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Restraint stress does not diminish the survival CF-1 mice (A). The Bryne score for each of the traits in the ITF analysis system. No significant differences between mice in the RS/4-NQO and 4-NQO groups (B).
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Pathogenic processes have been identified that could associate chronic stress and cancer, but these findings have not been observed in oral cancer. This study examined the role of chronic restraint stress on the incidence and severity of OSCC induced with 4-nitroquinoline-1-oxide (4-NQO) in the tongues of CF-1 mice. One hundred twenty CF-1 male mic...
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... stress did not increase the severity of any morpho- logical characteristics evaluated in ITF of 4-NQO-induced OSCC tongue lesions in CF-1 mice. The various parameters studied with Bryne's system are presented in Fig. 2B. Carcinomas of mice in the 4-NQO group tended to have a greater dispersion of scores. For each characteristic evaluated in the ITF, compari- son was made between groups by the Mann-Whitney U test, showing no statistically significant differences (p < ...
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This study aimed to examine the role of chronic restraint stress (RS) on oral squamous cell carcinomas induced by 4-nitroquinoline-1-oxide (4-NQO) in CF-1 mouse tongues, measured by the expression of argyrophilic staining of nucleolar organizer regions (AgNOR). Thirty one samples of lingual epithelial tissue of CF-1 mice with a diagnosis of oral sq...
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... However, it has also been reported that restraint stress alone did not significantly promote colorectal cancer growth in a similar xenograft mouse model (60). Another study showed that CRS did not decrease the survival of an oral squamous cell carcinoma mouse model (61). ...
The existence of a clear association between stress and cancer is still a matter of debate. Recent studies suggest that chronic stress is associated with some cancer types and may influence tumor initiation and patient prognosis, but its role in brain tumors is not known. Glioblastoma (GBM) is a highly malignant primary brain cancer, for which effective treatments do not exist. Understanding how chronic stress, or its effector hormones glucocorticoids (GCs), may modulate GBM aggressiveness is of great importance. To address this, we used both syngeneic and xenograft in vivo orthotopic mouse models of GBM, in immunocompetent C57BL/6J or immunodeficient NSG mice, respectively, to evaluate how different paradigms of stress exposure could influence GBM aggressiveness and animals’ overall survival (OS). Our results demonstrated that a previous exposure to exogenous corticosterone administration, chronic restraint stress, or chronic unpredictable stress do not impact the OS of these mice models of GBM. Concordantly, ex vivo analyses of various GBM-relevant genes showed similar intra-tumor expression levels across all experimental groups. These findings suggest that corticosterone and chronic stress do not significantly affect GBM aggressiveness in murine models.
... They found that the microbiome enhances tumorigenesis through several physiological processes (response to stress, nitrogen transport, interspecies interactions, Wnt pathway modulation, and amino acid and lipid biosynthesis). Among them, the response to acute and chronic stress was already shown to promote oral cancer development Rivera et al., 2011). Furthermore, specific pathogens, such as Candida albicans, have been reported to promote the transformation of oral dysplasia to OSCC (Dwivedi et al., 2009). ...
The early detection and management of oral premalignant lesions (OPMDs) improve their outcomes. Animal models that mimic histological and biological processes of human oral carcinogenesis may help to improve the identification of OPMD at-risk of progression into oral squamous cell carcinoma and to develop preventive strategies for the entire field of cancerization. No animal model is perfectly applicable for investigating human oral carcinogenesis. However, the 4-nitroquinoline 1-oxide (4-NQO) mouse model is well established and mimics several morphological, histological, genomic and molecular features of human oral carcinogenesis. Some of the reasons for the success of this model include its reproducible experimental conditions with limited variation, the possibility of realizing longitudinal studies with invasive intervention or gene manipulation, and sample availability for all stages of oral carcinogenesis, especially premalignant lesions. Moreover, the role of histological and molecular alterations in the field of cancerization (i.e., macroscopically healthy mucosa exposed to a carcinogen) during oral carcinogenesis can be easily explored using this model. In this review, we discuss the advantages and drawbacks of this model for studying human oral carcinogenesis. In summary, the 4-NQO-induced murine oral cancer model is relevant for investigating human oral carcinogenesis, including the immune microenvironment, and for evaluating therapeutic and chemoprevention agents.
... The main risk factors for developing oral cancer are tobacco smoking and alcohol consumption [3]. The development of oral cancer is a complex process, and for their understanding in animal models of carcinogenesis that accurately represents the cellular and molecular changes associated with initiation and progression of human oral cancer have been deployed [4]. The experimental oral carcinogenesis induced by the chemical 4NQO is one of the techniques that are most frequently used in the study of squamous cell carcinoma of the oral cavity. ...
