Social isolation stress facilitates chemically induced oral carcinogenesis.

Social isolation has affected a large number of people and may lead to impairment of physical and mental health. Although stress resulting from social isolation may increase cancer progression, its interference on tumorigenesis is poorly known. In this study, we used a preclinical model to evaluate the effects of social isolation stress on chemically induced oral carcinogenesis. Sixty-two 21-day-old male Wistar rats were divided into isolated and grouped groups. After 90 days of age, the rats from both groups underwent oral carcinogenesis with 4-nitroquinoline 1-oxide (4NQO) for 20 weeks. All rats were assessed for depressive-like behavior and euthanized for oral squamous cell carcinoma (OSCC) diagnosis and measurement of inflammatory mediators in the tumor microenvironment. Social isolation stress increased the OSCC occurrence by 20.4% when compared to control. Isolated rats also showed higher tumor volume and cachexia than the grouped rats. Social isolation did not induce changes in the depressive-like behavior after carcinogenic induction. Tumors from stressed rats had increased levels of the inflammatory mediators, TNF-alpha, IL1-beta and MCP-1. The concentrations of TNF-alpha and MCP-1 were significantly increased in the large tumors from isolated animals. Higher tumor levels of TNF-alpha, IL-6, IL1-beta and MCP-1 were positively correlated with OSCC growth. This study provides the first evidence that social isolation stress may facilitate OSCC occurrence and tumor progression, an event accompanied by increased local levels of inflammatory mediators.

Roles of Histone Deacetylases and Inhibitors in Anticancer Therapy.

Histones are the main structural proteins of eukaryotic chromatin. Histone acetylation/ deacetylation are the epigenetic mechanisms of the regulation of gene expression and are catalyzed by histone acetyltransferases (HAT) and histone deacetylases (HDAC). These epigenetic alterations of DNA structure influence the action of transcription factors which can induce or repress gene transcription. The HATs catalyze acetylation and the events related to gene transcription and are also responsible for transporting newly synthesized histones from the cytoplasm to the nucleus. The activity of HDACs is mainly involved in silencing gene expression and according to their specialized functions are divided into classes I, II, III and IV. The disturbance of the expression and mutations of HDAC genes causes the aberrant transcription of key genes regulating important cancer pathways such as cell proliferation, cell-cycle regulation and apoptosis. In view of their role in cancer pathways, HDACs are considered promising therapeutic targets and the development of HDAC inhibitors is a hot topic in the search for new anticancer drugs. The present review will focus on HDACs I, II and IV, the best known inhibitors and potential alternative inhibitors derived from natural and synthetic products which can be used to influence HDAC activity and the development of new cancer therapies.

Stress hormones concentrations in the normal microenvironment predict risk for chemically induced cancer in rats.

Evidence show that stress hormones can influence cancer progression, but its role in carcinogenesis is poorly understood. In this study, we used a new method based on oral carcinogenesis model in rats to test the hypothesis that physiological levels of stress hormones in the normal tissue microenvironment would have significant predictive value for chemically induced cancer occurrence. Male Wistar rats were submitted to a tongue biopsy for measuring not-stress induced levels of norepinephrine, corticosterone, adrenocorticotropic hormone (ACTH) and brain-derived neurotrophic factor (BDNF) in the tissue before carcinogenic induction. Rats were treated with the 4-nitroquinoline-1-oxide (4NQO) chemical carcinogen for twenty weeks and then euthanized for microscopic evaluation of the tongue lesions. Increased pre-carcinogen norepinephrine concentrations and reduced basal corticosterone levels in the normal tissue microenvironment were predictive for oral squamous cell carcinoma (OSCC) occurrence. Likewise, increased pre-carcinogen norepinephrine levels in the normal microenvironment were associated a lower expression of pCDKN2a-p16 in OSCCs. Post-carcinogen levels of corticosterone and BDNF in oral leukoplakia tissues (precursor lesion of OSCC) and post-carcinogen corticosterone concentrations in OSCCs were higher than basal levels in the normal mucosa. Increased norepinephrine concentrations in OSCCs were associated to a greater tumor volume and thickness. Furthermore, higher levels of norepinephrine, ACTH and BDNF in OSCCs were associated to a lesser intensity of the lymphoplasmocytic infiltrate. This study shows that pre-carcinogen stress hormones levels in the normal microenvironment may be predictive for chemically induced cancer in rats. Moreover, chemical carcinogenesis can promote stressor-like effects with hormonal changes in the tissue microenvironment, which may be associated to tumor progression.

