Multi-step lung carcinogenesis model induced by oral administration of N-nitrosobis(2-hydroxypropyl)amine in rats

Tsujiuchi, Toshifumi; Nakae, Dai; Konishi, Yoichi

doi:10.1016/j.etp.2013.11.006

Cited by 5 publications

(6 citation statements)

References 74 publications

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“…The primary difference in proliferative lesions in rats administered MWCNT-A and MWCNT-B was the induction of bronchiolo-alveolar cell hyperplasia: 3/20 and 2/20 in the 0.5 and 1.0 MWCNT-A groups and 6/20 and 9/20 in the 0.5 and 1.0 mg MWCNT-B groups. While hyperplastic lesions may or may not develop into tumors, cells that eventually become carcinogenic go through abnormal changes that result in development of hyperplasia, followed by development of benign tumors (adenomas), and finally development of malignant tumors (carcinomas) [ 25 , 26 ]. Thus, animals exposed to carcinogens will develop all three types of proliferative lesions.…”

Section: Discussionmentioning

confidence: 99%

Comparative carcinogenicity study of a thick, straight-type and a thin, tangled-type multi-walled carbon nanotube administered by intra-tracheal instillation in the rat

et al. 2020

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Background Multi-walled carbon nanotubes can be divided into two general subtypes: tangled and straight. MWCNT-N (60 nm in diameter) and MWCNT-7 (80–90 nm in diameter) are straight-type MWCNTs, and similarly to asbestos, both are carcinogenic to the lung and pleura when administered to rats via the airway. Injection of straight-type MWCNTs into the peritoneal cavity also induces the development of mesothelioma, however, injection of tangled-type MWCNTs into the peritoneal cavity does not induce carcinogenesis. To investigate these effects in the lung we conducted a 2-year comparative study of the potential carcinogenicities of a straight-type MWCNT, MWCNT-A (approximately 150 nm in diameter), and a tangled-type MWCNT, MWCNT-B (7.4 nm in diameter) after administration into the rat lung. Crocidolite asbestos was used as the reference material, and rats administered vehicle were used as the controls. Test materials were administered by intra-Tracheal Intra-Pulmonary Spraying (TIPS) once a week over a 7 week period (8 administrations from day 1 to day 50), followed by a 2-year observation period without further treatment. Rats were administered total doses of 0.5 or 1.0 mg MWCNT-A and MWCNT-B or 1.0 mg asbestos. Results There was no difference in survival between any of the groups. The rats administered MWCNT-A or asbestos did not have a significant increase in bronchiolo-alveolar hyperplasia or tumors in the lung. However, the rats administered MWCNT-B did have significantly elevated incidences of bronchiolo-alveolar hyperplasia and tumors in the lung: the incidence of bronchiolo-alveolar hyperplasia was 0/20, 6/20, and 9/20 in the vehicle, 0.5 mg MWCNT-B, and 1.0 mg MWCNT-B groups, respectively, and the incidence of adenoma and adenocarcinoma combined was 1/19, 5/20, and 7/20 in the vehicle, 0.5 mg MWCNT-B, and 1.0 mg MWCNT-B groups, respectively. Malignant pleural mesothelioma was not induced in any of the groups. Conclusions The results of this initial study indicate that tangled-type MWCNT-B is carcinogenic to the rat lung when administered via the airway, and that straight-type MWCNT-A did not have higher carcinogenic potential in the rat lung than tangled-type MWCNT-B.

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Section: Discussionmentioning

confidence: 99%

Comparative carcinogenicity study of a thick, straight-type and a thin, tangled-type multi-walled carbon nanotube administered by intra-tracheal instillation in the rat

et al. 2020

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“…Second, the genetic manipulation in many, probably most, of these animal models is not set in a "turn-on/turn-off" mode, and thus does not allow researchers to control the target gene to determine whether or not the lesions are inducer-dependent. Moreover, for the induction of visceral tumors, like the N-nitrosobis (2-hydroxypropyl)amine-instigated lung tumors [463], the determination is more difficult as it requires sacrifice of the animals. We surmise that most of the undetermined animal models may also show an inducer dependency until a late stage, with their carcinogenic procedures following the aforementioned trajectory of "induction, reversibility, and progression" described by Rusch [71].…”

Section: Most Animal Models Have Not Yet Been Tested For the Trajectomentioning

confidence: 99%

Evidence for immortality and autonomy in animal cancer models is often not provided, which causes confusion on key issues of cancer biology

