Introduction to Cancer Biology: The Nature of Cancer

Introduction

This lecture provides a foundational understanding of cancer biology, covering the classification of tumors, their developmental progression, cellular origins, and the factors influencing cancer incidence. It will also touch upon the principles and importance of cancer screening programs. Specifically, this lecture will cover:

The classification of tumors based on their cell of origin.
An overview of the progressive development of neoplasms, including benign, dysplastic, and malignant stages.
The concept of tumor clonality (monoclonal vs. polyclonal).
Variations in cancer incidence across different countries and the interplay of heredity versus environmental factors.
The role and criteria for effective cancer screening programs.

Tumour Classification Based on Cell of Origin

Tumours, also known as neoplasms (meaning "new growth"), are abnormal masses of tissue that arise from normal cells but grow in an unorganized and uncontrolled manner. They are broadly classified based on the cell type from which they originate. Histopathological analysis (microscopic examination of tissue) is crucial for classification and determining the nature of the tumor.

Main Categories of Tumours:

Carcinomas (Epithelial Origin):
- These are the most common types of cancer, accounting for approximately 80% of all known tumours.
- They arise from epithelial cells, which form the linings of organs and cavities, the outer layer of the skin, and glandular tissues. Epithelial cells secrete proteins to form a basement membrane, which separates them from the underlying connective tissue (stroma).
- Subtypes:
  - Squamous Cell Carcinomas: Develop from the flat, scale-like epithelial cells that form protective layers (e.g., skin, lining of the mouth, esophagus, cervix, nasal cavity, larynx, lungs).
  - Adenocarcinomas: Originate from glandular (secretory) epithelial cells. Common sites include the lung, colon, breast, pancreas, stomach, esophagus, prostate, endometrium, and ovary.
- Other types: Small-cell lung carcinoma, large-cell lung carcinoma, hepatocellular carcinoma (liver), renal cell carcinoma (kidney), transitional-cell carcinoma (e.g., of the urinary bladder).
Sarcomas (Mesenchymal Origin):
- Derived from mesenchymal cells, which form connective tissues such as bone, cartilage, fat, muscle, and blood vessels. These cells typically originate from the embryonic mesoderm.
- Sarcomas are relatively rare, accounting for about 1% of all tumours.
- Examples include:
  - Osteosarcoma: Originates from osteoblasts (bone-forming cells).
  - Liposarcoma: From adipocytes (fat cells).
  - Leiomyosarcoma: From smooth muscle cells (e.g., in the gut).
  - Rhabdomyosarcoma: From striated/skeletal muscle cells.
  - Fibrosarcoma: From fibroblasts (connective tissue cells).
  - Angiosarcoma: From endothelial cells (lining of blood vessels).
  - Chondrosarcoma: From chondrocytes (cartilage-forming cells).
  - Malignant fibrous histiocytoma: Thought to originate from adipocyte/muscle cells.
Haematopoietic Tumours (Blood-Forming and Immune Cell Origin):
- Arise from cells of the blood-forming tissues (bone marrow) and the immune system.
- Account for approximately 7% of tumours (this percentage can vary, and these are more common in children than some adult cancers).
- Leukaemias: Malignant derivatives of blood cells (e.g., white blood cells) that proliferate in the bone marrow and circulate freely in the bloodstream. They are often referred to as "liquid tumours."
- Lymphomas: Solid tumours that develop from B or T lymphocytes, typically forming in lymph nodes or other lymphoid tissues. Examples include Hodgkin's lymphoma and non-Hodgkin's lymphoma.
Neuroectodermal Tumours (Nervous System Origin):
- Derived from components of the central nervous system (CNS – brain and spinal cord) and peripheral nervous system (PNS).
- Account for about 1.5% of tumours (though brain and CNS tumours overall make up a small percentage of all cancers, they can be significant).
- Examples include:
  - Glioblastomas and Astrocytomas: Arise from glial cells (e.g., astrocytes, which support neurons) in the brain.
  - Neuroblastomas: Derived from immature nerve cells, often in infants and young children.
  - Schwannomas: From Schwann cells, which produce the myelin sheath around nerve fibers.
  - Medulloblastomas, Ependymomas, Oligodendrogliomas.

Atypical Classifications: Some tumours do not fit neatly into these four main categories. For example:
- Melanomas: Derived from melanocytes (pigment-producing cells), primarily in the skin but can occur elsewhere. Melanocytes originate from the neural crest during embryonic development.
- Germ Cell Tumours: Arise from pluripotent germ cells, most often in the testes or ovaries (e.g., seminoma, teratoma).
- Blastomas: Cancers derived from immature "precursor" cells or embryonic tissue, more common in children (e.g., nephroblastoma/Wilms' tumor of the kidney, hepatoblastoma of the liver, retinoblastoma of the eye).

The Progressive Nature of Cancer Development

Cancer is generally not an abrupt event but rather a multi-step process where cells gradually accumulate genetic and epigenetic changes, leading to increasingly abnormal behavior. Tumours can demonstrate different gradations of abnormality.

