Apoptosis and Its Significance in Oral Diseases: An Update

Oral Oncology, 2004

Oral cancer is one of the most disfiguring types of cancer, since the surgical removal of the tumor may result in facial distortion. Oral cancer is also known to exhibit "field cancerization", resulting in the development of a second primary tumor. Furthermore, the five-year survival rate of this disease has remained approximately 50% during the past 30 years. Prevention and early detection/ treatment of oral cancer could significantly improve the quality of life for individuals at risk. Recently, the targeted elimination of oral squamous cell carcinoma cells by inducing apoptosis has emerged as a valued strategy to combat oral cancer. Studies utilizing a variety of chemical or biological interventions demonstrated promising results for induction of apoptosis in oral malignant cells. This review summarizes the results of a number of investigations focused specifically on induction of apoptosis in oral cancer cells by synthetic compounds and naturally occurring chemopreventive agents with apoptotic potential.

Oral Oncology, 1999

Expression of apoptosis-associated proteins was evaluated in premalignant and malignant oral epithelial lesions, to test the hypothesis that protein regulation of apoptosis may be altered in the development of oral squamous cell carcinoma. Ninety archived paran-embedded specimens from 25 patients (two or more sequential biopsies each) and eight control specimens were evaluated in immunohistochemically stained sections for tumor suppressor protein p53, p53 binding protein mdm-2, and apoptosis regulatory proteins Bcl-2, Bcl-X, Bax, and Bak. The initial histologic diagnosis for 17/25 patients was either focal keratosis, mild dysplasia, or moderate dysplasia; the initial diagnosis for the remaining eight patients ranged from severe dysplasia to moderately dierentiated squamous cell carcinoma. Thirty of 90 specimens showed positive p53 expression, nine of which were dysplasias. In patients with one or more lesions displaying p53 expression, there was increased intensity of staining with disease progression. Bak was expressed in 57/90 specimens, including 27 dysplasias of various grades. There was also a signi®cantly increased intensity of Bak staining with disease progression, which did not appear to be dependent upon p53 status. Bcl-X was expressed in 73/90 specimens, with staining displayed earlier in premalignant lesions than either p53 or Bak. Ten of 90 specimens were positive for Bcl-2 (all were dysplasias or carcinomas), and only 2/90 specimens were positive for Bax. Eleven of 90 specimens were positive for mdm-2; six of which were also positive for p53. These data show that apoptosis-associated proteins are altered in variable patterns in both premalignant and malignant oral epithelial lesions. p53 and especially Bak and Bcl-X are expressed early; Bax is largely absent; and Bcl-2 and mdm-2 show sporadic expression in the development of oral premalignant and malignant disease. #

Critical Reviews in Oral Biology & Medicine, 1999

The term apoptosis, also known as programmed cell death (PCD), was coined by developmental biologists a number of years ago to describe a form of cell death characterized by several unique morphological and biochemical features. Genetic studies of the round worm Caeneorhabditis elegans, a simple multicellular organism, first revealed apoptosis to be an integral part of the developmental program. Subsequently, the importance of apoptosis in higher organisms was demonstrated in several eukaryotic systems. In mammals, apoptosis is widespread during embryogenesis and in adult tissues. It is required for normal tissue homeostasis and for clonal selection in the immune system. In both developing and adult organisms, apoptosis plays a central role in reinforcing appropriate cellular patterns and in regulating cell number by eliminating cells that are harmful or no longer needed. It is becoming increasingly clear that disruption in the apoptosis pathway can contribute to the development of a number of developmental, inflammatory, degenerative, and neoplastic diseases. The effector arm of the apoptotic program includes members of the Bcl-2 gene family that function as either death agonists or death antagonists. These proteins participate in an elaborate genetically controlled biochemical pathway that functions to maintain tissue and organ homeostasis and serve as a critical defense mechanism to guard against malignant transformation. Cancer is the result of a series of genetic lesions that include activation of oncogenes and inactivation or loss of tumor suppressor genes. Several groups of investigators have observed that deregulated expression of oncogenes can subvert apoptotic pathways, resulting in prolonged cell survival. In pathological settings such as cancer, members of the Bcl-2 gene family are able to synergize with oncogenes and tumor suppressor genes to transform cells. In this review, we describe the process of apoptosis in mammalian cells and define the role and biochemical pathways through which the Bcl-2 gene family induce and/or protect cells from apoptosis. Last, we will discuss the evidence which suggests that alterations in this pathway may play a central role in tumorigenesis by allowing genetically damaged cells normally destined for elimination to persist, predisposing them to additional mutations and driving them to malignancy.

