Tumor Promoting Effect of Phenolphthalein on Development of Lung Tumors Induced by N-ethyl-N-nitrosourea in Transgenic Mice Carrying Human Prototype c-Ha-ras Gene.

Imaoka, Masako; Kashida, Yoko; Watanabe, Takao; Ueda, Makoto; Oda, Hiroshi; Hirose, Masao; Mitsumori, Kunitoshi

doi:10.1292/jvms.64.489

Cited by 5 publications

(3 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…( 10 ) As this transgene is under the control of its own promoter region, it is expressed in the whole body, allowing the study of carcinogenesis in different organs. ( 11 ) RasH2 mice are highly susceptible to chemical carcinogenesis, ( 12–15 ) and currently being evaluated to characterize their biological features by worldwide validation studies with a variety of chemicals. ( 16–18 ) Mutational analysis of endogenous and transgenic c‐Ha‐ ras genes shows that point mutations of the transgene at codons 12 and 61 have been implicated in the development of spontaneous tumors such as lung adenocarcinoma, ( 9,19 ) skin and forestomach squamous cell carcinoma, ( 19,20 ) skin papillomas, ( 9 ) liver ( 21 ) and splenic ( 9 ) hemangiosarcomas, and of chemically induced tumors.…”

mentioning

confidence: 99%

Rapid induction of skin tumors in human but not mouse c‐Ha‐ras proto‐oncogene transgenic mice by chemical carcinogenesis

2006

View full text Add to dashboard Cite

The rasH2 transgenic mice carry human c-Ha-ras proto-oncogene, and are highly susceptible to chemical carcinogenesis. Previous studies showed that the mutation of c-Ha-ras induced by DMBA in the tumors of rasH2 were detected only in transgenes. To examine if the difference between the codons of the c-Ha-ras gene in human and mouse contributed to the tissue-specific sensitivity to DMBA, we generated a line of transgenic mice, mras, carrying mouse c-Ha-ras genome with its own promoter. Western blot analysis showed that the protein expression of H-RAS in the skin was increased in both rasH2 and mras compared with wild-type. Chemical skin carcinogenesis was induced by DMBA and TPA. In rasH2 mice, the latency of tumor formation was shorter than wild-type littermates. Both the number and the volume of skin tumors were increased in rasH2 than those of wild-type. However, in mras mice, enhancement of tumor formation was not observed as compared with wild-type. Based on work in experimental animal model systems, the carcinogenesis process can be divided both operationally and mechanistically into the initiation, promotion, and progression stages.(2,3) The initiation stage is an irreversible event in which carcinogens damage DNA and induce mutations in critical genes in target stem cells. During the promotion stage, initiated cells undergo selective clonal expansion due to the acquisition of a proliferative advantage, and/or of the ability to evade growth inhibitory or apoptotic signals.(3) This clonal expansion of initiated cells enhances the probability of additional genetic mutations that might lead to the development of malignant lesions.(2) Malignant neoplastic cells possess an indefinite proliferative capability, thus being able to elude a commitment to terminal differentiation and postmitotic quiescence that normally regulates tissue homeostasis in an organism. In order to achieve a proliferative autonomy, malignant neoplastic cells have to either switch to an autocrine production of mitogenic factors or acquire activating mutations within the components of the signal transduction pathways that mediate mitogenic signaling. An example of this is the activating mutations of c-Ha-ras.(4) The RAS proteins have essential roles in controlling the activity of several crucial signaling pathways that regulate normal cellular proliferation. The RAS proteins are members of a large superfamily of low-molecular-weight GTP-binding proteins that regulates proliferation, differentiation, and cell survival. Three members of the RAS family -H-RAS, K-RAS and N-RAS -are found to be activated by mutation in human tumors (5) and are postulated to be involved in tumor development. Almost all RAS activation in tumors is accounted for by mutations at codons 12, 13 and 61.(6) These mutations all compromise the GTPase activity of RAS, preventing GAP from promoting hydrolysis of GTP on RAS and therefore causing RAS to accumulate in the GTP-bound, active form. The pivotal role of RAS proteins in the development of cancer prompted the study of ...

show abstract

mentioning

confidence: 99%

Rapid induction of skin tumors in human but not mouse c‐Ha‐ras proto‐oncogene transgenic mice by chemical carcinogenesis