Normal Tissue: Cells are organized, well-differentiated (specialized for their function), and their growth is tightly regulated.
Benign Tumours:
- Characterized by excessive cell proliferation, but the cells themselves often retain a relatively normal appearance and function.
- They are typically localised (remain at the site of origin), non-invasive (do not spread into surrounding tissues), and are often encapsulated.
- While not cancerous, benign tumours can cause problems by pressing on nearby organs or tissues, or by overproducing hormones (if they are endocrine tumours).
- Once removed, they usually do not recur.
- Subtypes/Changes within Benign Growth:
  - Hyperplasia: An increase in the number of cells in a tissue or organ. The cells themselves appear normal, and the tissue architecture is generally preserved. However, the proliferation rate is higher than normal.
  - Metaplasia: A reversible change in which one differentiated cell type is replaced by another differentiated cell type not normally found in that tissue. This is often an adaptive response to chronic irritation or stress. For example, in smokers, the ciliated columnar epithelium of the bronchi may be replaced by stratified squamous epithelium. In the esophagus, chronic acid reflux can lead to Barrett's oesophagus, where the normal squamous epithelium is replaced by columnar epithelium similar to that in the intestine. Metaplasia can sometimes be a premalignant condition, increasing the risk of subsequent dysplasia and cancer.
Dysplasia (Dysplastic Tissue):
- Literally means "disordered growth." This is a more advanced precancerous state.
- Characterized by cytologically abnormal cells:
  - Variations in cell size and shape (pleomorphism).
  - Increased nuclear size and hyperchromasia (darkly stained nuclei due to increased DNA content).
  - Increased nuclear-to-cytoplasmic ratio.
  - Loss of normal tissue architecture and cellular orientation.
  - Increased mitotic activity, sometimes with abnormal mitoses.
  - Lack of normal differentiation markers.
- Dysplasia is considered a premalignant condition, indicating a higher risk of progression to cancer. It can be graded as mild, moderate, or severe. Severe dysplasia is often referred to as carcinoma in situ (CIS), where the abnormal cells have all the cytological features of malignancy but have not yet breached the basement membrane to invade surrounding tissues.
Malignant Tumours (Cancer):
- Exhibit uncontrolled proliferation and anaplasia (lack of differentiation; cells often appear primitive).
- Hallmark features include:
  - Invasion: Malignant cells breach the basement membrane and invade the surrounding stroma (connective tissue) and adjacent structures.
  - Metastasis: The ability to spread to distant sites from the primary tumour via the bloodstream or lymphatic system, forming secondary tumours. Metastasis is the primary cause of cancer-related death.
- Malignant cells often show significant genetic instability, accumulating further mutations.
- Histologically, malignant tissue shows loss of normal form and function. (e.g., Fig A comparing normal breast duct architecture with invasive breast carcinoma cells disrupting the stroma).

The progression from normal tissue through hyperplasia, metaplasia, dysplasia, to invasive carcinoma is a common model, particularly for epithelial cancers. An example is the development of colon cancer from normal colonic mucosa, through adenomatous polyps (benign but can become dysplastic), to invasive adenocarcinoma.

Ancestral Lineage of Tumour Cells: Monoclonal vs. Polyclonal Origin

A key question in cancer biology is whether a tumour arises from a single ancestral cell that underwent transformation (monoclonal origin) or from multiple independent cells (polyclonal origin).

Monoclonal Origin:
- The predominant theory for many cancers is that a tumour is a clonal outgrowth, meaning all the cells within the tumour are descendants of a single progenitor cell that acquired the initial cancer-causing mutations.
- This single cell then proliferates, and its descendants may acquire additional mutations over time, leading to tumour progression and heterogeneity (different subclones within the tumour).
- Evidence for monoclonality comes from studies of X-chromosome inactivation patterns in female tumours (where all tumour cells show inactivation of the same X chromosome) and from identifying unique genetic markers (like specific translocations or mutations) shared by all cells in a tumour.
Polyclonal Origin:
- In this scenario, a tumour arises from multiple independently transformed cells.
- This might occur if a field of tissue is exposed to a carcinogen, leading to multiple cells undergoing initial oncogenic changes simultaneously or in close succession.
- Some tumours, especially early lesions or those arising in the context of chronic inflammation or widespread field cancerization, might have polyclonal origins.
Polyclonal-to-Monoclonal Transition:
- Recent research suggests that some tumours may initially arise from multiple clones (polyclonal) but then, through processes of clonal evolution and selection, one dominant clone with a growth or survival advantage outcompetes the others, leading to a predominantly monoclonal tumour at later stages. This "polyclonal-to-monoclonal transition" is an area of active investigation.
- The image provided (Figure 2.19 from The Biology of Cancer) illustrates the concept: normal tissue undergoes transformation. If it's a monoclonal tumor, one cell type proliferates. If it's a polyclonal tumor, multiple different cell types (represented by different colours) proliferate and contribute to the tumor mass.

Understanding the clonality of tumours has implications for diagnosis, prognosis, and treatment, as it can influence tumour heterogeneity and the likelihood of resistance to therapy.

