Loading
Scientists have given more than a dozen answers to what cancer is: mutated genes, runaway evolution, misbehaving stem cells, disordered tissue, ancient cell programmes, broken chromosomes, metabolism, epigenetic switches, unhealed wounds, a failed immune system, ageing tissue, force or electricity. This map shows each theory, who proposed it, what held up, and how the ideas connect.
The mainstream trunk runs left to right along the top of the diagram. The somatic mutation theory (cancer starts when one cell accumulates mutations in growth-controlling genes) was refined into the driver and passenger model (only a handful of those mutations matter) and then set in motion by clonal evolution (Nowell 1976: the mutant cell's descendants compete, diversify and are selected, including by treatment). The hallmarks of cancer (Hanahan and Weinberg 2000, 2011, 2022) sit at the end of the trunk as a synthesis: whatever the origin, cancers converge on the same acquired capabilities.
Below the trunk are the theories that challenge or extend it. The aneuploidy theory (Boveri, Duesberg) says broken chromosomes, not point mutations, are the engine; modern work on chromosomal instability and chromothripsis has absorbed it as an accelerator rather than the sole cause. The epigenetic progenitor theory (Feinberg) says the first step is a reversible change in gene regulation, not a mutation, and it feeds the cancer stem cell and plasticity view (Dick, Weissman, Clevers), in which a tumour is a caricature of a tissue with a stem-like compartment that treatment misses. The metabolic theory (Warburg, Seyfried) puts damaged respiration first; its modern reading (Vander Heiden, Thompson) treats metabolic rewiring as a consequence of oncogenic signalling that is nonetheless druggable. The atavistic theory (Davies, Lineweaver, Vincent) frames all of this as a reversion to an ancient unicellular survival programme.
The tissue-level theories occupy the bottom row. The tissue organisation field theory (Sonnenschein and Soto) says cancer is a disease of tissue architecture in which mutations are secondary; the microenvironment and inflammation view (Virchow, Dvorak, Coussens, Bissell) says stroma, vessels and immune cells co-create the tumour; Paget's seed and soil hypothesis applies the same logic to where metastases grow; the immune surveillance and immunoediting theory (Burnet, Thomas, Schreiber) says the immune system continuously removes nascent tumours and sculpts the ones that survive. The ageing tissue view (DeGregori, Martincorena, Ebert) adds time: mutant clones fill normal tissue throughout life and cancer arrives when old tissue changes what is selected. The newest proposals are physical: the mechanical theory (Bissell, Weaver, Jain) treats stiffness and pressure as instructive signals, and the bioelectric theory (Levin) treats membrane voltage patterns as a tissue-level control layer that can override mutations in animal models.
The arrows record how the schools relate. Solid arrows mean one theory feeds another (driver mutations feed clonal evolution; inflammation and immune escape became hallmarks). Inhibiting arrows mean one theory was proposed against another (tissue organisation, aneuploidy, epigenetics, metabolism and bioelectricity were each framed as alternatives to the somatic mutation theory). In practice the field has stopped treating them as rivals: the 2022 hallmarks paper explicitly imports non-mutational epigenetic reprogramming, phenotypic plasticity, the microbiome and senescence, and the somatic mutation theory is now read as necessary but not sufficient.
Status: a scorecard rather than one verdict. Established: somatic mutation theory, driver and passenger model, clonal evolution, immune surveillance and immunoediting, seed and soil, hallmarks as a framework. Partly confirmed: cancer stem cells (real hierarchy in leukaemias, rigid hierarchy replaced by plasticity), epigenetic progenitor theory, aneuploidy and chromosomal instability, metabolic reprogramming, ageing tissue as a field, mechanical theory. Contested: tissue organisation field theory, atavistic theory, bioelectric theory. Superseded: the strong forms of the aneuploidy theory (chromosomes instead of genes) and of the metabolic theory (respiration damage as the origin), and Ewing's purely mechanical account of metastatic spread.
Sixteen detectives arguing over one crime scene. The geneticist blames the suspect's record (mutations), the ecologist blames the neighbourhood that let a small-time offender flourish (evolution and microenvironment), the architect blames the building (tissue organisation), the historian says the suspect is behaving as its ancestors did (atavism), the nutritionist blames what it ate (metabolism), the immunologist asks where the police were (surveillance), and the physicist checks the wiring (mechanics and bioelectricity). The hallmarks paper is the chief inspector's summary: whoever is right about the motive, here is what the culprit always does.
Cancer is now understood to change its identity and behaviour without new mutations, to be shaped by bacteria inside and around it, and to be helped along by ageing cells. This explains why some tumours escape targeted drugs by changing cell type and why gut bacteria affect immunotherapy response.
It supplies the chemistry behind the allele spectrum of lung cancer: the G to T transversion that the tobacco signature generates is why KRAS G12C dominates in lung and G12D dominates in bowel and pancreatic cancer.
There are not thousands of cancer genes, and any one patient's tumour is driven by only a few of them. That makes targeted sequencing panels sensible, but because most drivers are lost tumour suppressors, drugs exist for only a minority, which is why the same group turned to early detection.
One pathway page and one term page on OnCo cite this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing pages listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
Immunoediting is the conceptual backbone of modern immuno-oncology: it explains tumour heterogeneity, dormancy and late relapse, and why immunotherapy works by releasing pre-existing but suppressed immunity.
One pathway page and one term page on OnCo cite this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing pages listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
The hallmarks are the mental map most oncologists and researchers use to think about what cancer is and where drugs act. A newcomer can understand nearly every therapy as an attack on one hallmark: kinase inhibitors on proliferative signalling, checkpoint blockade on immune evasion, anti-VEGF drugs on angiogenesis.
Shares Mutational signatures associated with tobacco smoking in human cancer, Ageing tissue and clonal fields: cancer as a disease of old tissue, Driver and passenger mutations: the refined somatic mutation theory, Drivers, passengers & the two-hit model and the tags mechanism, mechanics-atlas.
Shares Cancer stem cell theory and phenotypic plasticity, Cancer stem cells & phenotypic plasticity, Epigenetic progenitor theory: cancer without a first mutation, Clonal evolution and the ecological view of cancer and the tags mechanism, mechanics-atlas.
Shares Tissue organisation field theory (Sonnenschein and Soto), Mechanical theory: stiffness, pressure and force as causes, Field cancerisation, Epithelial-mesenchymal transition & drug efflux and the tags mechanism, mechanics-atlas.
Shares Warburg effect, Metabolic theory of cancer: from Warburg to oncometabolites, Cancer metabolism, Tumour microenvironment (TME) and the tags mechanism, mechanics-atlas.
Shares Warburg effect, Metabolic theory of cancer: from Warburg to oncometabolites, Cancer metabolism and the tags mechanism, mechanics-atlas.
Shares Immune surveillance and cancer immunoediting, Fibroblast activation, desmoplasia & matrix stiffness, Tumour microenvironment (TME), The cancer-immunity cycle and the tags mechanism, mechanics-atlas.
Shares Mechanical theory: stiffness, pressure and force as causes, Fibroblast activation, desmoplasia & matrix stiffness, Epithelial-mesenchymal transition & drug efflux and the tags mechanism, mechanics-atlas.
Shares Immune surveillance and cancer immunoediting, The cancer-immunity cycle, Epigenetic reprogramming and the tags mechanism, mechanics-atlas.