Chapter 1: Introduction to neoplasia
Our discussion of neoplasia begins with a review of some definitions, the types of tissue growth, and the major differences between benign and malignant tumours. The next chapter discusses the biology of cancer, including cell cycle regulation, growth factors, apoptosis, and telomerase. Unregulated cell cycle progression, abnormal secretion of growth factors, evasion of apoptosis, and unlimited cell division are all biological mechanisms by which cancers override normal control of tissue growth. Following a discussion of the molecular mechanisms, the cancer genetics chapter focuses on the contribution of mutations to carcinogenesis (cancer formation). The progressive accumulation of non-lethal mutations that increase growth potential is essential to carcinogenesis, which will be described in chapter 4. In the final chapter, the process of metastasis, the cardinal feature of malignancy, is discussed.
Tumour: “swelling” – refers to any tissue mass, solid- or liquid-filled, benign or malignant.
Cancer: refers to malignant tumours, which have the potential to metastasize. Cancer is synonymous with neoplasia, a type of tissue growth that continues despite the absence of stimulus (see Types of tissue growth below).
Differentiation: refers to the morphology of cells compared to normal cells of the same tissue. Well differentiated tumour cells look and function like normal cells of the tissue. Poorly differentiated tumour cells (anaplastic cells) do not function like the normal tissue and appear abnormal on microscopy. Anaplastic cells have the following features:
- Pleomorphic: continual variation in size and shape.
- Hyperchromatic: cells are dark-staining with large nuclei.
- Loss of polarity: normal cells are anchored and oriented to the basement membrane; anaplastic cells lose this uniform orientation and the tumour cells grow in a disorganized way.
- Mitoses: increased proliferation results in abnormally large number of cells undergoing mitosis.
Grading: reflects the degree of differentiation in the tumour cells. High-grade tumours are poorly differentiated and more aggressive than low-grade tumours.
Staging: reflects the size of the primary tumour and the extent of local and distant spread. The TNM classification is commonly used:
- T = tumour size and local invasion; T0 = carcinoma in situ (no local invasion), followed by T1-T4
- N = regional lymph node involvement; N0 = no nodes, following by N1-N3 in increasing number of nodes
- M = distant metastases; M0 = no metastasis, follow by M1 for metastasis
Oncologists use grading and staging to describe the characteristics of the cancer and to determine prognosis. Staging is of greater clinical value because it predicts prognosis and affects management.
Types of tissue growth
Cells can increase in number or size to yield tissue growth. The types of tissue growth occur on a spectrum from controlled, physiologic growth to uncontrolled, disorganized growth. Cancer risk increases with both increased rate of cell proliferation as well as decreased cell differentiation.
|Definition||Increase in size of the cells without an increase in number.||Increase in the number of cells; can be physiologic or pathologic||Reversible replacement of one cell type with another; adaptation to external environment||Altered cell maturation, orientation, and tissue architecture; may progress to cancer or regress to normal cells.||“To form backward”
Lack of cell differentiation; a hallmark of malignancy
Unregulated cell proliferation as a result of genetic changes.