Geraniol, an acyclic monoterpene found in lemon grass and aromatic herb oil, has been shown to exert antitumor and antioxidant activities against various cancer types. The objective of this study was to investigate the potential chemoprotective role of geraniol against 4-nitroquinoline-1-oxide (4NQO)-induced oral carcinogenesis in male Wistar rats and furthermore to study anti-inflammatory mechanisms of action through possible NF-κB signaling. 4NQO was administered to rats at the dose of 50 ppm through drinking water to induce tongue cancer in 20 weeks. 4NQO provoked inflammation by upregulating the expressions of the p65 subunit nuclear factor kappa-β (NF-κB) in the nucleus, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). Additionally, staining for immature and mature mast cells in cancer niche by toluidine blue staining and alcian blue–safranin staining showed more accumulation. Co-treatment of geraniol 200 mg/kg b.w. showed a significant decrease in the level of p65 NF-κB in the nucleus, and this might be due to the inhibition of NF-κB activation/translocation into nucleus, which was further confirmed by decreased immature and mature mast cell density and the expression of inflammatory downstream mediators such as TNF-α, IL-1β, COX-2, and iNOS. Collectively, our results suggested that geraniol as a potential anti-inflammatory agent having the capability to obstruct 4NQO initiated NF-κB activation and modulated the expression of inflammatory mediators.
... Fatme Mouchref Hamasni*, Fady El Hajj classify tumor lesions; the International Histological Classification of Tumors and the pattern of the TIF (Rivera et al., 2011). The initial classification of lesions which is considered in the current study is based on the degree of tumor differentiation (well, moderately and undifferentiated), which is essential to evaluate the tumor's growth rate and ability to metastasize (Rivera and Venegas, 2014) Bone morphogenetic proteins (BMPs) are a protein family secreted to the extracellular environment as a mechanism of intercellular communication and work as ligands of specific receptors that are on target cells. ...
Background and Objective : Bone morphogenic protein-2 (BMP-2) plays an essential role in mesenchymal cell differentiation into osteoblasts، through many intracellular pathways which may also be active in tumors. Invasive oral squamous cell carcinomas account for more than 90% of head and neck malignancies in many cancer registries. They are classified into three types according to epithelial cell differentiation. The present study aimed to identify any relation between BMP-2 expression and tumor histology. Materials and methods: BMP-2 expression was compared immunohistochemically among 30 cases (19 male and 11 female, mean age 48 years) of oral squamous cell carcinoma, Division was into 3 groups (each containing 10 cases) according to the histological grade. Results: No significant correlation between BMP-2 expression and histological grade was observed. Changes in localization and cytoplasmic staining were also not apparent. Conclusion: From the results of this study BMP-2 does not appear to have any application as a prognostic marker for oral squamous cell carcinomas.
... Yet, studies are scarce to show a direct link between chronic stress and a decrease in survival [5,24]. Furthermore, Rivera et al. could not confirm the postulated relationship between chronic stress and the incidence and severity of oral cancer [10,43]. Finally, the beta-as well as the alpha-adrenergic systems have been implicated in stress-induced cancer growth. ...
Background/objectives:
Chronic stress could promote tumour growth and reduce survival of pancreatic cancer patients via beta-adrenergic receptors of tumour cells. We have tested the impact of chronic acoustic and restraint stress on tumour development in an orthotopic syngeneic murine model of pancreatic cancer.
Methods and results:
Tumour-bearing C57BL/6 mice exposed to chronic stress had 45% (p = 0.0138) higher circulating steroid and 111% (p = 0.0052) higher adrenal tyrosine hydroxylase levels. Their immune response was significantly suppressed: The in vitro LPS response of splenocytes was significantly reduced regarding Th1- and Th2-cytokines including IFN-gamma, IL-6, IL-10 and MCP-1 (0.0011 < p < 0.043). Also, tumours of stressed mice showed a tendency towards fewer total CD4 cells, more regulatory T cells (Treg), less T cell/tumour cell contacts and a reduction of CTLA-4 in CD4 cells (p > 0.05). TGF-beta in vitro was increased by 23.4% using catecholamines (p < 0.012) and in vivo employing chronic stress (p < 0.001). After 5 weeks tumour volumes were 130% (p = 0.0061) larger and median survival reduced by 13.5% (p = 0.0058). Tumours expressed more VEGF (p = 0.0334), had greater microvessel densities (p = 0.047), and an increased MMP-9 expression (p = 0.0456). Beta-catecholamines increased proliferation in tumour cells by 18% (p < 0.0001) and migration by 78% (p = 0.0348) whereas the beta-blocker propranolol reduced these effects by 25% (p < 0.0001) and 53% (p = 0.045), respectively. When stressed tumour-bearing animals were treated with propranolol tumour volumes were reduced by 69% (p = 0.0088) and survival improved by 14% (p < 0.0058).
