Experimental model of tumors associated with neurofibromatosis

Abstract

Four groups of animals, each composed of 22 pregnant Wistar rats, were used in this study. Single intraperitoneal (IP) injections of ethylnitrosourea (ENU) at a dose of 15 mg/kg body weight (BW) were given to the animals of two groups on days 15 and 21 of pregnancy, respectively. The progeny of a third group received by subcutaneous injection (SC) the same dose of ENU, 15 mg/kg BW, on day 1 postnatally. The descendants of the fourth group served as untreated controls. The most striking findings were observed in the progeny of the mothers treated on day 15 of pregnancy, in which group 64 of 180 descendants developed peripheral nervous system (PNS) tumors, 30% of which had plexiform pattern. One hundred fifteen of the 180 descendants developed central nervous system (CNS) gliomas, mainly oligodendrogliomas, and five animals presented with Wilms' tumors. No tumors of these types were observed in the untreated controls. Although descendants of mothers treated on day 21 of pregnancy had the highest number of PNS tumors (130 of 172 animals), only 21% of these tumors were plexiform; CNS gliomas were observed in 78 animals and Wilm's tumors in one animal. The lowest percentage of PNS tumors with plexiform pattern (16%) was found in the group of 157 descendants treated postnatally on day 1, in which 88 animals developed PNS tumors, 76 developed CNS gliomas, and no animals developed Wilms' tumors. The higher percentage of plexiform PNS tumors found in the descendants treated prenatally on day 15 of pregnancy was statistically significant (P less than 0.05) when compared with the percentage found in the group treated postnatally. This significance was also valid for the plexiform tumors that developed selectively from branches of the trigeminal nerves (of the PNS tumors from this location, 48% showed a plexiform pattern), but only in the progeny exposed to ENU on day 15 of pregnancy. This same progeny also had the highest numbers of CNS and Wilms' tumors. Because in humans, plexiform neurofibromas are considered to be the neoplastic markers of neurofibromatosis, and CNS gliomas as well as Wilms' tumors are associated with this disease, it is suggested that exposure to ENU on day 15 of pregnancy, under the experimental conditions described here, may offer a model for investigating tumors associated with neurofibromatosis, as well as aspects of the spontaneous, noninherited forms of this disease.

Proliferative and Nonproliferative Lesions of the Rat and Mouse Central and Peripheral Nervous Systems

“…Characteristics were compiled from the following references: Koestner, Swenberg, and Wechsler 1971;Stewart et al 1974;Mandybur and Brunner 1982;Swenberg 1982;Gough et al 1986;Alison et al 1987;Laber-Laird, Jokinen, and Jerome 1988;Landes et al 1988Landes et al , 1990Ward 1988a, 1988b;Cardesa et al 1989Cardesa et al , 1990Russel and Rubinstein 1989;Maekawa and Mitsumori 1990;White et al 1990;Yoshitomi and Brown 1990;Yoshitomi and Boorman 1991;Greaves, Faccini, andCourtney 1992, 2004;Jensen et al 1993;Walker et al 1994;Krinke 1996;Kleihues and Cavenee 1997;Ernst et al 2001;Ikeda, Sato, and Sueyoshi 2003;Stemmer-Rachamimov et al 2004;Teredesai and Wöhrmann 2005; expansive, compressing, usually encapsulated lesions located near a peripheral nerve or nerve plexus, commonly growing without inducing clinical signs; two basic patterns are characteristically observed: Comment: In the rat, characteristic lesions occur in the heart (endocardial schwannoma, schwannomatosis), near the ear pinna, inside the eye (intraocular) and orbit, and in the mandibular salivary gland. The incidence is quite low in all strains tested (Novilla et al 1991).…”

Expression of theneuproto‐oncogene by schwann cells during peripheral nerve development and wallerian degeneration

“…also plays a role in experimental tumorigenesis in the peripheral nervous system. Administration of ethylnitrosourea to rats in late gestation or in the early postnatal period frequently produces peripheral nervous system tumors of Schwann cell (SC) origin (Stoica and Koestner, 1984;Perantoni et al, 1987;Sukumar et al, 1988;Cardesa et al, 1989). In these tumors, neu is the most commonly identified transforming gene (Perantoni et al, 1987;Sukumar et al, 1988).…”

Transplacental Carcinogenicity of N-Ethyl-N-Nitrosourea in Sprague-Dawley Rats

“…Transplacental tumorigenesis has been studied with dimethylnitrosoamine 2 , 3,3-dimethyl-1-phenyltriazene 8 , azo-and azoxyethan 9 , and ENU [1][2][3][4][5][6][7] . Almost all of these studies, however, have reported their tumorigenesis in selected organs or tissues, such as the renal tumors 10-14 , including nephroblastoma [1][2][3]15 , and neuroectodermal tumors [5][6][7][16][17][18][19] .…”

“…Thirty-seven of 44 males (84.1%) and 55/64 females (85.9%) had one or more tumors of these kinds in the nervous system. These findings are again in agreement with transplacental induction of neuroectodermal tumors [5][6][7] as various kinds of gliomas in the CNS and schwannoma in the PNS. The changes in gross behavior or general appearance included decreased locomotor activity and abnormal gait in the ENU-treated rats on and after Week 16 (female) or Week 17 (male) of birth.…”

“…The transplacental exposure to ENU is known to induce not only nephroblastoma [1][2][3][4] and renal tubular cell tumor 3,4 in the kidney, but also neuroectodermal tumors [5][6][7] such as various kinds of gliomas in the central nervous system (CNS) and schwannoma in the peripheral nervous system (PNS). Although these studies have examined the carcinogenicity of transplacental ENU in selected organs or tissues individually, little is known about the details of transplacental carcinogenesis of ENU covering as many organs as possible at a time throughout the whole body.…”