|Example||Skeletal or cardiac muscle cells respond to increased workload by increasing in size.||Physiologic: breast glandular epithelium hyperplasia during puberty; compensatory hyperplasia of liver after resectionPathologic: Benign prostatic hyperplasia in response to androgen hormones.||Acid reflux: Metaplasia of esophageal squamous epithelium to intestinal-like glandular columnar epithelium in Barrett esophagus.||Cervical intraepithelial neoplasia is a premalignant lesion of the cervix with varying grades of epithelial dysplasia. Cells have dark-staining nucleus (hyperchromasia), pleomorphism (varying shapes and sizes), and loss of polarity (disorganized tissue architecture).||In colorectal cancer, there is progressive dedifferentiation of colon epithelial cell. High grade anaplastic cells are hyperchromatic, pleomorphic, and disorganized.||In adenocarcinoma of the lung, autonomous growth of glandular cells occurs as a result of oncogene expression (KRAS) and loss of tumour suppressor genes (p53).|
|Mechanism||Increase in protein production in response to mechanical stress and growth factors||Growth factors stimulate cell proliferation from existing mature cells or stem cells.||External stimuli triggers altered gene transcription, leading to differentiation of stem cells to a different cell type; not a conversion from one differentiated cell type to another.||Dysregulation of cell maturation and growth as a result of altered gene expression or genetic mutations.||New theories suggest that anaplasia results from lack of differentiation of cancer stem cells instead of dedifferentiation of mature cells.||See Carcinogenesis chapter.|
|Cancer risk||–||+||++||+++||++++||Cancer formed|
Benign vs malignant tumours
|Nomenclature||Ends in “-oma”||Ends in “-carcinoma” (cancer in cells of endodermal or ectodermal origin) or “-sarcoma” (cancer in cells of mesenchymal origin)|
|Local invasiveness||No, grows as a cohesive mass encapsulated by dense connective tissue||Yes, destroys surrounding tissue and lacks a well-defined capsule|
|Metastasis*||No||Yes, except for CNS and cutaneous basal cell carcinomas|
|Differentiation||Well differentiated||Poorly differentiated: anaplasia|
*Metastasis is the defining feature of malignancy. It is the key feature differentiating malignant from benign tumours.
Chapter 2: Cancer biology
Malignant transformation of normal cells to cancer cells involves disruption of key cellular processes:
- Cell cycle regulation
- Growth factor regulation of cell cycle progression
Cell cycle regulation
Nat Rev Genet. 2008 Feb;9(2):115-28.
Cell cycle: a series of highly regulated steps that governs cell proliferation. There are 4 phases:
- M phase (mitotic segregation): the cell undergoes mitosis and divides.
- G1 phase: the first gap phase can be divided into an early and a late stage, which is separated by the restriction (R) point. Cyclin and cyclin-dependent kinases (CDKs) control progression by phosphorylation of regulatory proteins. An example is the RB (retinoblastoma tumour suppressor) protein. Unphosphorylated RB binds to and inhibits E2F, the activation of which will drive gene transcription and cause progression to the late stage of G1 and forward. CDK4 binds with cyclin D to phosphorylate RB, which allows progression through the R point.
- Early G1 stage (mitogen-dependent): requires extrinsic growth factors (mitogens) which provide the stimulatory signal to proceed forward
- G0 phase (quiescence): cells can exit the cell cycle to the G0 phase if no mitogens are present. The cells are typically smaller and have reduced metabolic activity.
- R point: the “point of no return” where the cell is committed to progression to the next phase. Hyperphosphorylation of RB by CDK4/cyclin D is important in passing through the R point.
- Late G2 stage (mitogen-independent): no longer requires mitogen signal to proceed.
- G1/S checkpoint: controlled by CDK2, this important checkpoint requires no damage to the DNA structure before DNA replication proceeds. DNA damage may lead to DNA repair pathways or apoptosis.
- S phase (synthesis): DNA replication occurs.
- G2 phase: the second gap phase allows replicated DNA to be checked before mitosis at the G2/M checkpoint.
Cancer genetics: The regulators of the cell cycle are commonly mutated in cancers. Genes that stop cell cycle progression (an example of tumour suppressor genes) are often downregulated or missing, and genes that promote cell cycle progression (an example of proto-oncogenes) are often upregulated or made constitutively active. The end result is increased cell cycle progression, allowing tumour cells to proliferate without restraint. See the Cancer genetics chapter for details.
Upstream of the cell cycle are the signals that regulate the regulators of the cell cycle. Growth factors, or mitogens, are soluble factors released by cells to influence the growth of neighbouring cells or itself, which are called paracrine and autocrine signalling, respectively. Neoplastic cells can alter growth factor signalling to increase proliferation. Although it does not directly lead to malignant transformation, it can help increase the risk of mutation by reducing time for DNA repair during rapid progression of the cell cycle. A variety of changes can be made to growth factors and their receptors:
- Autocrine stimulation: tumour cells may secrete growth factors to stimulate self-growth in an autocrine fashion
- Constitutive activation: tumour cells may also harbour growth factor receptor mutations that make the receptor constitutively active; i.e., active without having a growth factor bound to it. This allows continuous stimulatory signal to proliferate.
