Introduction

An adenovirus is a DNA virus first discovered in the adenoid tissues, which make up the glands in the back of the nose. This classification of viruses can cause a variety of common infections, often affecting the respiratory system, including: common cold, bronchitis, pneumonia, conjunctivitis (also known as pink eye), and gastroenteritis.¹

43,000 people are diagnosed with lung cancer each year in the UK, making it one of the most common cancers. Primary lung cancer, which originates in the lungs, has two main forms classified by the type of cell: non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Due to the metastatic nature of cancer, or tendency of cancer to spread around the body, lung cancer can also occur as a result of cancers elsewhere in the body spreading (secondary cancer). Elderly patients with a previous history of smoking are the susceptible demographic to developing primary lung cancer.²

Research has shown associations between viruses and lung cancer development, however it is unclear whether adenovirus follows this trend. This article aims to explore the relationship between adenoviruses and lung cancer, and the clinical implications of current evidence.

Understanding adenovirus

Structure and types of adenovirus

Adenoviruses are non-enveloped, double stranded DNA viruses. This means that the genetic material is exposed to the host and in its most stable form, making it easier and more efficient for the virus to replicate and cause an infection. There are more than 50 types of adenoviruses that can infect humans:³

• Types 1,2 and 5 commonly cause minor respiratory illnesses such as common colds, bronchitis, and pneumonia
• Types 3, 4, 7, 8, 19 and 37 are associated with conjunctivitis
• Type 11 causes urinary tract infections (UTIs)
• Type 14 is known as “severe acute respiratory syndrome”, and is associated with serious respiratory illness
• Types 40 and 41 cause the stomach and intestines to become inflamed, known as gastroenteritis

Pathogenesis and infection mechanisms

Infections caused by adenovirus are transmitted either through inhalation of droplets from an infected person’s sneeze or cough, direct contact with surfaces contaminated with the virus then touching the face, and through exposure to water containing the virus such as a communal swimming pools.¹ Adenoviruses often enter the body through the respiratory system, attaching to host cells using specialised receptors, which are integral for maintenance of cellular barriers called tight junctions in health. Once the virus is bound to a receptor, host cells engulf (or swallow) the virus, which provides an ideal environment for viral replication. As the virus replicates, it is able to cause inflammation, cell death, and a host immune response, which are responsible for the clinical manifestations.³

Typical clinical presentations and complications

There are several presentations and complications of adenovirus-related infections, dependent on the infection cause:^1,3

Common cold

• Symptoms: sore throat, runny nose, cough, fever
• Complications: sinusitis, exacerbation of existing respiratory conditions such as asthma, otitis media (infection of the middle ear)

Bronchitis

• Symptoms: persistent cough, shortness of breath, wheezing, fever
• Complications: chronic bronchitis, secondary bacterial infections

Pneumonia

• Symptoms: fever, chills, coughing up mucus, tightness of chest, difficulty breathing
• Complications: secondary bacterial pneumonia, acute respiratory distress syndrome, failure of the respiratory system, death

Gastroenteritis

• Symptoms: diarrhoea, vomiting, pain in the abdomen, fever
• Complications: dehydration

Conjunctivitis 

• Symptoms: redness, discharge, itching and excess tearing of the eye
• Complications: inflamed cornea (keratitis), ulcers, visual impairment

UTIs

• Symptoms: painful urination, increased frequency and urgency to urinate, blood in the urine
• Complications: chronic bladder pain and impairment, kidney disease and failure

Understanding lung cancer

Classifications of lung cancer

Malignancies, or tumours, which begin in the lung are referred to as primary lung cancer and make up the majority of lung cancer cases. Primary lung cancer is classified depending on the type of cell in which the cancer starts growing: NSCLC and SCLC.²

NSCLC is the most common, accounting for 80-85% of primary lung cancer cases, and presents in three main forms:^2,4 

• Squamous cell carcinoma- cancer of the flat cells which line the surface of the airways, usually occurring near the centre of a lung
• Adenocarcinoma- most common NSCLC, where gland cells which are responsible for germ-catching mucus production in the lung become cancerous
• Large-cell carcinoma- develops from large epithelial cells in the lung which cannot be characterised into more specific subtypes

