The PI3K inhibitor PX-866 had anti-tumor efficacy in HNSCC models with PIK3CA alterations. Finally, PI3K inhibition was effective in two cases with NOTCH1 inactivating mutations. In summary, we have developed an HNSCC model covering its clinical spectrum whose major genetic alterations and susceptibility to anticancer agents represent contemporary HNSCC. This model enables to prospectively test therapeutic-oriented hypotheses leading to personalized medicine.

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“…For example, some groups describe surgical implantation of small (2–3 mm) tumor chunks into the flanks [14] while others mince the tumors to create a cell suspension and inject the suspension subcutaneously through a large gauge needle [15]. Furthermore, certain groups only use athymic nude mice [3], others use non-obese diabetic severe combined immunodeficiency (NOD-SCID) mice [7] and some employ both strains [1].…”

Section: Introductionmentioning

confidence: 99%

Influence of Handling Conditions on the Establishment and Propagation of Head and Neck Cancer Patient Derived Xenografts

et al. 2014

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BackgroundPatient derived xenografts (PDXs) for head and neck cancer (HNC) and other cancers represent powerful research platforms. Most groups implant patient tissue into immunodeficient mice immediately although the significance of this time interval is anecdotal. We tested the hypothesis that the time from tumor excision to implantation is crucial for PDX passaging and establishment.MethodsWe examined whether time or storage medium affected PDX viability for passaging two established HNC PDXs (UW-SCC34, UW-SCC52). Tumors were harvested, stored in ice-cold media or saline for 0–48 hours, and implanted into new mice. Tumor growth was compared by two-way ANOVA with respect to time and storage condition. Three new HNC PDXs (UW-SCC63-65) were generated by implanting patient tissue into mice immediately (Time 0) and 24 hours after receiving tissue from the operating room.ResultsSimilar quantities of tumor were implanted into each mouse. At the end of the experiment, no significant difference was seen in mean tumor weight between the media and saline storage conditions for UW-SCC34 or UW-SCC52 (p = 0.650 and p = 0.177, respectively). No difference in tumor formation prevalence was seen on the basis of time from harvest to implantation (≥13 of 16 tumors grew at every time point). Histological analysis showed strong similarity to the initial tumor across all groups. Tumors developed at both Time 0 and 24 hours for UW-SCC63 and UW-SCC64.ConclusionsWe demonstrated that neither storage medium nor time from tumor excision to implantation (up to 48 hours) affected viability or histological differentiation in a subsequent passage for two HNC PDXs. Moreover, we revealed that fresh patient tissue is viable up to 24 hours post-resection. This information is important as it applies to the development and sharing of PDXs.

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Growth of xenografted squamous cell carcinoma of the head and neck ‐ possible correlation with patient survival

Cited by 8 publications

References 15 publications

Tumor grafts derived from patients with head and neck squamous carcinoma authentically maintain the molecular and histologic characteristics of human cancers

Tumor grafts derived from patients with head and neck squamous carcinoma authentically maintain the molecular and histologic characteristics of human cancers

A patient tumor transplant model of squamous cell cancer identifies PI3K inhibitors as candidate therapeutics in defined molecular bins

Influence of Handling Conditions on the Establishment and Propagation of Head and Neck Cancer Patient Derived Xenografts

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