Molecular Characteristics of Cancer

Cancer does not arise from a single genetic event. For a cell to become fully malignant, multiple mutations must accumulate within that single cell — one mutation alone is insufficient. This principle of multi-step carcinogenesis underpins much of cancer biology and explains why cancer becomes more common with age, as the probability of accumulating the required number of mutations increases over a lifetime of cellular replication and exposure to mutagens.

The molecular hallmarks of cancer describe the capabilities that cancer cells must acquire through these accumulated mutations. These can be remembered using the mnemonic RISE LIER: Resistance to cell death, Induction of and access to vasculature, Sustained proliferative signalling, Evasion of growth suppressors, Limitless replication, Invasion and metastasis, Evasion of the immune system, and Reprogramming of cellular metabolism.

Sustained proliferative signalling is one of the most fundamental hallmarks. Normal cells require external growth factor signals to proliferate. Cancer cells bypass this requirement through several mechanisms: they can produce their own growth factors, promote growth factor signalling from surrounding stromal cells (including inflammatory cells), increase the number of receptors on the cell surface (receptor amplification), or carry mutations that cause growth factor receptors to signal constitutively — that is, in the permanent absence of growth factor binding. The result is uncontrolled, self-sufficient proliferation.

Evasion of growth suppressors complements the above. Normal tissues regulate cell division through inhibitory signals — tumour suppressor genes encode proteins that act as molecular brakes on proliferation. Cancer cells acquire mutations that either allow them to ignore inhibitory extracellular signals or directly inactivate tumour suppressor genes, removing these brakes entirely.

Resistance to cell death is acquired through mutations in genes that control apoptotic pathways. In normal cells, DNA damage or oncogenic stress triggers programmed cell death — apoptosis — as a protective mechanism. Cancer cells mutate the genes governing these pathways, making them resistant to apoptosis-inducing signals and allowing abnormal cells to survive and proliferate.

Limitless replication potential relates to the biology of telomeres. In normal somatic cells, telomeres — repetitive DNA sequences (TTAGGG) at chromosome ends that protect chromosomal integrity — shorten by approximately 10–20 repeats with each cell division. After approximately 60–70 divisions, telomeres are too short to protect chromosome ends, triggering cell senescence or death. In stem cells, the enzyme telomerase maintains telomere length. Malignant cells exhibit enhanced telomerase activity, allowing them to maintain telomeres, preserve chromosomal stability, and replicate indefinitely.

Invasion and metastasis requires cancer cells to escape the primary tumour and colonise distant sites. This involves loss of cell-to-cell adhesion (allowing cells to detach), degradation of the extracellular matrix (enabling penetration into surrounding tissue), and active movement of tumour cells into other tissue layers, the lymphatic system, the peritoneal cavity, or blood vessels.

Induction of and access to vasculature (angiogenesis) addresses the metabolic needs of a growing tumour. Cells must be within approximately 100 micrometres of a capillary to access nutrients and oxygen. To support continued growth beyond this limit, tumours promote formation of new blood vessels by upregulating vascular endothelial growth factor (VEGF). VEGF secreted by cancer cells migrates to nearby capillaries and enhances angiogenesis. This process is further augmented by inflammation.

Evasion of the immune system occurs because the immune system normally surveils for and destroys abnormal cells. Cancer cells evade this by hiding tumour-specific antigens — for example, by downregulating MHC antigen-presenting complexes on their surface. They can also reprogram immune cells: cancer cells upregulate the PD-L1 protein, which binds to the PD-1 receptor on T cells and signals that the cell is normal, preventing immune destruction. This mechanism is the biological basis for PD-1 checkpoint inhibitor therapies (e.g. pembrolizumab), which restore immune recognition of cancer cells.

Reprogramming of cellular metabolism reflects a fundamental shift in how cancer cells generate energy. Unlike normal cells, which rely primarily on oxidative phosphorylation, cancer cells preferentially use glycolysis even in the presence of oxygen — the Warburg effect. This involves increased glucose uptake and consumption and a shift to anaerobic metabolism. The functions of this metabolic reprogramming include providing glycolytic intermediates for biosynthetic pathways required for cell growth and proliferation, and compensating for the poor oxygen supply within the hypoxic cores of large tumours.