Social isolation stress increases the incidence and growth of chemically induced oral cancer in rats / Estresse por isolamento social aumenta a ocorrência e a progressão do câncer de boca induzido quimicamente em ratos

Estudos têm mostrado que o estresse crônico pode influenciar a progressão do câncer, porém sua influência sobre o início da doença é pouco compreendida. Dentre os eventos estressores, o estresse por isolamento social (EIS) afeta grande número de indivíduos, podendo induzir alterações neuro-hormonais e desordens emocionais. Embora estudos mostrem que o EIS pode aumentar a progressão de alguns tipos de neoplasias malignas, sua influência sobre o início e progressão do câncer de cabeça e pescoço é desconhecida. O objetivo deste estudo foi avaliar os efeitos do EIS sobre a incidência e progressão do carcinoma espinocelular (CEC) de boca induzido por 4-nitroquinolina 1- óxido (4NQO), bem como seus efeitos sobre o comportamento depressivo e a expressão de genes envolvidos na progressão do tumor. Sessenta ratos Wistar machos foram divididos em dois grupos de 30 animais: grupo isolado (ratos isolados socialmente desde os 21 dias de idade) e grupo controle (ratos mantidos em grupo). Ao atingirem 90 dias de idade, os animais de ambos os grupos foram submetidos à avaliação do comportamento depressivo pelos testes de suspensão pela cauda (TSC) e natação forçada (TNF). Logo em seguida, os animais foram submetidos à indução carcinogênica por meio da ingestão de 4NQO diluído na água de beber. Após 20 semanas, os animais foram avaliados quanto ao comportamento depressivo e posteriormente eutanasiados para análise histopatológica das lesões induzidas em língua. PCR em tempo real foi realizada para avaliar a expressão de RNAm para os genes TNF-alpha, IL-6, VEGF, MMP-2 e MMP-9 nos tumores de ambos os grupos. Os resultados mostraram que EIS aumentou a ocorrência de CEC de boca em 20.4% em relação ao grupo de ratos não estressados (p=0.002). Os tumores dos animais isolados apresentaram volume tumoral cerca de duas vezes maior (p=0.0366) em relação aos tumores dos animais do grupo controle. Os ratos estressados perderam mais peso corporal (p=0.006) e apresentaram menor peso do baço (p=0.0121) em relação aos ratos não estressados. EIS induziu aumento da expressão de RNAm para os genes TNF-alpha, IL-6, VEGF, MMP-2 e MMP-9, porém os resultados não atingiram significância estatística (p>0.05). O EIS induzido precocemente não induziu alterações significativas no comportamento depressivo mensurado pelo TSC e TNF antes e após a indução carcinogênica (p>0.05). Este estudo fornece as primeiras evidências de que o estresse crônico por isolamento social pode influenciar a incidência e progressão do CEC de boca induzido quimicamente em animais(AU)

Clinical and preclinical studies have shown that chronic stress may influence cancer progression, but its influence on the onset of the disease is poorly understood. Among the stressful events, social isolation stress (SIS) affects a large number of individuals, and may induce neurohormonal dysregulation and emotional disorders. Although investigations show that SIS may increase the progression of some types of malignancies, its influence on the onset and progression of head and neck cancer is unknown. In this study, we have evaluated the SIS effects on the occurrence and progression of induced oral squamous cell carcinoma (OSCC), as well as its effects on depression-like behavior and expression of genes involved in tumor progression. Sixty male Wistar rats were divided into two groups of 30 animals: isolated group (rats submitted to SIS) and grouped (rats non-stressed). In the SIS group, the animals remained individually isolated after completing 21 days of life, while in the control group the rats were kept in group. At 90 days of age, both groups were tested for depression-like behavior by the tail suspension (TST) and forced swimming (FST) tests. Afterwards, the animals were submitted to oral carcinogenesis induction with 4- nitroquinoline 1-oxide (4NQO) carcinogen diluted in drinking water. After 20 weeks, the animals were again tested for depressive behavior and euthanized for histopathological analysis in the tongue specimens. Real-time PCR was performed to evaluate mRNA expression for TNF-alpha, IL-6, VEGF, MMP-2 and MMP-9 genes in tumors from the both groups. The results showed that SIS increased OSCC occurrence by 20.4% in relation to control group (p=0.002). Isolated rats displayed tumor volume two-fold higher than grouped rats (p=0.0366). Stressed rats lost more body weight (p=0.006) and showed lower spleen weight (p = 0.0121) compared to non-stressed rats. SIS induced increase of mRNA expression for TNF-alpha, IL-6, VEGF, MMP-2 and MMP-9 genes, but these results did not reach statistical significance (p>0.05). SIS did not induce significant changes in depression-like behavior measured by TST and FST before and post-carcinogenesis induction (p>0.05). This study provides the first evidence that chronic stress by social isolation may influence the chemically induced OSCC occurrence and progression in animals(AU)