- Overexpression: more commonly, tumour cells may overexpress growth factor receptors, leading to increased signalling. For example, a type of epidermal growth factor (EGF) receptor, called HER2, is overexpressed in a special group of breast tumours (HER-positive). Trastuzumab (Herceptin) is a monoclonal antibody directed against the HER2 receptor that is used to treat HER2-positive breast cancers.
Cell death: apoptosis vs necrosis
N Engl J Med. 2009 Oct 15;361(16):1570-83.
Curr Opin Cell Biol. 2004 Dec;16(6):663-9.
Cell death can be a consequence of cellular injury (e.g. by ischemia) or regulated genetic process (e.g. by apoptosis). The two major forms of cell death, apoptosis and necrosis, differs by the pattern of cellular breakdown.
|Definition||“leaves falling from a tree” – features cell and nuclear shrinkage with preserve plasma membrane integrity||“corpse” – features early loss of membrane integrity, leading to cellular swelling and rupture, releasing cellular contents into the extracellular space|
|Process||Physiological or pathological||Pathological|
|Initiated by||One of two causes:
||Anything that causes irreversible cell injury, e.g. ischemia.|
|Mechanism||One of two pathways
||Cell ischemia, leading to rapid depletion of ATP and influx of calcium ions across the cell membrane
Apoptosis and cancer
- The accumulation of DNA damage in carcinogenesis usually triggers the intrinsic pathway to induce cell apoptosis.
- Thus, for neoplasia to form, the cell must evade the protective mechanism of apoptosis.
- BCL2, an anti-apoptotic protein, is commonly upregulated in cancers to protect against apoptosis.
- p53, a pro-apoptotic protein, is commonly downregulated in cancers to evade apoptosis, even in the face of irreparable DNA damage.
Nat Rev Cancer. 2008 Jun;8(6):450-8.
- Healthy cells can only divide a limited number of times before becoming senescent
- The process of cell senescence is governed by the shortening of telomeres after each cycle of cell division. Once the telomeres shorten to a certain threshold, DNA-repair mechanisms like p53 and pRB detect the abnormal telomere length and induce cell cycle arrest, thereby stopping further replication of this senescent cell.
- If p53 is lost, a special type of DNA “repair” occurs, called non-homologous end joining. The ends of random chromosomes are joined together, forming a dicentric chromosome (with two centromeres). Continuation of mitosis would lead to mitotic catastrophe with breakage of the chromosomes because of the pulling apart of aberrantly located centromeres. This leads to cell death.
- In tumour cells, an enzyme called telomerase, typically only present in self-regenerating stem cells, allows lengthening of telomeres after each cell division. The tumour cell evades senescence and can continue replicating despite accumulation of DNA damage.
The major changes in cellular biology that characterize cancer cells include:
1) Self-sufficiency in growth signals: refers to activation of oncogenes that allow continuous cell proliferation.
2) Insensitivity to anti-growth signals: refers to inactivation of tumour suppressor genes that restrict cell cycle progression. Another important hallmark of cancer is the lack of contact inhibition, a normal self-regulatory process where cells stop proliferating once cell-to-cell contact is made. This is best demonstrated by a two-dimensional culture experiment where normal cells stop growing on the medium once a monolayer of cells has been made. In contrast, cancer cells often continue dividing despite sufficient cell-to-cell contact, suggesting a loss of self-regulatory function.
3) Evasion of apoptosis: allows cancer cells to survive even with substantial DNA damage; results from upregulation of anti-apoptotic genes and downregulation of pro-apoptotic genes. Emerging evidence also demonstrates the ability of cancer cells to use the necrosis pathway to recruit inflammatory cells that can secrete growth-stimulating cytokines, which ultimately enhance carcinogenesis.
