Cyclin D1 overexpression increases susceptibility to 4‐nitroquinoline‐1‐oxide‐induced dysplasia and neoplasia in murine squamous oral epithelium

Abstract

The cyclin D1 oncogene is frequently amplified/overexpressed in oral squamous cell carcinomas. Mice with overexpression of cyclin D1 targeted to the stratified squamous epithelia of the tongue, esophagus and forestomach develop a phenotype of epithelial dysplasia at these sites. In this study, we examined the effect cyclin D1 overexpression on susceptibility of mice to carcinogeninduced tumorigenesis, using 4-nitroquinoline-1-oxide (4NQO), an established potent oral carcinogen in mice. Cyclin D1 overexpressing mice and non-transgenic littermates were administered 4NQO (20 ppm or 50 ppm in the drinking water) for 8 weeks and monitored for an additional 16 weeks. Histopathological analyses of the tongue revealed significantly higher severity of dysplasia in the cyclin D1 overexpression mice, compared with non-transgenic controls and with untreated controls. Moreover, only the cyclin D1 overexpression mice developed neoplastic lesions in the oro-esophageal epithelia. Examination of the dysplastic and neoplastic lesions reveled abnormal proliferation. Our findings suggest that cyclin D1 overexpression enhances susceptibility to carcinogen-induced oral tumorigenesis. These results underscore the importance of cyclin D1 in the process of oral neoplastic development. Further, they emphasize the value of this transgenic model to study the pathogenesis of oral precancer and cancer and establish it as a model system to test candidate agents for chemoprevention of upper aero-digestive cancer.

Roles of coinhibitory molecules B7-H3 and B7-H4 in esophageal squamous cell carcinoma

“…Aberrant expression of B7-H3 and B7-H4 in 4-NQO-induced esophageal carcinogenesis in mice 4-NQO-induced esophageal cancer in mice is an ideal animal model for study of human ESCC [29,30]. Table 3 experienced a series of classical squamous cell transformations from normal esophageal squamous cell through dysplasia to carcinoma.…”

Potential therapeutic applications of muscle-derived mesenchymal stem and progenitor cells

“…In a recent study, co-transfection of MDSCs with the gene coding for BMP-4 and the gene for VEGF led to enhanced endochondral ossification to form bone tissue compared to MDSCs that were transfected with only BMP-4 [74]. VEGF is an important mediator of fracture healing [88], and the synergistic interaction of VEGF with BMP-4 appeared to enable greater recruitment of local MSCs from the bone marrow, promoted angiogenesis of the regenerating tissue and accelerated the process of cartilage tissue resorption [89]. A similar synergistic relationship has been observed in terms of VEGF and BMP-2 expression.…”

Genome-wide analysis of DNA methylation in UVB- and DMBA/TPA-induced mouse skin cancer models

“…This model has been widely used to investigate the anti-tumor efficacy of chemicals and the molecular events that occur during each stage of tumor development. Several genetic alterations identified in human skin cancer patients have also been described in the mouse multistage skin carcinogenesis model, such as changes in cyclin D1 [14], TP53 [15], CDKN21 [16] and PTEN [17]. The underlying similarity in the biology of cancer between mice and humans implies that genes related to mouse tumor development may also be relevant to human tumor development.…”