Cancer Biology

Cancer is not one disease — it is a collection of over 200 different diseases, all sharing one fundamental characteristic: cells that divide and grow in an uncontrolled way, ignoring the body's normal signals to stop. Every cancer starts with a single cell that has accumulated enough mutations to escape normal growth controls. That cell divides, its daughter cells divide, and over months or years an expanding mass of abnormal cells — a tumour — forms. Two key types of tumour: - Benign tumour — abnormal cells that grow in one place but do NOT invade surrounding tissue and do NOT spread. Usually not life-threatening (e.g. a lipoma — a benign fatty lump under skin; or a uterine fibroid). Can still cause problems if they press on vital structures. - Malignant tumour (cancer) — invades surrounding tissue AND can spread to other parts of the body (metastasize). The spread — metastasis — is what makes cancer so dangerous. Metastasis — how cancer spreads: Malignant cells can break away from the primary tumour, enter the bloodstream or lymphatic system, travel to distant organs, and start secondary tumours (metastases). Common sites of metastasis include the liver, lungs, brain, and bones. Most cancer deaths are caused by metastases rather than the original primary tumour — once cancer has spread widely, treatment becomes much harder. Naming cancers: Cancers are named by the tissue they originate from: - Carcinomas — from epithelial cells (skin, lung, breast, colon, prostate — ~85% of all cancers) - Sarcomas — from connective tissue (bone, muscle, fat) - Leukaemias — from blood-forming cells (blood cells) - Lymphomas — from lymphatic tissue (lymph nodes) - Gliomas — from glial cells in the brain

In 2000, scientists Douglas Hanahan and Robert Weinberg published a landmark paper describing the "Hallmarks of Cancer" — a set of capabilities that cancer cells acquire that normal cells do not have. Understanding these hallmarks has transformed cancer biology and drug development. The key hallmarks: 1. Sustaining proliferative signalling: Normal cells only divide when they receive growth signals (like growth factors). Cancer cells generate their own growth signals — or are permanently switched on. Oncogenes like RAS are found mutated in ~30% of all cancers, constantly telling the cell to divide. 2. Evading growth suppressors: Normal cells obey "stop dividing" signals from tumour suppressor genes. Cancer cells inactivate these. The most important tumour suppressor is p53 — called the "guardian of the genome." Mutated or deleted in ~50% of all cancers. 3. Resisting cell death (apoptosis): Normal cells self-destruct when badly damaged. Cancer cells disable apoptosis, allowing damaged cells to survive and keep dividing. Mutations in BCL-2 (an anti-apoptotic protein) are common in lymphomas. 4. Enabling replicative immortality: Normal cells can only divide a limited number of times before dying (the Hayflick limit) — because their telomeres (protective caps on chromosome ends) shorten with each division. Cancer cells reactivate telomerase — an enzyme that rebuilds telomeres — giving them unlimited replicative potential. 5. Inducing angiogenesis: Tumours need blood supply for nutrients and oxygen. Cancer cells release signals (especially VEGF — vascular endothelial growth factor) that stimulate the growth of new blood vessels into the tumour. Without angiogenesis, a tumour cannot grow beyond ~1–2mm. Anti-VEGF drugs (like bevacizumab) starve tumours of their blood supply. 6. Activating invasion and metastasis: Cancer cells acquire the ability to break through the basement membrane, invade surrounding tissue, and enter blood and lymph vessels to spread.

Cancer is caused by mutations in genes that control cell division — particularly proto-oncogenes and tumour suppressor genes. These mutations can arise from many sources. Inherited vs acquired mutations: - Inherited (germline) mutations — present in every cell from birth, inherited from a parent. Examples: BRCA1/BRCA2 mutations (greatly increase breast and ovarian cancer risk); APC mutations (cause familial adenomatous polyposis — hundreds of colon polyps → near-certain colon cancer without intervention). - Acquired (somatic) mutations — occur during a person's lifetime in individual cells. The vast majority of cancers are caused by acquired mutations — they are not inherited. Major causes of acquired mutations: Chemical carcinogens: - Tobacco — contains ~70 known carcinogens. Causes lung (~85% of lung cancers), bladder, kidney, mouth, throat, oesophageal, and pancreatic cancers. Smoking is the single largest preventable cause of cancer worldwide. - Alcohol — metabolised to acetaldehyde, which damages DNA. Causes cancers of the mouth, throat, oesophagus, liver, and breast. - Aflatoxin — a mould toxin on stored grains in some regions; a major cause of liver cancer in Sub-Saharan Africa and Asia. Radiation: - UV radiation — causes mutations in skin cell DNA (thymine dimers) → skin cancers - Ionising radiation — X-rays, nuclear radiation → breaks DNA strands → leukaemia and other cancers (Chernobyl, Hiroshima survivors) Viruses (oncoviruses): About 15–20% of all cancers worldwide are linked to viral infections: - HPV (Human papillomavirus) → cervical, throat, anal, and penile cancers - Hepatitis B and C viruses → liver cancer - EBV (Epstein-Barr virus) → Burkitt lymphoma, nasopharyngeal cancer - H. pylori (not a virus but a bacterium) → stomach cancer Why age increases cancer risk: Most cancers require multiple mutations in the same cell — a statistically unlikely event. Over a lifetime, cells accumulate mutations with each division and each environmental exposure. This is why cancer incidence rises dramatically with age — the older you are, the more mutations your cells have accumulated.