4) Limitless replicative potential: the expression of telomerase allows cancer cells to evade senescence and proliferate infinitely.
5) Sustained angiogenesis: tumours grow rapidly and require a source of nutrients and oxygen for sustained growth; the creation of a stable blood supply enables this. Angiogenesis is the sprouting of blood vessels from existing ones, while vascularization is the assembly of blood vessels by endothelial cells. In normal tissue, angiogenesis is transiently switched on for wound healing or endometrial growth in women. Tumours express pro-angiogenic factors (VEGF, FGF) and suppress anti-angiogenic factors (thrombospondin-1) to promote blood vessel formation.
6) Tissue invasion and metastasis: metastasis is the cardinal feature of malignancy. Cancer cells acquire the ability to invade into the basement membrane and detach from neighbouring cells, allowing dissemination to distant sites via blood vessels (hematogenous route) or lymphatics. See Metastasis chapter for details.
Chapter 3: Cancer genetics
Surg Clin North Am. 2008 Aug;88(4):681-704, v.
Nat Rev Cancer. 2010 May;10(5):353-61. (Inherited cancers)
Nat Rev Cancer. 2001 Oct;1(1):77-82. (History of cancer genetics)
- Cancer is fundamentally a genetic disease. During the process of carcinogenesis, pre-malignant cells accumulate genetic mutations until a fully malignant phenotype forms.
- Although cancer has a genetic basis, it is not necessarily hereditary. Most cancers arise from sporadic mutations instead of inherited mutations.
- There are two main groups of genes implicated in cancer: oncogene and tumour suppressor genes. A malignant tumour often has both activation of oncogenes and inactivation of tumour suppressor genes.
- In general, most blood cancers and soft-tissue sarcomas are initiated by activation of an oncogene
- Most carcinomas are initiated by loss of a tumour suppressor gene
- Subsequent progression to malignancy involves both additional gain of oncogenes and loss of tumour suppressors in all types of cancers
- A single tumour is monoclonal in origin. At various points during carcinogenesis, one cell gains a mutation that confers a survival advantage. That transformed cell proliferates to form a monoclonal cell mass. This process repeats, allowing further mutations to select for subclonal populations that harbour increasing proliferative potential.
- Even though tumours are monoclonal in origin, the cells within a tumour are heterogeneous because each subclonal population accumulates different mutations that cause cancers from one cell type (e.g. breast myoepithelial cells) to behave differently from tumour to tumour.
- Cancer stem cells have high proliferative potential, while other cancer cells behave like post-mitotic, differentiated cells with limited proliferative potential. Cancer stem cells have several unique abilities: to self-renew, to give rise to differentiated cell populations, and to metastasize. Surgical removal of a tumour must remove all cancer stem cells for successful remission.
Nat Rev Cancer. 2003 Dec;3(12):895-902.
- Driver versus passenger mutations: there are numerous mutations in a tumour mass but only a certain number are “drivers” in the carcinogenesis process. The rest are merely passive mutations acquired because of cancer’s inherent predisposition to accumulate genetic mutations.
- Epigenetic changes are commonly found in tumours. Epigenetics refer to heritable changes in gene expression that are reversible and not due to changes in the coding sequence. Silencing of certain genes by DNA methylation and activation of certain genes by DNA demethylation or acetylation can alter gene expression without changing the base sequence. Cancers often have hypomethylation of the cell genome (increases gene expression overall for increased metabolic activity) with hypermethylation of tumour suppressor genes (silences genes that control cell growth).
N Engl J Med. 2008 Jan 31;358(5):502-11.
- Definition: oncogenes are mutated versions of proto-oncogenes that confer a proliferative advantage to the tumour cell by augmenting the proto-oncogenes’ endogenous growth-promoting function. Oncoproteins are the products of oncogenes.
- Viral oncogenes: The Rous sarcoma virus is a retrovirus that harbours the oncogene src, which when integrated into the host genome can cause the development of a sarcoma. The host of the Rous sarcoma virus is the chicken, but a homologue of the src gene exists in humans as well. Conservation of proto-oncogenes in evolution suggests that they carry out essential growth functions in the normal host.