Journal of Oral Pathology and Medicine, 2003

In the last three decades, more work has been done on apoptosis and its role in the pathogenesis of many diseases including cancer. In almost all instances of cancer, dysregulation of cell death (apoptosis) and cell proliferation have been found to play a major role in tumourigenesis. A lot of progress has been made on understanding the molecular basis of apoptosis and its regulatory mechanisms. This review focuses on current knowledge on the regulation of apoptosis in oral squamous cell carcinoma, current methodologies and methodological consideration in estimation of cell death in tissue sections and the clinical significance of apoptosis related molecules in progression of oral squamous cell carcinoma.

Apoptosis, 2013

Apoptotic processes are important for physiologic renewal of an intact epithelial barrier and contribute some antimicrobial resistance for bacteria and viruses, as well as anti-inflammatory effects that benefits the mucosa. The oral cavity presents a model of host-bacterial interactions at mucosal surfaces, in which a panoply of microorganisms colonizes various niches in the oral cavity and creates complex multispecies biofilms that challenge the gingival tissues. This report details gene expression in apoptotic pathways that occur in oral mucosal tissues across the lifespan, using a nonhuman primate model. Macaca mulatta primates from 2 to 23 years of age (n = 23) were used in a cross-sectional study to obtain clinical healthy gingival tissues specimens. Further, mRNA was prepared and evaluated using the Affymetrix Rhesus GeneChip and 88 apoptotic pathway genes were evaluated. The results identified significant positive correlations with age in 12 genes and negative correlations with an additional five genes. The gene effects were predicted to alter apoptosis receptor levels, extrinsic apoptotic pathways through caspases, cytokine effects on apoptotic events, Ca ?2-induced death signaling, cell cycle checkpoints, and potential effects of survival factors. Both the positively and negatively correlated genes within the apoptotic pathways provided evidence that healthy tissues in aging animals exhibit decreased apoptotic potential compared to younger animals. The results suggested that decreased physiologic apoptotic process in the dynamic septic environment of the oral mucosal tissues could increase the risk of aging tissues to undergo destructive disease processes through dysregulated inflammatory responses to the oral microbial burden.

Journal of Oral Pathology & Medicine, 2008

Apoptosis is a genetically regulated cell death involved in the deletion of cells in normal or malignant tissues. Proteins of the Bcl-2 family play a key role in the control of apoptosis and carry out both proapoptotic and anti-apoptotic functions. The present study evaluated the prognostic value of Bcl-2 and Bax expression at the invasive front of oral squamous cell carcinoma (OSCC), taking clinicopathological findings into account. METHODS: Fifty-six specimens of OSCC were randomly selected, and Bcl-2 and Bax expression was evaluated by immunohistochemistry in formalin-fixed, paraffinembedded pre-treated specimens at the invasive front of OSCC. Clinicopathological data were gathered and patient survival was analysed. RESULTS: No significant relationship was found between Bcl-2 or Bax expression and clinical variables. Patients with Bcl-2 expression had a worse prognosis than those without Bcl-2 expression, but the difference did not reach statistical significance. Patients with Bax expression had a significantly better prognosis than those without Bax expression (P < 0.05). In univariate analyses, T category, mode of cancer invasion and Bax expression showed significant correlations. Multivariate analysis revealed that the mode of cancer invasion and Bax expression were significant and independent variables. Bax expression was found to be the strongest independent prognostic parameter. Patients with negative Bcl-2 expression and positive Bax expression had a significantly better prognosis (P < 0.005). CONCLUSION: We suggest that Bax expression at the invasive front of OSCC is a significant predictor of prognosis and that it is therefore important to investigate the expression of Bcl-2 and Bax in this disease.

Journal of Dental Research, 2007

Variations in the balance between cell proliferation and apoptosis could contribute to the etiology of gingival overgrowth. The aim of this study was to test the hypothesis that, in fibrotic gingival lesions, fibroblast proliferation is stimulated and apoptosis is decreased. Apoptotic index, caspase 3 expression, the proliferative index, FOXO1 expression, and histological inflammation were measured in situ. Analysis of data showed that apoptosis decreased in all forms of gingival overgrowth examined (p &amp;lt; 0.05), and inflammation caused a small but significant increase compared with non-inflamed tissues (p &amp;lt; 0.05). The greatest decrease of apoptosis occurred in the most fibrotic tissues. Cell proliferation was elevated in all forms of gingival overgrowth tested, independent of inflammation (p &amp;lt; 0.05). To identify potential mechanisms of transcriptional regulation of apoptosis, we assessed FOXO1 and caspase 3 expression levels and found them to correlate well with diminished apoptosis. Analysis of data suggests that increased fibroblast proliferation and a simultaneous decrease in apoptosis contribute to gingival overgrowth.

