Cancer

Abstract

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.
close

References

Alison MR, Islam S and Wright NA (2010) Stem cells in cancer: instigators and propagators? Journal of Cell Science 123 (14): 2357–2368.

Alison MR, Lim SM and Nicholson LJ (2011) Cancer stem cells: problems for therapy? Journal of Pathology 223: 147–161.

Alison MR, Lin WR, Lim SM, et al. (2012) Cancer stem cells: in the line of fire. Cancer Treatment Reviews 38 (6): 589–598.

Allen J and Sears CL (2019) Impact of the gut microbiome on the genome and epigenome of colon epithelial cells: contributions to colorectal cancer development. Genome Medicine 11 (1): 11.

Barker N, Ridgway RA, van Es JH, et al. (2009) Crypt stem cells as the cells‐of‐origin of intestinal cancer. Nature 457: 608–611.

Batlle E and Clevers H (2017) Cancer stem cells revisited. Nature Medicine 23: 1124–1134.

Beltraminelli T and De Palma M (2020) Biology and therapeutic targeting of tumour‐associated macrophages. Journal of Pathology 250 (5): 573–592.

Bergers G and Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nature Reviews Cancer 3 (6): 401–410.

Blagih J, Buck MD and Vousden KH (2020) p53, cancer and the immune response. Journal of Cell Science 133 (5): jcs237453. DOI: 10.1242/jcs.237453.

Brabletz T, Kalluri R, Nieto MA, et al. (2018) EMT in cancer. Nature Reviews Cancer 18 (2): 128–134.

Clarke PA, Roe T, Swabey K, et al. (2019) Dissecting mechanisms of resistance to targeted drug combination therapy in human colorectal cancer. Oncogene 38 (25): 5076–5090.

Conway JR, Kofman E, Mo SS, et al. (2018) Genomics of response to immune checkpoint therapies for cancer: implications for precision medicine. Genome Medicine 10 (1): 93.

Cross WCH, Graham TA and Wright NA (2016) New paradigms in clonal evolution: punctuated equilibrium in cancer. Journal of Pathology 240: 126–136.

Crusz SM and Balkwill FR (2015) Inflammation and cancer: advances and new agents. Nature Reviews. Clinical Oncology 12 (10): 584–596.

Dart A (2017) Cell migration: shall we travel together? Nature Reviews Cancer 17 (4): 205.

De Palma M, Biziato D and Petrova TV (2017) Microenvironmental regulation of tumour angiogenesis. Nature Reviews Cancer 17 (8): 457–474.

Depil S, Duchateau P, Grupp SA, et al. (2020) 'Off‐the‐shelf' allogeneic CAR T cells: development and challenges. Nature Reviews Drug Discovery 19 (3): 185–199.

Dobbelstein M and Levine AJ (2020) Mdm2: open questions. Cancer Science 111 (7): 2203–2211.

Fidler IJ and Kripke ML (2015) The challenge of targeting metastasis. Cancer Meta stasis Reviews 34 (4): 635–641.

Friedl P and Mayor R (2017) Tuning collective cell migration by cell‐cell junction regulation. Cold Spring Harbor Perspectives in Biology 9 (4): a029199.

Galluzzi L, Vitale I, Aaronson SA, et al. (2018) Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death and Differentiation 25 (3): 486–541.

Goh AM, Coffill CR and Lane DP (2011) The role of mutant p53 in human cancer. Journal of Pathology 223 (2): 116–126.

Gonzalez H, Hagerling C and Werb Z (2018) Roles of the immune system in cancer: from tumor initiation to metastatic progression. Genes and Development 32 (19‐20): 1267–1284.

Green DR (2019) The coming decade of cell death research: five riddles. Cell 177 (5): 1094–1107.

Hanahan D and Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144 (5): 646–674.

Hanahan D and Coussens LM (2012) Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21 (3): 309–322.

Hannen R and Bartsch JW (2018) Essential roles of telomerase reverse transcriptase hTERT in cancer stemness and metastasis. FEBS Letters 592 (12): 2023–2031.

Hirohashi S and Kanai Y (2003) Cell adhesion system and human cancer morphogenesis. Cancer Science 94 (7): 575–581.

Keller L and Pantel K (2019) Unravelling tumour heterogeneity by single‐cell profiling of circulating tumour cells. Nature Reviews Cancer 19 (10): 553–567.

Labernadie A, Kato T, Brugués A, et al. (2017) A mechanically active heterotypic E‐cadherin/N‐cadherin adhesion enables fibroblasts to drive cancer cell invasion. Nature Cell Biology 19 (3): 224–237.

Labuschagne CF, Zani F and Vousden KH (2018) Control of metabolism by p53 ‐ Cancer and beyond. Biochimica et Biophysica Acta, Reviews on Cancer 1870 (1): 32–42.

Langley RR and Fidler IJ (2011) The seed and soil hypothesis revisited‐‐the role of tumor‐stroma interactions in metastasis to different organs. International Journal of Cancer 128 (11): 2527–2535.

Lane DP (1992) Cancer. p53, guardian of the genome. Nature 358: 15–16.