Conclusions:
The potential treatment with beta-blockers of patients with pancreatic cancer or other malignancies should be further evaluated as an adjuvant anti-neoplastic agent in clinical trials.
... Experimental carcinogenesis induced by 4-nitroquinoline 1-oxide (4-NQO) in mice is one of the most frequently used animal models for the study of oral cancer (17). In this system, the clinical, histological and molecular changes of the oral mucosa are similar to those observed in humans during oral carcinogenesis (18,19). ...
... The use of 4-NQO is a valuable technique for inducing OSCC, and induces carcinogenesis in animal models in a manner similar to the natural progression of OSCC in humans (17,18). 4-NQO is a water-soluble quinoline derivative and is known to form DNA adducts. ...
Oral squamous cell carcinoma (OSCC) is the most common form of head and neck cancer, and oxidative damage is associated with the development of OSCCs. Antioxidants have therefore been proposed for use as chemoprotective agents against different types of cancer. In the present study, the effect of the antioxidant quercetin, administered at doses of 10 and 100 mg/kg/day, was investigated in an experimental murine model of 4-nitroquinoline 1-oxide (4-NQO)-induced carcinogenesis. The survival of the treated animals, the plas-matic levels of reduced glutathione and the type and severity of lesions (according the International Histological Classification of Tumors and Bryne's Multifactorial Grading System for the Invasive Tumor Front) were assessed. Additionally, the organization of the extracellular matrix was analyzed by carbohydrate and collagen histochemistry, and immunohistochemistry was used to assess the expression of the tumor markers proliferating cell nuclear antigen and mutated p53. The results indicate that, despite the promising effect of quercetin in other studies, this drug is ineffective as a chemoprotective agent against 4-NQO-induced OSCC in mice at the assayed doses.
... Genetic manipulation of cells allows silencing and overexpression of certain products, which can also be brought in vitro or in vivo (animal models). Chemical carcinogenesis is useful to study the progressive changes that occurs throughout oral carcinogenesis from normal tissues, through dysplastic changes until the invasive carcinoma [47]. The most frequently used chemicals are the 9,10-dimethyl-1,2-benzanthracene (DMBA) and 4-nitroquinoline-1 oxide (4NQO). ...
Oral cancer is one of the 10 most common cancers in the world, with a delayed clinical detection, poor prognosis, without specific biomarkers for the disease and expensive therapeutic alternatives. This review aims to present the fundamental aspects of this cancer, focused on squamous cell carcinoma of the oral cavity (OSCC), moving from its definition and epidemiological aspects, addressing the oral carcinogenesis, oral potentially malignant disorders, epithelial precursor lesions and experimental methods for its study, therapies and future challenges. Oral cancer is a preventable disease, risk factors and natural history is already being known, where biomedical sciences and dentistry in particular are likely to improve their poor clinical indicators.
... Experimental carcinogenesis induced by 4-nitroquinoline 1-oxide (4-NQO) in mice is one of the most frequently used animal models for the study of oral cancer (17). In this system, the clinical, histological and molecular changes of the oral mucosa are similar to those observed in humans during oral carcinogenesis (18,19). ...
... The use of 4-NQO is a valuable technique for inducing OSCC, and induces carcinogenesis in animal models in a manner similar to the natural progression of OSCC in humans (17,18). 4-NQO is a water-soluble quinoline derivative and is known to form DNA adducts. ...
Oral squamous cell carcinoma (OSCC) is the most common form of head and neck cancer, and oxidative damage is associated with the development of OSCCs. Antioxidants have therefore been proposed for use as chemoprotective agents against different types of cancer. In the present study, the effect of the antioxidant quercetin, administered at doses of 10 and 100 mg/kg/day, was investigated in an experimental murine model of 4-nitroquinoline 1-oxide (4-NQO)-induced carcinogenesis. The survival of the treated animals, the plas-matic levels of reduced glutathione and the type and severity of lesions (according the International Histological Classification of Tumors and Bryne's Multifactorial Grading System for the Invasive Tumor Front) were assessed. Additionally, the organization of the extracellular matrix was analyzed by carbohydrate and collagen histochemistry, and immunohistochemistry was used to assess the expression of the tumor markers proliferating cell nuclear antigen and mutated p53. The results indicate that, despite the promising effect of quercetin in other studies, this drug is ineffective as a chemoprotective agent against 4-NQO-induced OSCC in mice at the assayed doses.