Cancer treatment has been transformed in recent decades. The major approaches: 1. Surgery: Physically removing the tumour. Effective for solid tumours that have not spread. Often combined with other treatments. The surgeon aims for "clear margins" — removing a rim of normal tissue around the tumour to ensure no cancer cells are left behind. 2. Radiotherapy: Uses high-energy radiation (X-rays, proton beams) to damage cancer cell DNA. Cancer cells often have impaired DNA repair mechanisms, making them more sensitive to radiation than normal cells. Can be targeted precisely at the tumour to minimise damage to surrounding tissue. 3. Chemotherapy: Drugs that kill rapidly dividing cells — by damaging DNA (e.g. cisplatin), blocking DNA replication, or preventing spindle formation (e.g. paclitaxel — from Pacific yew tree bark). Because chemotherapy targets all rapidly dividing cells (not just cancer cells), it also damages the gut lining, hair follicles, and bone marrow → nausea, hair loss, and low blood counts. 4. Targeted therapy: Drugs designed to block a specific mutated protein that is driving a particular cancer: - Imatinib (Gleevec) — blocks the BCR-ABL kinase in chronic myeloid leukaemia. Changed CML from near-fatal to manageable with a daily pill. - Trastuzumab (Herceptin) — targets HER2 receptor in HER2-positive breast cancer - Vemurafenib — targets mutated BRAF protein in melanoma These work only in cancers with that specific mutation — hence the importance of molecular tumour testing. 5. Immunotherapy: Harnessing the immune system to fight cancer: - Checkpoint inhibitors (pembrolizumab, nivolumab) — block proteins (PD-1, CTLA-4) that tumours use to hide from T cells. Released T cells can then attack the tumour. Transformed outcomes in melanoma, lung cancer, and others. - CAR-T cell therapy — a patient's T cells are extracted, genetically engineered to recognise cancer cells, grown in large numbers, and reinfused. Highly effective in some blood cancers. - Cancer vaccines — e.g. the HPV vaccine prevents infection with cancer-causing HPV strains, preventing the virus from causing cervical cancer.

Around 40–50% of cancers are preventable through lifestyle changes and vaccination. This is one of the most important messages in medicine. Key preventable risk factors: 1. Smoking — causes ~30% of all cancer deaths. Stopping smoking at any age reduces risk; the earlier you stop, the greater the benefit. 2. Obesity — the second leading preventable cause of cancer in many countries. Excess body fat increases risk of breast, bowel, uterine, kidney, oesophageal, and pancreatic cancers through hormonal and inflammatory mechanisms. 3. Alcohol — causes 7 types of cancer. No safe level of alcohol for cancer risk, though risk increases substantially at higher intake. 4. UV radiation — use sunscreen, avoid sunbeds. Melanoma rates have risen dramatically in young people, largely due to sunbed use. 5. Infection — HPV vaccination prevents ~70% of cervical cancers. Hepatitis B vaccination prevents liver cancer. H. pylori testing and treatment reduces stomach cancer risk. Cancer screening — catching it early: Early-stage cancer is far more treatable than late-stage. Screening finds cancer before symptoms appear: - Cervical screening (smear test) — detects pre-cancerous cell changes from HPV before they become cancer - Mammography — X-ray breast screening detects early breast cancer - Bowel cancer screening — stool testing for blood (FIT test), followed by colonoscopy if positive - PSA testing — prostate-specific antigen blood test for prostate cancer (controversial — many low-risk prostate cancers are over-treated) The CAUTION warning signs of cancer: A classic memory aid taught in medical education: Change in bowel or bladder habits, A sore that does not heal, Unusual bleeding or discharge, Thickening or lump in breast or elsewhere, Indigestion or swallowing difficulty, Obvious change in wart or mole, Nagging cough or hoarseness. Any of these warrants medical review — not panic, but investigation.