Levine AJ (2020) p53: 800 million years of evolution and 40 years of discovery. Nature Reviews. Cancer 20 (8): 471–480.

Levine AJ, Jenkins NA and Copeland NG (2019) The roles of initiating truncal mutations in human cancers: the order of mutations and tumor cell type matters. Cancer Cell 35 (1): 10–15.

Li Z, Pearlman AH and Hsieh P (2016) DNA mismatch repair and the DNA damage response. DNA Repair (Amst) 38: 94–101.

Lopes A, Vandermeulen G and Préat VJ (2019) Cancer DNA vaccines: current preclinical and clinical developments and future perspectives. Experimental and Clinical Cancer Research 38 (1): 146.

McGranahan N and Swanton C (2017) Clonal heterogeneity and tumor evolution: past, present, and the future. Cell 168: 613–628.

Nash DB, Fabius RJ and Skoufalos A (2020) Preventing colorectal cancer: pathway to achieving an 80% screening goal in the United States: overview and proceedings of a Population Health Advisory Board. Population Health Management. DOI: 10.1089/pop.2020.0076.

Rupaimoole R and Slack FJ (2017) MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nature Reviews Drug Discovery 16 (3): 203–222.

Sahai E, Astsaturov I, Cukierman E, et al. (2020) A framework for advancing our understanding of cancer‐associated fibroblasts. Nature Reviews Cancer 20 (3): 174–186.

Sánchez‐Danés A, Hannezo E, Larsimont JC, et al. (2016) Defining the clonal dynamics leading to mouse skin tumour initiation. Nature 536: 298–303.

Schneider G, Schmidt‐Supprian M, Rad R, et al. (2017) Tissue‐specific tumorigenesis: context matters. Nature Reviews Cancer 17 (4): 239–253.

Sheng R, Li X, Wang Z, et al. (2020) Circular RNAs and their emerging roles as diagnostic and prognostic biomarkers in ovarian cancer. Cancer Letters 473: 139–147.

Shimasaki N, Jain A and Campana D (2020) NK cells for cancer immunotherapy. Nature Reviews Drug Discovery 19 (3): 200–218.

Shlush LI, Zandi S, Mitchell A, et al. (2014) Identification of pre‐leukaemic haematopoietic stem cells in acute leukaemia. Nature 506: 328–333.

Singh AK and McGuirk JP (2020) CAR T cells: continuation in a revolution of immunotherapy. Lancet Oncology 21 (3): e168–e178.

Sottoriva A, Kang H, Ma Z, et al. (2015) A Big Bang model of human colorectal tumor growth. Nature Genetics 47: 209–216.

Steeg PS (2016) Targeting metastasis. Nature Reviews Cancer 16 (4): 201–218.

Sulak M, Fong L, Mika K, et al. (2016) TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants. eLife 5: e11994.

Tsagakis I, Douka K, Birds I, et al. (2020) Long non‐coding RNAs in development and disease: conservation to mechanisms. Journal of Pathology 250 (5): 480–495.

Vessoni AT, Filippi‐Chiela EC, Lenz G, et al. (2020) Tumor propagating cells: drivers of tumor plasticity, heterogeneity, and recurrence. Oncogene 39: 2055–2068.

Yap TA, Gerlinger M, Futreal PA, et al. (2012) Intratumor heterogeneity: seeing the wood for the trees. Science Translational Medicine 4 (127): 127ps10.

Zhang Y and Weinberg RA (2018) Epithelial‐to‐mesenchymal transition in cancer: complexity and opportunities. Frontiers of Medicine 12 (4): 361–373.

Further Reading

Aguilar‐Cazares D, Chavez‐Dominguez R, Carlos‐Reyes A, et al. (2019) Contribution of Angiogenesis to Inflammation and Cancer. Frontiers in Oncology 9: 1399.

Alberts B, Johnson AD, Lewis J, et al. (2015) Molecular Biology of the Cell, 6th edn. Kindle edition 2018. Garland Science: New York.

Blanpain C (2013) Tracing the cellular origin of cancer. Nature Cell Biology 15: 126–134.

Derynck R and Weinberg RA (2019) EMT and cancer: more than meets the eye. Developmental Cell 49 (3): 313–316.

Kastenhuber ER and Lowe SW (2017) Putting p53 in context. Cell 170 (6): 1062–1078.

Levine AJ, Jenkins NA and Copeland NG (2019) The roles of initiating truncal mutations in human cancers: the order of mutations and tumor cell type matters. Cancer Cell 35 (1): 10–15.

Paul CD, Mistriotis P and Konstantopoulos K (2017) Cancer cell motility: lessons from migration in confined spaces. Nature Reviews Cancer 17 (2): 131–140.

Pearce OMT, Delaine‐Smith RM, Maniati E, et al. (2018) Deconstruction of a metastatic tumor microenvironment reveals a common matrix response in human cancers. Cancer Discovery 8 (3): 304–319.

Weinberg RA (2013) The Biology of Cancer, 2nd edn. Garland Science: New York.

Wilson J and Hunt T (2014) Molecular Biology of the Cell – The Problems Book. Garland Science: New York.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Alison, Malcolm R(Dec 2020) Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0029230]