... Se determinó el efecto de Quercetina sobre la sobrevida de ratones CF-1 que fueron sometidos a carcinogénesis inducida por 4-NQO según se describio previamente (Tang et al., 2004;Rivera et al., 2011). Ratones tratados solamente con 4-NQO presentaron una sobrevida del 65% a las 30 semanas, mientras que los grupos tratados con 4-NQO y/o Quercetina 10 mg/kg/día ó 100 mg/kg/día presentaron una sobrevida de un 60% y 45%, respectivamente (Fig. 8). ...
... CCECOs bien y moderadamente diferenciados con un bajo puntaje del frente de invasión tumoral (Rivera et al., 2011), por lo que el probable efecto quimiopreventivo no sea lo suficientemente marcado. Lo mismo es válido para el análisis de las láminas basales y colágeno I de la MEC del tejido conectivo adyacente al tumor. ...
... n=20): tratamiento con 4-NQO + Quercetina 100 mg/kg/día. Grupo 4 (n=10): control con propilenglicol.Los animales de los tres primeros grupos fueron sometidos a la inducción química de carcinógenos mediante 4-NQO, el que se les administró en el agua de beber a una concentración de 100 µg/mL, equivalentes a una dosis de 12 mg/kg/día, durante 16 semanas, entre la semana 2 a 17(Tang et al., 2004;Rivera et al., 2011). Los animales de los grupos dos y tres recibieron además 0,2 mL de Quercetina disuelta en propelenglicol en dosis de 10 mg/kg/día (grupo 2) y de 100 mg/kg/día (grupo 3) mediante cánula oral entre las semanas 1 y 18 de manera diaria. ...
Cancer is a worldwide public health problem, affecting both developed and developing countries. Oropharyngeal cancer is one of the most prevalent carcinomas (5,7%), affecting approximately 400.000 individuals annually. Squamous cell carcinoma of the oral cavity (SCCOC) represents 80% of these tumors. Treatment of this type of cancer is extremely expensive and radical, and has serious consequences for the patient throughout their lives. Early detection of this neoplasm is the best alternative to prevent these consequences.
Quercetin is one of the most common and widely distributed flavonoids in fruits and vegetables. It is a powerful antioxidant which could induce cellular responses that might contribute to reduce the severity of tumors, making it a candidate as a chemopreventive agent. However, the scientific reports indicates that Quercetin may have oxidant effects in vitro and that the doses required for in vivo antioxidant effects are hardly applicable.
The objetive of this study was to determine the potential chemopreventive effect of Quercetin over 4-NQO induced SCCOC in mice. We determined the effect of Quercetin on preneoplastic and neoplastic lesions, lipoperoxidation levels and reduced glutathione levels in the blood of treated animals. Additionally, the potential toxic effects on lung fibroblast cell cultures (MCR-5) was assessed.
Quercetin at low concentrations prevent the decrease of cell viability caused by 4-NQO, but does not improve survival, nor the incidence or severity of preneoplastic lesions and SCCOC in mice treated with 4-NQO. Quercetin also maintains low blood GSH levels in CF-1 mice exposed to 4-NQO and quercetin.
We conclude, that Quercetin has no chemopreventive effect on lesions in the lingual mucosa in mice subjected to experimental carcinogenesis with 4-NQO.
... Organization) and the tumor invasion front (TIF). Currently, two systems are used to histologically classify tumor lesions; the International Histological Classification of Tumors ( Fig. 1C-E) and the pattern of the TIF (19). The initial classification of lesions is based on the degree of tumor differentiation (well-, moderately-and undifferentiated) (20), which is essential to evaluate the tumor's growth rate and ability to metastasize (14). ...
Oral squamous cell carcinoma (OSCC) represents 95% of all forms of head and neck cancer, and over the last decade its incidence has increased by 50%. Oral carcinogenesis is a multistage process, which simultaneously involves precancerous lesions, invasion and metastasis. Degradation of the cell cycle and the proliferation of malignant cells results in the loss of control mechanisms that ensure the normal function of tissues. The aim of the current review is to present the histopathological features of OSCC, including potentially malignant changes, the international classification of tumors, the tumor invasion front and tumor biomarkers (Ki-67, p53, homeobox genes and collagen type IV), as well as the tumor microenvironment and function of cancer-associated fibroblasts in the most common type of oral cancer that is encountered by dental surgeons. In OSCC, associations have been identified between the proliferation, basal lamina degradation and connective tissue modulation. Therefore, the comparison of these factors with the survival time of OSCC patients from the histopathological diagnosis is of interest.