- Proto-oncogenes are a normal part of the genome. These genes promote cell growth in normal cells. In general, extracellular growth factors bind growth factor receptors, which activate intracellular downstream signal transducers. The signal initiates DNA transcription of genes involved in cell growth, which involves transcription factors binding to DNA regulatory elements and recruiting chromatin remodellers to carry out gene transcription. There are 6 categories of proto-oncogenes:
- Transcription factors: proteins that can bind to DNA regulatory domains to cause transcription of genes. The MYC proto-oncogene is a transcription factor that is frequently activated in cancers. It promotes transcription of cyclin genes, which in turn promote cell cycle progression. MYC also has a variety of other functions controlling cell growth, differentiation, and apoptosis. Common cancers with MYC mutations include Burkitt lymphoma (a type of B-cell cancer), small-cell lung cancer, breast cancer, and neuroblastoma.
- Chromatin remodellers: proteins that alter chromatin structure to promote or repress gene transcription. In general, histone methylation inhibits gene transcription while histone acetylation promotes gene transcription. Methylation and acetylation changes the charge of histone proteins, which modulates the histones’ effect on compaction or loosening of DNA. DNA must be loosened in order for transcription to occur, a process facilitated by histone acetylation. The ALL1 gene (also called MLL) is an example of a chromatin remodelling protein; it is mutated in acute lymphoblastic leukemia.
- Growth factors (mitogens): soluble factors that influence the growth of neighbouring cells (paracrine) or the releasing cell itself (autocrine). Cancer cells often acquire the ability to stimulate its own growth by releasing growth factors in an autocrine loop. For example, certain brain tumours (glioblastoma) can secrete platelet-derived growth factor (PDGF). PDGF is normally released following injury that requires platelet activation. PDGF stimulates proliferation of numerous cell types to participate in wound healing. Cancer cells can both acquire the ability to secrete PDGF and to express PDGF receptor, creating a self-stimulatory loop.
- Growth factor receptors: transmembrane proteins that signal intracellular molecules to carry out cell proliferation when bound by a growth factor. Growth factor receptors in cancer cells can either be overexpressed or mutated to become independent of growth factor activation, allowing the receptor to signal downstream cell proliferation even in the absence of mitogens. For example, members of the epidermal growth factor receptor (EGFR) family are commonly activated in cancers. In HER2-positive breast cancer, the tumour cells overexpress HER2 receptor (also called ERBB2, an EGFR), which greatly increases tumour growth. Trastuzumab is a monoclonal antibody that targets HER2 receptor to stop downstream signalling. It is effective in treating HER2-positive breast cancers.
- Signal transducers: downstream proteins that carry out receptor signals to initiate gene transcription. Examples include PI3K and AKT, which can be mutated in cancers to permit intracellular growth signalling in the absence of extrinsic growth factors.
- Apoptosis regulators: increased anti-apoptotic molecules help tumour cells evade apoptotic mechanisms. For example, BCL2 inhibits apoptosis and is upregulated in many cancers including lymphomas, leukemias, and lung cancer.
- Gain-of-function mutations to proto-oncogenes give rise to oncogenes, which contribute to unregulated cell growth. In contrast, tumour suppressor genes are lost or suppressed in cancer. Mutations of oncogenes can either be quantitative, i.e. by increasing the amount of gene product, or qualitative, i.e. by altering the gene product to make it constitutively active. There are 3 main mechanisms of gene alteration that activate oncogenes:
- Mutations: point mutations in certain oncogenes can create oncoproteins that promote carcinogenesis. For example, the RAS oncogenes can be mutated in certain codons that render it constitutively active. RAS is involved in signal transduction, the constitutive activation of which is found in lung, colon, and pancreatic cancers.
