Cancer develops through a process of somatic evolution underpinned by genetic alterations in genomic DNA and epigenetic mechanisms that alter gene expression. Early neoplastic development that typically occurs well before tumour diagnosis is characterized by changes in a relatively small set of driver genes that accumulate in a linear fashion generating little intratumoural genetic heterogeneity (IGH). Thereafter, a process of branched evolution occurs generating cell populations containing subclonal (private) mutations; this increased IGH impedes successful therapy. Founder cells of cancer are most likely normal stem cells, and cancers themselves may have stem cells that could be key cellular targets for tumour eradication. The tumour microenvironment is a significant player in tumour behaviour, but tumour metastasis signals a poor prognosis. Improvements in treatment are underway, chemotherapy with cytotoxic drugs and associated unwanted side‐effects often being replaced by immunotherapies such as cancer vaccines or strategies that harness the power of T cells.

Key Concepts

  • More than 90% of all cancers are derived from epithelial cells because epithelial cells are the first line of defense against the environment, the sunlight we are exposed to, the air we breathe, the food and drink we consume.
  • Tissue stem cells are the likely founder cells of most cancers and some cancer themselves have cells with stem cell properties.
  • The nature of the tumour microenvironment has a very significant influence on tumour behaviour.
  • Alterations in gene expression that characterize cancer are not just the result of physical changes to the genome, but also due to epigenetic mechanisms such as DNA methylation and non‐coding RNAs.
  • Cancer treatment is changing with the traditional non‐specific cell cycle poisons being accompanied or even replaced by more bespoke immunotherapies.

Keywords: apoptosis, chemotherapy; immunotherapy; metastasis; proto‐oncogenes; stem cells; tumour suppressor genes

Figure 1. The defining characteristics (‘hallmarks’) of cancer as envisaged by Hanahan and Weinberg with modification. These are discussed in the text. The tumour microenvironment (TME) is an enabling factor that promotes many of these characteristics and is primarily composed of tumour‐associated macrophages (TAMs), cancer‐associated fibroblasts (CAFs) and tumour‐infiltrating lymphocytes (TILs). Modified from Hanahan D, Weinberg RA. (2011) Hallmarks of cancer: the next generation. Cell 144(5): 646–674.
Figure 2. Does tumour phenotype inform on tumour histogenesis? Current dogma suggests that most tumours arising in continually renewing systems (haematopoietic cells, gut lining cells, epidermis) with a hierarchical organisation (as illustrated) are initiated in stem cells or closely related progenitor cells, since ordinarily these are the only cells with a sufficient lifespan to accrue the mutational burden required for a malignant habitus. Moreover, stem cells possess the ability for seemingly continual turnover and are anchored to the niche. Inter‐tumoural diversity is unlikely to be because tumours can be initiated stochastically from any stage of lineage differentiation, and is most likely a reflection of either further differentiation and/or blocked differentiation/maturation arrest imposed by the oncogenic regime. Thus, tumours are unlikely to be similar to their cell‐of‐origin but may possess some of their features, for example, stemness or multipotentiality. The cell‐of‐origin may be further disguised by antecedent metaplasia, for example, intestinal metaplasia in the oesophagus and stomach, mucinous cell metaplasia in the pancreas or by proceeding epithelial–mesenchymal transition (EMT).
Figure 3. Invasion and metastasis occur either as single cells or cell clusters (collective migration) from the primary tumour, often epithelial cells undergo EMT, loosing contact with their neighbours. Migrating cells secrete matrix‐degrading proteases that break down the ECM and facilitate invasion into the lymphatics or bloodstream. The location of extravasation might be the first capillary bed that the tumour emboli become immobilised at, although it may have more to do with the CAMs expressed by the tumour and endothelial cells (see ‘seed and soil’ hypothesis). Exit from the vasculature may be followed by a period of dormancy as a micrometastasis, but once the angiogenic switch occurs then a secondary tumour can be established.
Figure 4. (a) Experimental studies suggest that tumour growth is initially described by a sigmoid growth curve on a semi‐logarithmic plot, with a middle period of exponential growth. Net growth is determined by the balance between the cell production rate and the cell loss rate; at the time of clinical detection, most primary tumours are on this near‐plateau phase of growth. As tumours grow, cell loss becomes an ever more significant factor by analogy with the container filling up with water. Based on a cartoon devised by G. Gordon Steel. Approaching the plateau phase, the cell production rate is almost matched by the cell loss rate. In a mouse weighing 25 g, exponential growth is curtailed once the tumour approaches 1 g in weight; in a human, the same phenomenon might occur after reaching a weight of ∼100 g (b) An adenocarcinoma will typically present with lakes of necrosis (asterisks) in the glandular lumina, derived from sloughed‐off cancer cells. Benign tumours rarely have necrotic areas.
Figure 5. Models of somatic cell evolution in cancer. (a) Early growth is likely to conform to a selective sweep (linear progression) model, (b) but at some point in time branched evolution results in subpopulations with private (subclonal) mutations. Tumour evolution has been likened to tree growth, with the early ubiquitous mutations referred to as truncal mutations, branching evolution increasing the level of IGH. MRCAs: most recent clonal ancestors. *A driver event (α, β, …) can be any genetic change brought about by the likes of mutation, chromosomal loss/addition, epigenetic event.
Figure 6. Assays for human CSCs. Selected cells (e.g. those being CD133+, coloured yellow in this illustration) can be assessed either for their in vitro clonogenicity or for their ability to initiate new tumour growth after xenotransplantation into immunocompromised mice. (a) Cells can be seeded at low density in non‐adherent conditions in a semi‐liquid medium, and the percentage of cells generating ‘spheres’ (e.g. colonospheres) can be measured. Spheres should be composed of both CD133+ and CD133 cells. The resulting CD133+ cells can be serially passaged, generating secondary and tertiary spheres with a cellular composition resembling that of the primary spheres. (b) The ‘gold standard’ assay for CSCs is the tumour initiating cell (TIC) assay in which the selected cells are orthotopically (common for brain) or ectopically (e.g. subcutaneous site, commonly for colon) xenotransplanted into an immunocompromised mouse. The cellular composition of the xenografted tumour should resemble the primary tumour from which the selected cells were enriched. The suspected CSCs would be the most clonogenic (have the highest plating efficiency (PE), where PE = number of macroscopic colonies/number of cells plated × 100) and should be ones that can also form tumours in mice with the fewest number of cells transplanted. From Alison MR, Lim SM, Nicholson LJ. (2011) Cancer stem cells: problems for therapy? Journal of Pathology 223: 147–161. © 2011 John Wiley & Sons.


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Further Reading

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Alison, Malcolm R(Dec 2020) Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0029230]