Abstract: Oral cancer is one of the ten most common cancers worldwide and accounts for 30-40% of all cancers detected in India. In normal circumstances, the process of apoptosis effectively eliminates genetically damaged cells from tissues to guard against their continued growth and progression toward malignancy. Dysregulation of apoptosis has been involved in carcinogenesis. Hence oral cancer tissues were examined and markers (bcl-2 and bax expression along with p53) were analysed using immunohistochemistry. In the present study we observed overexpression of p53 and bcl2 and decreased expression of bax in patients with oral squamous cell carcinoma. Thus altered apoptotic mechanism can be accounted for oral carcinogenesis. Key words: P53, immunohistochemistry, apoptosis, bcl2, bax

Cancer Biology & Therapy, 2008

Apoptin, a chicken anemia virus-derived protein, induces apoptosis in various tumor cell lines and xenografted tumors. Its apoptotic activity is not hampered by tumor-suppressor p53 mutations or overexpression of anti-apoptosis proteins Bcl-2 or Bcl-x L . We report for the first time the effects of apoptin expression in primary oral tumors, induced by the carcinogen 4-Nitroquinoline-1-oxide in immunocompetent mice. In vivo a significant amount of primary oral tumor cells expressing apoptin cells underwent apoptosis, whereas synthesis of the LacZ control product did not. Ectopical expression of apoptin in passage 1 cell cultures derived from these oral tumors also resulted in apoptin-induced. Both in-vivo and in-vitro treated cells underwent apoptosis via the activation of caspase-3. The fact that apoptin induces apoptosis in primary squamous cell carcinoma cells indicates that apoptin is a potential therapeutic agent for treatment of head and neck squamous cell carcinoma.

Japanese Dental Science Review, 2010

Cancer Letters, 1996

With the ultimate goal of characterizing the molecular pathogenesis of oral cancer, the most predominant malignancy in India, immmunocytochemical evaluation of p53 and bcl-2 proteins was carried out in hypeplastic oral mucosa, dysplastic oral mucosa and invasive oral cancer. All subjects gave a similar and almost uniform history of prolonged use of betal quid and tobacco. Expression of p53 was insignificant while bcl-2 was absent in hyperplastic leukoplakia lesions. Both proteins were however expressed in leukoplakia with apparent dysplasia. Almost all invasive cancer lesions showed high levels of both p53 and bcl-2. Good correlation was therefore evident between expression of these two proteins and increasing histologic abnormality. Moreover relative risk evaluation revealed that lesions expressing p53 and bcl-2 had a high probability of having a histology of dysplasia or worse. Since it has been previously shown that wild type p53 regulates the expression of bcl-2, it may be presumed that the protein detected in the dysplastic and malignant oral tissue is of the mutant type. It is also known that p53 is a positive regulator of programmed cell death or apoptosis while bcl-2 is an anti-apoptotic protein. This suggests the possibility that alterations in p53 followed by over-expression of bcl-2 occur early in oral carcinogenesis resulting in defective apoptosis and subsequent tumor progression.

European journal of dentistry, 2022

OBJECTIVES The malondialdehyde (MDA) level and TA count represent the progression of oral potentially malignant disorders (OPMD) to malignancy and thus may be used as an indicator of oral epithelial dysplasia (OED). This study aimed to determine the MDA level and tissue apoptosis (TA) count in oropharyngeal tissue of Wistar rats exposed to sidestream cigarette smoke. MATERIALS AND METHODS Wistar rats were divided into three groups: T4 group (4-week cigarette smoke exposure), T8 group (8-week cigarette smoke exposure), and control group, which was not exposed to cigarette smoke. The oropharyngeal tissue of the rats from each group was examined histopathologically to count the number of apoptotic cells, and then the blood serum was made to measure the MDA level. STATISTICAL ANALYSIS Bonferroni test was performed to see the differences in each group for MDA level. While the data from tissue apoptosis were analyzed using Mann-Whitney U test for the significance. All data were conside...

Journal of Periodontology, 2005

American Journal of Orthodontics and Dentofacial Orthopedics, 2001

Critical Reviews in Oral Biology & Medicine, 1999

The study of signal transduction pathways for mechanisms of apoptosis and proliferation has significantly advanced our understanding of human cancer, subsequently leading to more effective treatments. Discoveries of growth factors and oncogenes, especially those that function through phosphorylation on tyrosine residues, have greatly benefited our appreciation of the biology of cancer. The regulation of proliferation and apoptosis through phosphorylation via tyrosine kinases and phosphatases is discussed, as well as the contributions of other systems, such as serine and threonine kinases and phosphatases. Receptors with seven-transmembrane domains, steroid hormones, genes, and "death domains" will also be discussed. This review attempts to compare the regulation of the growth of normal tissues and cancers with an effort to highlight the current knowledge of these factors in the growth regulation of oral/oropharyngeal cancers. Despite the strides made in our understanding of growth regulation in human cancers, the study of oral/oropharyngeal cancer specifically lags behind. More research must be done to further our understanding of oral cancer biology, if we are to develop better, more effective treatment protocols.