Creating oral squamous cancer cells: A cellular model of oral–esophageal carcinogenesis

Goessel, Gitta; Quante, Michael; Hahn, William C.; Harada, Hideki; Heeg, Steffen; Suliman, Yasir; Doebele, M; Werder, Alexander von; Fulda, Christine; Nakagawa, Hiroshi; Rustgi, Anil K.; Blum, Hubert E.; Opitz, Oliver G.

doi:10.1073/pnas.0409730102

Cited by 47 publications

(48 citation statements)

References 51 publications

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“…More recently, we and others have demonstrated that expression of mammalian proteins can achieve the same feat (Kendall et al, 2006). Specifically, inactivation of p53 and Rb pathways by expression of a dominant-negative p53 protein (p53 DD ) and an activated cyclin-dependent kinase (CDK)/cyclin complex (cyclin D1/CDK4 R24C ) in conjunction with activation of c-Myc, Ras and hTERT pathways via expression of oncogenic forms of c-Myc (c-Myc T58A ) and H-Ras (H-Ras G12V ) and hTERT is sufficient to drive human kidney cells, mammary epithelial cells and myoblasts to a tumorigenic state (Kendall et al, 2005), whereas human keratinocytes (Goessel et al, 2005) and melanocytes (Chudnovsky et al, 2005) (Kendall et al, 2005), it should be possible to similarly drive normal porcine cells to a tumorigenic state by the enforced expression of the same mammalian proteins.…”

Section: Generation Of Porcine Cells Harboring Genetic Changes Commonmentioning

confidence: 99%

Genetic induction of tumorigenesis in Swine

et al. 2006

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The transition from basic to clinical cancer research for a number of experimental therapeutics is hampered by the lack of a genetically malleable, large animal model. To this end, we genetically engineered primary porcine cells to be tumorigenic by expression of proteins known to perturb pathways commonly corrupted in human cancer. Akin to human cells, these porcine cells were quite resistant to transformation, requiring multiple genetic changes. Moreover, the transformed porcine cells produced tumors when returned to the isogenic host animal. The ability to now rapidly and reproducibly genetically induce tumors of sizes similar to those treated clinically in a large mammal similar to humans in many respects will provide a robust cancer model for preclinical studies dependant on generating large tumors.

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Section: Generation Of Porcine Cells Harboring Genetic Changes Commonmentioning

confidence: 99%

Genetic induction of tumorigenesis in Swine

et al. 2006

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“…38 These genetic alterations resulted in keratinocyte immortalization. Immortalization is known to be dependent on telomere maintenance, and it was determined that telomeres were maintained by alternative lengthening of telomeres (ALT), presumably due to a spontaneous mutation.…”

Section: Human Cancer Models Driven By the Expression Of Mammalian Genesmentioning

confidence: 99%

“…36,38,39 In the remaining two models, which used epidermal keratinocytes or melanocytes, 35,37 c-Myc expression was not evaluated. The increased presence of c-Myc may be cell type specific, as both models lacking ectopic expression of the protein focused on skin cells.…”

Section: Cancer Pathwaysmentioning

confidence: 99%

Genetically Engineered Human Cancer Models Utilizing Mammalian Transgene Expression

Kendall¹,

Adam²,

Counter³

2006

Cell Cycle

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Cancer models are vital to cancer biology research, and multiple cancer models are currently available that utilize either murine or human cells, each with particular strengths and weaknesses. The ability to transform primary human cells into tumors through the expression of specific transgenes offers many advantages as a cancer model, including genetic malleability and the ability to transform specific cell types. Until recently, the conversion of primary human cells into tumors through transgene expression required the use of viral genetic elements, which unfortunately adds uncertainty regarding which cancer pathways are affected and how they are affected. In recent years multiple reports have described the transformation of primary human cells into tumors using only mammalian transgenes. This review focuses on these five cancer models, comparing the different cell types which were transformed into tumors and which transgenes were expressed, as well as the cancer pathways affected in the disparate models. These genetically-engineered human cancer models offer a valuable tool to complement existing cancer models and further cancer research.

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“…Because of the risk factors commonly associated with the development of ESCC and HNSCC, several studies have revealed that ESCC and HNSCC have similar molecular alterations (1)(2)(3)(4)(5)(6)(7)(8). For instance, cyclin D1, p53, EGFR, and c-myc are common important genetic alterations in ESCC and HNSCC carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

Afatinib against Esophageal or Head-and-Neck Squamous Cell Carcinoma: Significance of Activating Oncogenic HER4 Mutations in HNSCC

Nakamura

Togashi

Nakahara

et al. 2016

Molecular Cancer Therapeutics

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The prognosis for patients with advanced esophageal or head-and-neck squamous cell carcinoma (ESCC or HNSCC) remains poor, and the identification of additional oncogenes and their inhibitors is needed. In this study, we evaluated the sensitivities of several ESCC and HNSCC cell lines to HER inhibitors (cetuximab, erlotinib, and afatinib) in vitro and found two cell lines that were hypersensitive to afatinib. Sequence analyses for the afatinib-targeted HER family genes in the two cell lines revealed that one cell line had a previously reported activating EGFR L861Q mutation, whereas the other had an HER4 G1109C mutation of unknown function. No amplification of HER family genes was found in either of the two cell lines. The phosphorylation level of HER4 was elevated in the HER4 G1109C mutation-overexpressed HEK293 cell line, and the mutation had a transforming potential and exhibited tumorigenicity in an NIH3T3 cell line, indicating that this HER4 mutation was an activating oncogenic mutation. Afatinib dramatically reduced the phosphorylation level of EGFR or HER4 and induced apoptosis in the two cell lines. In vivo, tumor growth was also dramatically decreased by afatinib. In a database, the frequencies of HER family gene mutations in ESCC or HNSCC ranged from 0% to 5%. In particular, HER4 mutations have been found relatively frequently in HNSCC. Considering the addiction of cancer cells to activating oncogenic EGFR or HER4 mutations for proliferation, HNSCC or ESCC with such oncogenic mutations might be suitable for targeted therapy with afatinib.

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Creating oral squamous cancer cells: A cellular model of oral–esophageal carcinogenesis

Cited by 47 publications

References 51 publications

Genetic induction of tumorigenesis in Swine

Genetic induction of tumorigenesis in Swine

Genetically Engineered Human Cancer Models Utilizing Mammalian Transgene Expression

Afatinib against Esophageal or Head-and-Neck Squamous Cell Carcinoma: Significance of Activating Oncogenic HER4 Mutations in HNSCC

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