- Chromosomal rearrangements: translocation of genetic material from one chromosome to another is commonly found in blood cancers. The translocation activates an oncogene by using regulatory elements from a heavily transcribed gene to drive expression of the oncogene. For example, some B-cell lymphomas evade apoptosis by using the promoter of an immunoglobulin gene to drive expression of the anti-apoptotic BCL2 protein in the t(14:18) translocation. Another example is the Philadelphia chromosome, which is found in chronic myelogenous leukemias and some acute leukemias. The Philadelphia chromosome is a t(9:22) translocation that juxtaposes the BCR gene on chromosome 22 with the c-ABL proto-oncogene on chromosome 9. The BCR-ABL fusion gene creates a constitutively active tyrosine kinase product that promotes cell proliferation independent of extrinsic regulation.
- Gene amplification: sometimes, proto-oncogenes only need to be overexpressed (not mutated) to cause cancer. An example is the aforementioned HER2 gene in HER2-positive breast cancers.
Tumour suppressor genes
Nature. 2011 Aug 10;476(7359):163-9. (revisiting the Knudson hypothesis)
Carcinogenesis. 2005 Dec;26(12):2031-45.
- Definition: tumour suppressor genes are endogenous genes that restrict cell proliferation by controlling cell division, repairing damaged DNA, and inducing apoptosis when other mechanisms fail. Cancer cells harbour loss-of-function tumour suppressor mutations because less restriction of cell growth is advantageous to survival of the tumour. The loss of both alleles of a tumour suppressor gene is required for cancer formation (see Knudson hypothesis below).
- There are two categories of tumour suppressor genes:
- Gatekeeper genes: stop cell cycle progression when DNA damage is detected
- p53: “Guardian of the genome” p53 is a transcription factor that is activated by DNA damage, hypoxia, or cell injury. p53 activates p21, which in turn inhibits the cyclin complexes required for promotion of the cell cycle past G1 phase (see cell cycle figure). Cell cycle arrest allows time for DNA repair to occur. If the DNA damage is beyond repair, p53 can induce apoptosis in the mutated cell, a function that is crucial to preventing cancer formation. Without p53, the cell cycle progresses despite DNA damage. The cell eventually accumulates enough mutations through activation of oncogenes or inactivation of tumour suppressor genes to become cancerous. The lack of apoptosis allows multiple cycles of DNA damage and cell proliferation to occur.
- pRB: pRB is a transcription inhibitor that prevents cell cycle progression past G1 phase by inhibiting expression of S phase genes. Loss of pRB via mutation of the RB1 gene results in retinoblastoma (see cell cycle figure).
- Caretaker genes: repair damaged DNA during cell cycle arrest
- BRCA: A group of DNA repair proteins that resolve DNA crosslinks. Loss of BRCA results in DNA strands breaks and aneuploidy after cell division. BRCA1 and BRCA2 are the most commonly mutated genes in familial breast and ovarian cancer.
- Mismatch repair (MMR) genes: MSH2, MLH1, and other MMR genes are responsible for fixing mismatched nucleotides during DNA replication (a proofreading function). In addition to causing increased mutation rates in all genes, the lack of mismatch repairs also causes instability regions of repeating nucleotides called microsatellite regions. While microsatellite instability does not directly affect carcinogenesis, it is indicative of the pathogenicity of tumours, likely reflective of the underlying defect in DNA repair. Colorectal tumours with high microsatellite instability confer a poorer prognosis.
- Gatekeeper genes: stop cell cycle progression when DNA damage is detected
- Knudson two-hit hypothesis: explains the predisposition to cancer when an individual inherits a germline mutation of a tumour suppressor gene. Since both alleles of a tumour suppressor gene must be lost for cancer formation, two “hits” are required. If an individual is born with a mutation in one allele of a tumour suppressor gene, that person already has one “hit,” and only one other somatic mutation (the second “hit”) in the functional allele of the gene is necessary for cancer formation. The acquisition of the second “hit” is called loss of heterozygosity (LOH).