2006

View full text Add to dashboard Cite

show abstract

“…In einem entsprechenden Versuch war ein Ergebnis bereits nach sechs Monaten zu erhalten -bei Kontrolltieren erst nach zwei Jahren, einem Alter, zu dem die Lebensspanne einer Maus zu Ende geht, und somit viele Tiere nicht mehr für eine statistische Analyse des Experimentes genutzt werden können. Mit Hilfe dieser transgenen Tiere kann also bei entsprechender Fragestellung wesentlich schneller und mit wesentlich weniger Tieren eine statistisch signifikante Aussage erreicht werden (Imaoka et al 2002.…”

Section: Testsystemeunclassified

Transgene Tiere

2006

View full text Add to dashboard Cite

“…RasH2 mice carry the human c‐Ha‐ ras protooncogene with its own promoter region, ( 9 ) and are highly susceptible to chemical carcinogenesis. ( 10–12 ) We previously reported that rasH2 mice had enhanced chemical skin carcinogenesis in response to treatment with DMBA and TPA. ( 9 ) In rasH2 mice, the number and total volume of papillomas were far greater than those of their wild‐type littermates, presumably because of the increased abundance of initiated cells in rasH2 mice.…”

mentioning

confidence: 99%

Decreased c‐kit function inhibits enhanced skin carcinogenesis in c‐Ha‐ras protooncogene transgenic mice

2007

View full text Add to dashboard Cite

We previously showed that rasH2 transgenic mice carrying the human c-Ha-ras protooncogene are highly susceptible to chemical skin carcinogenesis. In the dermis of rasH2 mice, mast cells are recruited constitutively, and the number of mast cells increases more than in wild-type mice in response to treatment with 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate. To determine whether enhanced skin tumor development in rasH2 mice is dependent on the recruitment of mast cells, we generated rasH2 (1) Based on the results of work in experimental animal model systems, the carcinogenesis process can be divided into the initiation, promotion and progression stages.(2,3) The initiation stage is an irreversible event in which carcinogens damage DNA and induce mutations in critical genes in target stem cells. During the promotion stage, initiated cells undergo selective clonal expansion due to the acquisition of a proliferative advantage, or the ability to evade growth inhibitory or apoptotic signals. An example of this is the activating mutations of c-Ha-ras.(4) Three members of the RAS family -H-RAS, K-RAS and N-RASare activated by mutations in human tumors.(5) Almost all RAS activation in tumors is accounted for by mutations at codons 12, 13 and 61.(6) These mutations all compromise the GTPase activity of RAS, preventing GAP from promoting hydrolysis of the GTP binding to RAS and therefore causing RAS to accumulate in the GTP-bound, active form.The mouse skin carcinogenesis model is one of the most well-defined in vivo models of experimental carcinogenesis. In DMBA-initiated mouse skin, repeated applications of the tumor promoter TPA promotes papillomas and eventually carcinomas. DMBA induces a mutation at either codon 12 or 61 of the Ha-ras gene. Consequent addition of TPA has a promotion effect, activating Stat3. (8) RasH2 mice carry the human c-Ha-ras protooncogene with its own promoter region, (9) and are highly susceptible to chemical carcinogenesis. (10)(11)(12) We previously reported that rasH2 mice had enhanced chemical skin carcinogenesis in response to treatment with DMBA and TPA. (9) In rasH2 mice, the number and total volume of papillomas were far greater than those of their wildtype littermates, presumably because of the increased abundance of initiated cells in rasH2 mice. Furthermore, the latency of the formation of both squamous cell papilloma and squamous cell carcinoma after treatment with DMBA was shorter in rasH2 mice. This shorter duration of latency in tumor development compared with wild-type mice suggests that the activated rasH2 gene functions as a tumor promoter. (9) Ras oncogene expression promotes and sustains the tumorhost interactions that are essential for neoplastic development. Constitutive Ras activity has been shown to contribute to increased tumor cell invasiveness through the activation of matrix metalloproteinases.(13) During tumor progression, cancer cells recruit immune cells, which remodel the tumor stroma and initiate angiogenesis. (14)(15)(16) Indeed, mast...

show abstract

Tumor Promoting Effect of Phenolphthalein on Development of Lung Tumors Induced by N-ethyl-N-nitrosourea in Transgenic Mice Carrying Human Prototype c-Ha-ras Gene.

Cited by 5 publications

References 11 publications

Rapid induction of skin tumors in human but not mouse c‐Ha‐ras proto‐oncogene transgenic mice by chemical carcinogenesis

Rapid induction of skin tumors in human but not mouse c‐Ha‐ras proto‐oncogene transgenic mice by chemical carcinogenesis

Transgene Tiere

Decreased c‐kit function inhibits enhanced skin carcinogenesis in c‐Ha‐ras protooncogene transgenic mice

Contact Info

Product

Resources

About