The 4-NQO mouse model: An update on a well-established in vivo model of oral carcinogenesis

Bouaoud, Jebrane; Souza, Geneviève De; Darido, Charbel; Tortereau, Antonin; Elkabets, Moshe; Bertolus, Chloé; Saintigny, Pierre

doi:10.1016/bs.mcb.2020.09.004

Cited by 17 publications

(14 citation statements)

References 129 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Loss of heterozygosity (LOH) at specific chromosomal sites has been validated prospectively as the most robust biomarker of risk of oral cancer development in patients with OPMD. Using the 4-NQO murine model of oral carcinogenesis, 7 we have previously shown the role of early epithelial gene expression changes during OPMD malignant transformation. 8 …”

Section: Introductionmentioning

confidence: 99%

Early changes in the immune microenvironment of oral potentially malignant disorders reveal an unexpected association of M2 macrophages with oral cancer free survival

et al. 2021

View full text Add to dashboard Cite

Understanding the dynamics of the immune microenvironment is critical to the development of immuno-based strategies for the prevention of oral potentially malignant disorders transformation to oral squamous cell carcinoma (OSCC). We used laser capture microdissection and RNA-sequencing to profile the expression of 13 matched pairs of epithelial versus stromal compartments from normal mucosa, hyperplasia, dysplasia, and invasive tumors in the 4-nitroquinolein (4-NQO) murine model of oral carcinogenesis. Genes differentially expressed at each step of transformation were defined. Immune cell deconvolution and enrichment scores of various biological processes including immune-related ones were computed. Immunohistochemistry was also performed to characterize the immune infiltrates by T-cells (T-cells CD3+, helper CD4+, cytotoxic CD8+, regulatory FoxP3+), B-cells (B220+), and macrophages (M1 iNOS+, M2 CD163+) at each histological step. Enrichment of three independent M2 macrophages signatures were computed in 86 oral leukoplakia with available clinical outcome. Most gene expression changes were observed in the stromal compartment and related to immune biological processes. Immune cell deconvolution identified infiltration by the macrophage population as the most important quantitatively especially at the stage of dysplasia. In 86 patients with oral leukoplakia, three M2 macrophages signatures were independently associated with improved oral cancer-free survival. This study provides a better understanding of the dynamics of the immune microenvironment during oral carcinogenesis and highlights an unexpected association of M2 macrophages gene expression signatures with oral cancer free survival in patients with oral leukoplakia.

show abstract

Section: Introductionmentioning

confidence: 99%

Early changes in the immune microenvironment of oral potentially malignant disorders reveal an unexpected association of M2 macrophages with oral cancer free survival

et al. 2021

View full text Add to dashboard Cite

show abstract

“…The induction of oral carcinogenesis was optimized for our experiments as previously described(César Andrés Rivera Martínez, 2012; Bouaoud et al, 2021 ). Briefly, 4-nitroquinoline-1-oxide (4NQO) (Sigma-Aldrich, USA) was dissolved in water at 50 μg/mL and stored in a bottle protected by light at 22°C.…”

Section: Methodsmentioning

confidence: 99%

Polypodium leucotomos targets multiple aspects of oral carcinogenesis and it is a potential antitumor phytotherapy against tongue cancer growth

et al. 2023

View full text Add to dashboard Cite

Introduction: Oral cancer refers to malignant tumors, of which 90% are squamous cell carcinomas (OSCCs). These malignancies exhibit rapid progression, poor prognosis, and often mutilating therapeutical approaches. The determination of a prophylactic and/or therapeutic antitumor role of the polyphenolic extract Polypodium leucotomos(PL) would be relevant in developing new tools for prevention and treatment.Methods: We aimed to determine the antitumor effect of PL by treating OSCC cell lines with PL metabolites and evaluating its action during OSCC progression in vivo.Results: PL treatment successfully impaired cell cycling and proliferation, migration, and invasion, enhanced apoptosis, and modulated macrophage polarization associated with the tumoral immune-inflammatory response of tongue cancer cell lines (TSCC). PL treatment significantly decreased the expression of MMP1 (p < 0.01) and MMP2 (p < 0.001), and increased the expression of TIMP1 (p < 0.001) and TIMP2 (p < 0.0001) in these cells. The mesenchymal-epithelial transition phenotype was promoted in cells treated with PL, through upregulation of E-CAD (p < 0.001) and reduction of N-CAD (p < 0.05). PL restrained OSCC progression in vivo by inhibiting tumor volume growth and decreasing the number of severe dysplasia lesions and squamous cell carcinomas. Ki-67 was significantly higher expressed in tongue tissues of animals not treated with PL(p < 0.05), and a notable reduction in Bcl2 (p < 0.05) and Pcna (p < 0.05) cell proliferation-associated genes was found in dysplastic lesions and TSCCs of PL-treated mice. Finally, N-cad(Cdh2), Vim, and Twist were significantly reduced in tongue tissues treated with PL.Conclusion: PL significantly decreased OSCC carcinogenic processes in vitro and inhibited tumor progression in vivo. PL also appears to contribute to the modulation of immune-inflammatory oral tumor-associated responses. Taken together, these results suggest that PL plays an important antitumor role in processes associated with oral carcinogenesis and may be a potential phytotherapeutic target for the prevention and/or adjuvant treatment of TSCCs