- The Knudson two-hit hypothesis explains why children who inherit one mutated RB1 allele are predisposed to retinoblastoma (embryonic cancer of the retina). Although children who have normal RB1 alleles can also develop retinoblastoma (sporadic form), those who inherit a mutation (hereditary form) have (1) earlier onset of disease, (2) increased risk of bilateral retinal involvement, and (3) multifocal rather than unifocal in origin, compared with the sporadic form.
Chapter 4: Carcinogenesis
Robbins 8E, chapter 7
Walsh: Palliative Medicine 1E, chapter 217
Carcinogenesis: the multistep process of transformation of a normal tissue cell to a cancer cell.
Transformation: the conversion of one cell phenotype to another.
Carcinogen: an agent (chemical, radiation, or microbial) that induces changes to a cell population that can cause cancer.
- Initiation: a carcinogen induces non-lethal mutation(s) in a cell. The cell must undergo one cycle of proliferation to make the mutation heritable (i.e. permanent in the cell genome).
- Promotion: an initiated cell proliferates (clonal expansion), allowing additional mutations to accumulate.
- Progression: continual accumulation of multiple mutations results in an invasive phenotype and distant metastasis.
Basic classes of carcinogens
|Initiator||Induces non-lethal mutation(s) in a cell||Irreversible changes to DNA||Must be exposed to tissue before promoter for carcinogenesis||
|Promoter||Induces cell proliferation||Reversible influence on cell growth (no changes to DNA)||Must be exposed to tissue after initiator for carcinogenesis||
- Neither exposure to an initiator or a promoter on its own is sufficient for carcinogenesis. The two must act sequentially for carcinogenesis to occur. The time delay between initiation and promotion can be long or short because initiation is permanent.
- Partial carcinogen: can only carry out either initiation or promotion functions, e.g. hormones (can only promote but not initiate).
- Complete carcinogen: can carry out both initiation and promotion functions, e.g. tobacco smoke, UV radiation, and ionizing radiation. Exposure to a complete carcinogen alone is sufficient to cause carcinogenesis. See table below for more examples of complete carcinogens.
- Heritable cancer: an inherited mutation in an oncogene or tumour suppressor gene does not require further initiation for carcinogenesis; further promotion will lead to cancer formation.
Types of environmental carcinogens
Chemical carcinogens are electrophilic and they react with nucleophilic sites in cells, particularly DNA but also RNA and proteins. Changing the base structure of DNA causes mutations in genes. Certain genes, such as RAS and p53, are frequently mutated first because changes in their function permit cells to increase proliferative potential.
Direct- vs indirect-acting carcinogens
- Direct-acting carcinogens: do not require further activation to become carcinogenic; e.g. alkylating chemotherapy drugs.
- Indirect-acting carcinogens: not carcinogenic in its original state (procarcinogen); requires metabolic activation to become carcinogenic. Most carcinogens are in this category. For example:
- Polycyclic aromatic hydrocarbons in tobacco requires activation by heat (smoking) and chemical processing (cytochrome P-450) to become active carcinogens. Thus, particular isoforms of the CYP enzymes may predispose or protect individuals from potential of carcinogens.
- Alcohol: consumption causes oropharyngeal, esophageal, liver, breast, and colorectal cancers. Alcohol is an indirect-acting carcinogen through a variety of mechanisms depending on organ. For the gastrointestinal organs, the natural metabolism of alcohol to acetaldehyde may be an important factor. Having reduced function of the enzyme aldehyde dehydrogenase (ALDH2*2) is associated with increased cancer risk with alcohol consumption due to accumulation of acetaldehyde (i.e. reduced metabolism of acetaldehyde to acetate). Acetaldehyde is known to cause DNA adducts, cellular damage, and trigger cell proliferation, which allows it to act as a complete carcinogen. Alcohol also causes oxidative stress by induction of CYP2E1, allowing reactive oxygen species to react with and damage DNA. Furthermore, alcohol consumption causes vitamin deficiencies (B12, B6, A) that may lead to separate carcinogenic mechanisms. See Breast cancer chapter for alcohol’s role in that disease.
Lancet Oncol. 2006 Feb;7(2):149-56.