SCLC, although less common than NSCLC, tends to spread much faster and has a worse prognosis, leading to worse outcomes. Typically occurring in the central airways, SCLC is often associated with smoking and develops in the neuroendocrine cells of the lung, which are essential for controlling air and blood flow in the lungs.⁵

Risk factors

There are several factors which contribute to an increased likelihood of developing lung cancer:⁵

• Smoking tobacco- 60% of lung cancer cases are directly linked to smoking, including occasional and second-hand smoking
• Chemicals- asbestos, silica, and diesel engine exhaust fumes, often encountered in the workplace, increase the risk of lung cancer
• Air pollution- outdoor air pollution is associated with 8% of primary lung cancer diagnoses in the UK each year
• Previous history of lung disease- such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis
• Radon gas exposure- naturally occurring from uranium in soils and rocks, build-up inside the home can predispose to lung cancer and can further increase risk in smokers
• Family history- uncommon, however genetics can influence lung cancer development
• Beta-carotene- often obtained from supplements, high doses of 20-30 mg per day can predispose lung cancer, especially in smokers

Pathophysiology and lung cancer progression

Exposure to lung cancer risk factors can disrupt the normal cellular mechanisms of the lungs through damage to the DNA, causing cells to grow abnormally and at an increased rate. The growing cells form a tumour, which is able to manipulate the cells of the lungs into supplying oxygen and nutrients through a rich blood supply directly to the expanding mass. As the tumour grows, cancer cells are able to flake away from the primary tumour and travel through the blood and/or lymphatic systems to spread the cancer to other parts of the body. This is called metastasis, and often affects the brain, liver and bones. The environment around the cancer cells is specialised to enhance the tumours growth, using defence mechanisms of the immune system to avoid attack and ultimately, aid its survival.

Evidence supporting a connection between adenovirus and lung cancer

There are two main hypotheses showing a link between adenoviruses and lung cancer: viral oncogenesis, and immune modulation and chronic inflammation.⁶

Viral oncogenesis is another term for virus-induced cancer, directly linking a viral infection with the development of a tumour. This is thought to occur through genes in the virus, termed viral oncogenes, disrupting host DNA, causing a lack of cellular regulation. Without regulation of cellular mechanisms, such as division, cells are able to multiply in a less controlled manner and form tumours.

Immune modulation and chronic inflammation create ideal environments for cancer growth and survival. Viruses are able to invade the immune system and suppress it from noticing any abnormalities, enabling pre-cancerous and cancerous cells to grow without the immune system noticing the cells are unhealthy. Chronic infections can also create an inflamed environment perfect for tumour growth. In addition, inflammatory conditions can further cause DNA damage, which accelerates uncontrolled cell growth and cancer development.

Evidence against a connection between adenovirus and lung cancer

Whilst viruses as a whole have been shown to be connected to lung cancer, there is no direct evidence that adenovirus infections are directly correlated with lung cancer development. Despite adenovirus infections occurring prior to lung cancer development in some patients, there is no evidence to suggest a connection.

There have also been studies showing the effectiveness of adenovirus as a treatment for lung cancer, instead of causing it. There are three main theories as to how adenovirus works as a treatment:⁷

1. Direct attack: scientists are able to manipulate the viral cells to infect cancer cells, alerting the immune system of their presence and causing cancer-specific destruction, without affecting surrounding healthy cells
2. Immune system boost: the presence of the virus kickstarts the immune system, and in turn enables the recognition and destruction of cancer cells
3. Gene therapy: adenoviruses can deliver genes to increase the sensitivity of cancer cells to cancer treatments, such as chemotherapy and radiotherapy

Summary

• Adenoviruses, DNA viruses initially found in adenoid tissues, cause respiratory infections like the common cold, bronchitis, and pneumonia
• Lung cancer is common, with 43,000 cases annually in the UK, mainly affecting older smokers. It has two primary types: NSCLC and SCLC
• Research explores if adenoviruses contribute to lung cancer via viral oncogenesis (virus-induced cancer) and immune modulation, although direct evidence is lacking
• Modified adenoviruses are being studied for lung cancer treatment through direct cancer cell targeting, immune system enhancement, and gene therapy