The Cellular Basis of Cancer and Carcinogens

Cancer is a group of diseases in which cells divide without normal control, invade nearby tissues and may spread to other parts of the body, and it is caused by accumulated mutations in genes that control cell growth and division; agents that cause such mutations or promote cancer are called carcinogens. In brief: cancer arises when proto-oncogenes become overactive (oncogenes) and tumor suppressor genes (such as TP53) are lost. Several mutations are normally needed, which is why cancer is more common with age. Carcinogens include tobacco smoke, ultraviolet and ionizing radiation, some chemicals and some viruses.

About one in six deaths worldwide is due to cancer, according to WHO estimates. This guide describes how normal cells control division, how mutations lead to a tumor, the difference between benign and malignant tumors and metastasis, the main carcinogens, compares oncogenes and tumor suppressors in a table, works through a tumor growth calculation and corrects common mistakes.

How do normal cells control division?

Cells divide in the cell cycle, which is regulated by signals. Growth factors bind to receptors and start a signaling pathway that stimulates division. Checkpoints (G₁, G₂ and in mitosis) check for DNA damage and correct chromosome attachment. If damage cannot be repaired, the cell undergoes apoptosis (programmed cell death). Most cells also stop dividing when they touch their neighbors (contact inhibition) and divide a limited number of times, because telomeres at the chromosome ends shorten.

How do mutations cause cancer?

Cancer is a genetic disease of somatic cells: it is caused by mutations in the DNA of body cells, which are usually not inherited. Three groups of genes are important:

• Proto-oncogenes normally stimulate cell division. A mutation or amplification can turn one into an oncogene that is permanently active, like a stuck accelerator. Examples: RAS (mutated in about a quarter of human cancers) and MYC.
• Tumor suppressor genes slow division, repair DNA or trigger apoptosis. Both copies usually need to be lost, which is the “two-hit” idea of Alfred Knudson. TP53, which codes for the protein p53 (“guardian of the genome”), is mutated in about half of all cancers. BRCA1 and BRCA2 are tumor suppressors involved in DNA repair, and inherited faults raise the risk of breast and ovarian cancer.
• DNA repair genes correct errors. When they fail, mutations accumulate faster.

Usually several mutations in the same cell lineage are needed (the number varies with the type of cancer), and each one gives the cell a growth advantage, so the clone expands and further mutations occur. This multi-step process explains why risk rises with age. Hanahan and Weinberg summarized the “hallmarks of cancer”: self-sufficiency in growth signals, insensitivity to anti-growth signals, resistance to apoptosis, unlimited replication (often by the enzyme telomerase), sustained blood vessel growth (angiogenesis), and invasion with metastasis.

Oncogenes and tumor suppressors compared

What are benign and malignant tumors?

A tumor (neoplasm) is a mass of abnormal cells. A benign tumor remains in one place, usually has a capsule and grows slowly (a wart or a lipoma), and is rarely life-threatening unless it presses on an organ. A malignant tumor (cancer) invades the surrounding tissue and can spread. Metastasis is the process in which cancer cells enter the blood or lymph, travel to distant sites and form secondary tumors. It is responsible for most cancer deaths. Cancers are named by the tissue of origin: carcinoma (epithelial tissue, the most common), sarcoma (connective tissue), leukemia (blood-forming tissue) and lymphoma (lymphatic system).

What are carcinogens?

A carcinogen is any agent that can cause cancer, usually by damaging DNA (a mutagen) or by promoting the division of damaged cells.

• Tobacco smoke: contains dozens of known carcinogens, such as benzo[a]pyrene; it is the cause of most lung cancer and is linked with many other cancers.
• Ultraviolet radiation: from the sun and sunbeds, which causes thymine dimers in DNA and skin cancer, including melanoma.
• Ionizing radiation: X-rays, gamma rays and radon gas. Exposure after nuclear accidents has been linked with thyroid cancer and leukemia.
• Chemicals: asbestos (mesothelioma), benzene (leukemia), aflatoxin (liver cancer), and some industrial chemicals. Alcohol and processed meat are classified by the International Agency for Research on Cancer (IARC) as carcinogenic to humans.
• Infectious agents: human papillomavirus (cervical cancer), hepatitis B and C viruses (liver cancer), Helicobacter pylori (stomach cancer) and Epstein-Barr virus (some lymphomas).
• Other factors: obesity, inactivity, age and inherited susceptibility.

The IARC classification describes the strength of evidence that an agent can cause cancer, not how strong the risk is. Processed meat and tobacco are both in Group 1, but the risk from tobacco is much larger.

How is cancer detected and treated?

Early detection improves outcomes: screening includes mammography (breast), cervical smears and HPV tests, colonoscopy and tests for blood in stool (colorectal). Diagnosis uses imaging and biopsy, an examination of tissue. Treatments include surgery, radiotherapy, chemotherapy (drugs that kill rapidly dividing cells, and therefore also affect hair follicles and the gut lining), hormone therapy, targeted drugs (such as imatinib for chronic myeloid leukemia) and immunotherapy, which helps the immune system to attack cancer cells. Vaccination against HPV and hepatitis B prevents cancers.

Worked example: how long does a tumor take to grow?

Suppose a tumor begins from one cell and the cell number doubles every 60 days. A tumor of about 10⁹ cells is roughly 1 cm across and weighs about 1 gram, and is around the smallest size that can be detected by many methods. (This is a simplified model, because real tumors grow irregularly, and some cells die.)

1. Number of doublings: after n doublings the number of cells is 2ⁿ. We need 2ⁿ ≈ 10⁹.
2. Solve: n = log₂(10⁹) = 9 × 3.32 ≈ 30. Check: 2³⁰ = 1,073,741,824, which is about 1.07 × 10⁹.
3. Time to detectable size: 30 doublings × 60 days = 1,800 days, which is about 4.9 years.
4. Further growth: 10 more doublings (n = 40) give 2⁴⁰ ≈ 1.1 × 10¹² cells, about 1 kg, a size that is often fatal. This takes 10 × 60 = 600 days, about 1.6 years.

The calculation shows that most of the life of a tumor is spent below the level of detection: of the 40 doublings, 30 occur before the tumor reaches 1 cm. It also shows why early screening can find small tumors that are easier to treat.

How was the cause of cancer discovered?

In 1775 Percivall Pott described scrotal cancer in chimney sweeps, one of the first links between an environmental agent and cancer. Peyton Rous showed in 1911 that a virus could cause sarcoma in chickens, and received the Nobel Prize in 1966. Doll and Hill’s studies in the 1950s established the link between smoking and lung cancer. In 1976 Michael Bishop and Harold Varmus found that the oncogene of the Rous virus has a normal counterpart in cells (the proto-oncogene), and received the Nobel Prize in 1989. Knudson proposed the two-hit hypothesis in 1971, and the first human tumor suppressor, RB1, was cloned in 1986. Harald zur Hausen showed the link between HPV and cervical cancer, which gave him a share of the 2008 Nobel Prize.

Which mistakes are common?

Mistake 1: Saying that cancer is a single disease

There are over a hundred types, with different causes, behavior and treatment.

Mistake 2: Thinking that cancer is mostly inherited

Most cancers arise from somatic mutations acquired during life. Inherited mutations account for a minority of cases, perhaps 5 to 10 percent.

Mistake 3: Confusing tumor and cancer

A tumor can be benign or malignant. Cancer refers to malignant growth.

Mistake 4: Assuming that a carcinogen always causes cancer

Carcinogens raise the probability. Many exposed people do not develop the disease, and the risk depends on dose, duration and individual susceptibility.