Cancer Incidence: Heredity vs. Environment

The incidence of different types of cancer varies dramatically across different countries and populations. This variation provides clues about the underlying causes, particularly the relative contributions of genetic predisposition (heredity) and environmental/lifestyle factors.

Geographical Variation:
- Examples from the lecture slides show significant differences in the incidence rates of prostate and breast cancer worldwide. North America and Western Europe often show higher rates for these specific cancers compared to regions in Asia or Africa.
- These variations suggest that environmental and lifestyle factors play a substantial role, as genetic makeup alone is unlikely to account for such large differences between populations.
Environmental Factors: Broadly include:
- Lifestyle choices: Diet (e.g., high fat, low fiber), obesity, physical inactivity, tobacco use, alcohol consumption.
- Carcinogen exposure: Occupational exposures (e.g., asbestos), pollution (air, water), radiation (UV from sunlight, ionizing radiation).
- Infectious agents: Certain viruses (e.g., HPV and cervical cancer, Hepatitis B/C and liver cancer), bacteria (e.g., H. pylori and stomach cancer), and parasites.
- It's estimated that environmental factors (including lifestyle) are responsible for the vast majority (80-90%) of cancers.
Hereditary Factors (Genetic Predisposition):
- Some individuals inherit faulty genes (mutations) from their parents that increase their risk of developing certain cancers. These are called germline mutations and are present in every cell of the body.
- However, only a smaller proportion of cancers (estimated 5-12%) are strongly linked to inherited gene changes (hereditary cancer syndromes, e.g., BRCA1/2 mutations and breast/ovarian cancer, Lynch syndrome and colorectal cancer).
- Even with an inherited predisposition, environmental factors often still play a role in whether and when cancer develops.
Migration Studies:
- Studies of populations migrating from low-incidence to high-incidence countries (or vice versa) often show that their cancer rates (and those of their descendants) tend to shift towards the rates of the host country. This strongly supports the significant influence of environmental and lifestyle factors.
Gene-Environment Interactions:
- The development of most cancers is likely due to a complex interplay between an individual's genetic makeup and their cumulative environmental exposures over their lifetime.

Screening for Cancer

Cancer screening aims to detect cancer at an early stage, often before symptoms appear, when treatment is more likely to be effective and lead to better outcomes.

Why Screen?
- Early Detection: To find cancer when it is small, localized (has not spread beyond the primary site), and potentially curable.
- Improved Treatment Success: Early-stage cancers are generally easier to treat successfully than late-stage cancers that have metastasized.
- Reduced Morbidity and Mortality: Effective screening programs can lead to a decrease in illness and death from specific cancers.
- Detection of Precancerous Lesions: Some screening tests can detect precancerous conditions (e.g., dysplasia), allowing for removal or treatment before cancer develops (primary prevention).
WHO Criteria for an Effective Screening Programme: The World Health Organization has established criteria that should be met for a screening program to be justifiable and effective:
1. The Condition:
  - The disease should be a major health problem.
  - The natural history of the disease (its progression from early to late stages) should be adequately understood.
  - There should be a detectable early or latent stage.
  - Known risk factors should be identified.
2. The Test:
  - The screening test must be safe and reliable (accurate).
  - It should be acceptable to the target population.
  - It needs to be specific (correctly identifies individuals without the disease, minimizing false positives) and sensitive (correctly identifies individuals with the disease, minimizing false negatives).
3. The Treatment:
  - There must be an effective treatment available for patients diagnosed with the disease at an early stage.
  - Facilities for diagnosis and treatment should be available.
4. The Screening Programme:
  - There should be evidence from randomized clinical trials that the screening program reduces morbidity (illness) and/or mortality (death) from the cancer.
  - The benefits of screening must outweigh the potential physical and psychological harm (e.g., anxiety from false positives, complications from follow-up procedures).
  - Patients must be fully informed of the potential benefits, risks, and consequences of being tested.
  - The program must be economically effective and viable (cost-effective).
  - There should be a plan for quality assurance and continuous monitoring.
UK Cancer Screening Programmes (Examples):
- Colorectal Cancer:
  - Test: Faecal Occult Blood Test (FOBt) or Faecal Immunochemical Test (FIT) to detect hidden blood in stool. Followed by colonoscopy if positive.
  - Target Group (NHS): Typically offered to adults aged around 55/60 to 74 years, with invitations sent every two years. Bowel scope screening (flexible sigmoidoscopy) is also offered once at age 55 in some areas.
- Cervical Cancer:
  - Test: Primary Human Papillomavirus (HPV) testing. Samples positive for high-risk HPV are then examined by cytology (smear test/Pap test) to look for abnormal cells.
  - Target Group (NHS): Women/people with a cervix aged 25 to 64 years. Screening is usually every 3 years for ages 25-49 and every 5 years for ages 50-64.
- Breast Cancer:
  - Test: Mammography (X-ray of the breasts).
  - Target Group (NHS): Women aged 50 to 70/71 years, invited every three years. Women over this age can request screening.