Introduction
Oral cancer currently stands as the eighth-leading cause of cancer-related deaths worldwide, with tobacco-related carcinogens being the major cause of oral squamous cell carcinomas (OSCC). This article talks about the causes, pathogenesis, and molecular progression of cancers linked to tobacco constituents.
How Is Tobacco Related to Carcinogenicity?
Oral squamous cell carcinoma (OSCC) is a major type of cancer that originates in the squamous cells, lining the oral cavity and is commonly associated with factors like tobacco and alcohol use. Major risk factors contributing to the development of OSCC and other oral cancers include poor oral hygiene, tobacco exposure, chronic alcohol consumption, betel nut chewing, and dietary or nutritional factors that can compromise an individual's overall health. Numerous epidemiological studies have consistently highlighted tobacco use as the most significant risk factor. It exhibits a dose-response relationship, meaning that the more an individual uses tobacco, the greater their susceptibility to oral cancers and premalignant lesions.
In recent years, there has been a growing awareness of the strong relationship between oral cancer and smoking. This awareness begins from the fact that the oral cavity serves as a common and direct route for the introduction of tobacco smoke into the body. The pathogenesis of tobacco-related cancers and premalignant lesions primarily hinges on the direct contact between tobacco components, nicotine, and the oral mucosa. Nicotine, the principal constituent of tobacco, possesses the potential for rapid diffusion into the central nervous system, making it highly addictive. With elevated concentrations of nicotine in the bloodstream of smokers, it can eventually exert an impact on, or even alter, the oral microbiome. This can affect one of the most critical signaling pathways: the epidermal growth factor receptor signaling (EGFR), which plays a pivotal role in the development, staging, and eventual progression of oral cancer.
What Is the Impact Of Tobacco-Specific Nitrosamines (TSNA)?
Nicotine consumption takes various forms, including tobacco smoking (such as cigarette smoking), tobacco chewing, sucking, and snuff dipping (a practice where snuff is placed between the cheek and gum, known to be a risk factor for snuff dippers cancer), and snusing (placing moist snuff on the upper lip). Additionally, electronic cigarettes (E-cigarettes) have emerged as a growing concern due to their prolonged nicotine exposure.
Both smoking and smokeless tobacco consumption carry multiple health risks. These risks extend beyond exposure to toxic alkaloid metabolites found in nicotine to tobacco-specific nitrosamines, which can disrupt molecular pathways responsible for cancer staging. These nitrosamines can also deoxyribonucleic acid (DNA) mutations and impact blood hemoglobin levels. They can be detected in saliva and their metabolites can be measured through urine analysis.
Research suggests that these tobacco toxins can:
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Cause cellular injury.
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Exacerbate toxic effects on the endocrine system due to exposure to tobacco metabolites.
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Disrupt crucial intracellular signaling mechanisms.
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Interfere with DNA formation and protein synthesis pathways.
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Impair metabolic function, leading to generalized systemic oxidative stress and inflammation.
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Contribute to neurodegeneration.
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Resulting in insulin resistance-related diseases.
How Does Tobacco Use Progress Into Systemic Diseases?
Globally, tobacco and alcohol stand out as two of the most frequently abused legal substances, having a great impact on public health. Medical research and worldwide surveys have revealed that tobacco abuse affects nearly half of its users, subjecting them to several adverse consequences. In lower and middle-income countries, tobacco abuse has emerged as a major public health crisis, with increasing mortality rates year after year on a global scale. The harmful effects of using tobacco go beyond just causing cancer. They can also lead to various other health problems and diseases throughout the body. Using tobacco does not just cause cancer; it can also lead to many other health issues:
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Lung Cancer: A type of cancer that starts in the lungs.
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Emphysema: A lung disease that makes it hard to breathe.
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Cardiovascular Diseases: Problems with the heart and blood vessels.
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Cerebrovascular Diseases: Issues affecting the blood vessels in the brain.
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Premature Aging: Tobacco use can make the person look and feel older than they are.
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Asthma: A condition that makes it hard to breathe and can cause wheezing.
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Chronic Obstructive Pulmonary Disease (COPD): A group of lung diseases that block airflow and make it hard to breathe.
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Diabetes: A disease that affects how the body uses sugar, which can be worsened by tobacco use.
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Developmental Abnormalities in Fetus: Smoking during pregnancy can harm the development of the baby and lead to birth defects.
What Are the Key Findings From the Molecular Analysis of Oral Cancers?
While studies are still going on how oral tumors form, it looks like nicotine, the stuff in tobacco, plays a big role. It makes cells in the mouth multiply a lot, which could be a big reason why oral cancer happens.
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HSC-2 Cell Growth: HSC-2 cells are a type of cancer cell line commonly used in scientific research related to oral and other cancers. Nicotine has a strong effect on how fast HSC-2 cells multiply.
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Activating EGFR: The epidermal growth factor receptor (EGFR) is a protein found on the surface of cells that plays a crucial role in regulating cell growth and division. Nicotine also turns on certain things connected to the EGFR.
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p44/42 Pathway Activation: The p44/42 pathway, also known as the ERK (extracellular signal-regulated kinase) pathway, is a signaling pathway within cells that plays a significant role in regulating cell growth, differentiation, and survival. Nicotine affects a pathway called p44/42 mitogen-activated protein kinases, which is important.
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Role of p53 Gene: The p53 gene is a tumor suppressor gene that plays a critical role in regulating cell growth and preventing the formation of cancer. In oral cancer, the p53 gene becomes a big player. Normally, it controls how cells work, but when it changes (mutates), it cannot control cell growth anymore. This makes it act like a cancer-causing gene instead.
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GLUT-1 Gene: The GLUT-1 gene codes for a protein known as glucose transporter 1. This protein is responsible for transporting glucose, a type of sugar, from the bloodstream into cells to provide them with energy. Another important thing is the GLUT-1 gene. In cancer cells, it is more active, and this makes the cancer cells grow fast and resist radiation therapy. Doctors look at GLUT-1 when they study oral cancer to understand how bad it might be.
How Is Oral Cancer Connected to Epstein-Barr Virus (EBV) Infection?
Recent oncological research shows links between specific viruses like EBV and HPV and the development of oral squamous cell carcinoma. Studies have explored the possible connection between tobacco use and the incidence of Epstein-Barr virus as a precursor to OSCC.
EBV Reactivation
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EBV, also known as human herpesvirus 4 (HHV-4), typically remains latent in healthy individuals.
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However, under certain conditions, including predisposing risk factors and a weakened immune response, EBV can periodically and repeatedly reactivate during an individual's lifetime.
Systemic Malignancies Associated with EBV
EBV has been linked to several systemic malignancies, including:
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Burkitt's lymphoma is an aggressive type of non-Hodgkin lymphoma characterized by fast-growing tumors.
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Hodgkin's disease, or Hodgkin lymphoma, is a type of cancer that affects the lymphatic system and is known for the presence of specific abnormal cells called Reed-Sternberg cells.
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Nasopharyngeal carcinoma is a cancer that develops in the nasopharynx, the area behind the nose, and at the upper part of the throat, often associated with Epstein-Barr Virus infection and prevalent in certain regions like Southeast Asia.
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Stomach cancers, among others.
Conclusion
Tobacco-related carcinogenicity stands out as a significant risk factor, primarily recognized for its impact on epigenetic alterations within oral epithelial and mucosal cells. By compromising the host's immune defenses and releasing toxic metabolites over extended periods, tobacco demonstrates its potential to initiate oral cavity cancers. This association can be attributed to the oxidative tissue stress on oral tissues in tobacco users, significantly increasing their chances of developing oral squamous cell carcinoma.