Dou¹,

Tong²,

Huang³

et al. 2020

J. Cancer

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Modern research into carcinogenesis has undergone three phases. Surgeons and pathologists started the first phase roughly 250 years ago, establishing morphological traits of tumors for pathologic diagnosis, and setting immortality and autonomy as indispensable criteria for neoplasms. A century ago, medical doctors, biologists and chemists started to enhance "experimental cancer research" by establishing many animal models of chemical-induced carcinogenesis for studies of cellular mechanisms. In this second phase, the two-hit theory and stepwise carcinogenesis of "initiation-promotion" or "initiation-promotion-progression" were established, with an illustrious finding that outgrowths induced in animals depend on the inducers, and thus are not authentically neoplastic, until late stages. The last 40 years are the third incarnation, molecular biologists have gradually dominated the carcinogenesis research fraternity and have established numerous genetically-modified animal models of carcinogenesis. However, evidence has not been provided for immortality and autonomy of the lesions from most of these models. Probably, many lesions had already been collected from animals for analyses of molecular mechanisms of "cancer" before the lesions became autonomous. We herein review the monumental work of many predecessors to reinforce that evidence for immortality and autonomy is essential for confirming a neoplastic nature. We extrapolate that immortality and autonomy are established early during sporadic human carcinogenesis, unlike the late establishment in most animal models. It is imperative to resume many forerunners' work by determining the genetic bases for initiation, promotion and progression, the genetic bases for immortality and autonomy, and which animal models are, in fact, good for identifying such genetic bases.

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“…Active ERK was observed in scattered areas of the tumors (Figure 4I), similarly to spontaneous tumorlets (Figure 3G). No tumors were developed in control mice, which is unexpected, given the reported activation of Kras in DHPN-induced mouse lung tumors [20]. …”

Section: Resultsmentioning

confidence: 99%

“…In an attempt to provide further clarification to these possible oncogenic inputs required, we performed chemical carcinogenesis using two well known lung carcinogens, DHPN and urethane, that cause Kras activation [19, 20, 22]. We observed that under our experimental conditions DHPN is insufficient to cause tumor development in control mice, probably due to the mixed background of the strain used [44], although a potential role of p107 deficiency can not be discarded at present.…”

Section: Discussionmentioning

confidence: 97%

“…DHPN, a potent mutagen and a wide-spectrum carcinogen in rodents induces lung tumors when given in drinking water [16–18]. Mutational activation of Kras has been described in these rodent lung tumors [19, 20]. Urethane (ethyl carbamate), a component of various food products and cigarette smoke, induces the formation of lung tumors in animal models.…”

Section: Introductionmentioning

confidence: 99%

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Ablating all three retinoblastoma family members in mouse lung leads to neuroendocrine tumor formation

et al. 2016

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Lung cancer is a deadly disease with increasing cases diagnosed worldwide and still a very poor prognosis. While mutations in the retinoblastoma (RB1) tumor suppressor have been reported in lung cancer, mainly in small cell lung carcinoma, the tumor suppressive role of its relatives p107 and p130 is still a matter of debate. To begin to investigate the role of these two Rb family proteins in lung tumorigenesis, we have generated a conditional triple knockout mouse model (TKO) in which the three Rb family members can be inactivated in adult mice. We found that ablation of all three family members in the lung of mice induces tumorlets, benign neuroendocrine tumors that are remarkably similar to their human counterparts. Upon chemical carcinogenesis, DHPN and urethane accelerate tumor development; the TKO model displays increased sensitivity to DHPN, and urethane increases malignancy of tumors. All the tumors developing in TKO mice (spontaneous and chemically induced) have neuroendocrine features but do not progress to fully malignant tumors. Thus, loss of Rb and its family members confers partial tumor susceptibility in neuroendocrine lineages in the lungs of mice. Our data also imply the requirement of other oncogenic signaling pathways to achieve full transformation in neuroendocrine lung lesions mutant for the Rb family.

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Multi-step lung carcinogenesis model induced by oral administration of N-nitrosobis(2-hydroxypropyl)amine in rats

Cited by 5 publications

References 74 publications

Comparative carcinogenicity study of a thick, straight-type and a thin, tangled-type multi-walled carbon nanotube administered by intra-tracheal instillation in the rat

Comparative carcinogenicity study of a thick, straight-type and a thin, tangled-type multi-walled carbon nanotube administered by intra-tracheal instillation in the rat

Evidence for immortality and autonomy in animal cancer models is often not provided, which causes confusion on key issues of cancer biology

Ablating all three retinoblastoma family members in mouse lung leads to neuroendocrine tumor formation

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