show abstract

“…Furthermore, the progression from OPMD to OSCC has shown increased number of CD163+ cells (M2 Macrophages), PD-L1 expression and a decreased number of CD8+ cells [ 52 , 53 , 56 , 57 , 58 , 59 ]. More recently, the Saintigny Team (JB, PS) studied the dynamic of the IME in the 4-NQO murine model of oral carcinogenesis [ 60 ], an accepted model for the human disease in particular at early steps of tumorigenesis [ 61 ]. They found that changes in the composition of immune infiltrate (T-cells, B-cells, M1/M2 macrophages) can already be observed in histologically proven premalignant stages.…”

Section: The Opmd Immune Microenvironment (Ime)mentioning

confidence: 99%

“…Several agents, including coal tar, cigarette smoke, benzo[a]pyrene (B[a]P), 3-methylcholanthrene, 7,12-dimethylbenz(a)anthracene (DMBA) and 4-nitroquinoline-1-oxide (4-NQO) have been used to induce OSCC in rodent models. In particular, the 4-NQO-induced oral carcinogenesis murine model closely resembles human OSCC in terms of pathogenesis, pathological changes, host immune activity, and molecular levels, thus making this model widely acceptable to study OSCC, especially for the identification of biomarkers for early diagnosis and the transformation of the epithelium [ 61 ]. The major limitations of the carcinogen-induced models are (i) the requirement of prolonged animal and carcinogen handling, making them laborious and time-consuming, (ii) the resulting tumours do not recapitulate the tumours in patients, and (iii) it is not possible to study specific gene alterations in the development and malignant transformation process.…”

Section: Preclinical Modelsmentioning

confidence: 99%

Unmet Needs and Perspectives in Oral Cancer Prevention

Bouaoud

Bossi

Elkabets

et al. 2022

Cancers

View full text Add to dashboard Cite

Oral potentially malignant disorders (OPMD) may precede oral squamous cell carcinoma (OSCC). Reported rates of malignant transformation of OPMD range from 3 to 50%. While some clinical, histological, and molecular factors have been associated with a high-risk OPMD, they are, to date, insufficiently accurate for treatment decision-making. Moreover, this range highlights differences in the clinical definition of OPMD, variation in follow-up periods, and molecular and biological heterogeneity of OPMD. Finally, while treatment of OPMD may improve outcome, standard therapy has been shown to be ineffective to prevent OSCC development in patients with OPMD. In this perspective paper, several experts discuss the main challenges in oral cancer prevention, in particular the need to (i) to define an OPMD classification system by integrating new pathological and molecular characteristics, aiming (ii) to better identify OPMD at high risk of malignant transformation, and (iii) to develop treatment strategies to eradicate OPMD or prevent malignant transformation.

show abstract

The 4-NQO mouse model: An update on a well-established in vivo model of oral carcinogenesis

Cited by 17 publications

References 129 publications

Early changes in the immune microenvironment of oral potentially malignant disorders reveal an unexpected association of M2 macrophages with oral cancer free survival

Early changes in the immune microenvironment of oral potentially malignant disorders reveal an unexpected association of M2 macrophages with oral cancer free survival

Polypodium leucotomos targets multiple aspects of oral carcinogenesis and it is a potential antitumor phytotherapy against tongue cancer growth

Unmet Needs and Perspectives in Oral Cancer Prevention

Contact Info

Product

Resources

About