Comprehensive Toxicology 2E, Chapter 14.10
- Ionizing radiation: X-rays, gamma rays, and particulate radiation are all carcinogenic. Ionizing radiation is electromagnetic or particulate radiation strong enough to cause ionization of atoms and damage DNA and other macromolecules inside cells. There are two types of radiation-induced DNA damage:
- Direct DNA damage: ionizing radiation penetrates cell membrane and cytoplasm, breaking bonds in DNA and protein. Single or double strand breaks, deamination, or apurination can all occur with radiation exposure. In addition, radiation can break off the amino acid side chains of proteins to cause reduced function or changes in the tertiary protein structure.
- Indirect DNA damage: ionizing radiation can induce formation of reactive oxygen species like hydroxyl (OH·) and peroxy (HO2·) radicals from water. These free radicals can react with DNA bases to cause mutations or break hydrogen bonds in macromolecules.
- Bystander effects: besides causing mutations or macromolecule destruction, ionizing radiation can also induce changes in signalling pathways, causing cytokine and growth factor release. These “bystander effects” may be responsible for causing cell proliferation in irradiated cells, allowing promotion to occur.
- Adaptive response: cells can adaptive to chronic radiation exposure if they are primed by a low-dose radiation exposure. DNA repair and cell cycle regulation pathways are upregulated to prepare for impending radiation damage. This effect lasts weeks to months.
- Basis of radiation therapy for cancer: ionizing radiation can be used to treat cancer. The principle of radiation therapy is to irradiate the tumour at specific time intervals. After each radiation exposure, DNA in both the cancer cells and surrounding normal cells are damaged by the above mechanisms. The difference is that cancer cells often have defective DNA repair pathways, which is usually beneficial for increasing the chances of developing a malignant phenotype, but it does so at the cost of insufficient genome protection. While normal cells can stop the cell cycle to repair damaged DNA, the tumour cells continue dividing despite lethal DNA damage, causing cell death. The fractional kill refers to the proportion of tumour cells killed by each dose of radiation.
Lancet. 1992 Jan 18;339(8786):156-9.
- Ultraviolet radiation: causes pyrimidine dimers in DNA, which gives rise to C → T transition mutations. (see Melanoma chapter for details)
- UV radiation can affect the function of proteins and lipids as well, leading to changes in cell signalling. Like ionizing radiation, UV radiation cause cell proliferation and carcinogenesis.
Robbins 8E, Chapter 7
- Human papillomavirus (HPV): a DNA virus that causes cervical, anogenital, and oral carcinomas. The oncogenic potential of HPV is related to expression of E6 and E7 viral genes. These gene products disrupt cell cycle regulation by interrupting checkpoint proteins (p53 and RB) and pro-apoptotic factors (Bcl-2 associated X-protein, Bax). They also activate telomerase to evade cell senescence. Furthermore, HPV integrates its DNA into the host genome, which is associated with genomic instability. The mutagenic potential along with reduced cell cycle regulation allows HPV to induce carcinogenesis in host cells.
- Epstein-Barr virus (EBV): a DNA virus that causes infectious mononucleosis, Burkitt lymphoma (a B cell lymphoma), nasopharyngeal carcinomas as well as other tumours in immunosuppressed patients. EBV infects B cells and integrates its DNA into the host genome. It expresses several genes that increase cell proliferation and survival (prevents apoptosis from occurring). In Burkitt lymphoma, EBV does not cause mutations in the host cell, but does provide proliferative potential once an oncogene has been activated by another carcinogen. Similarly, in nasopharyngeal carcinoma, EBV most likely act as a promoter, offering growth advantage to cells harbouring certain mutations prior to EBV infection.
Nat Rev Cancer. 2004 Oct;4(10):757-68.
- Helicobacter pylori: the first bacteria found to cause cancer. H. pylori infects the gastric mucosa, causing chronic inflammation and epithelial cell proliferation. Inflammation generates reactive oxygen species that can react with and mutate DNA. The gastric epithelial cells are eventually transformed, forming gastric adenocarcinoma. H. pylori itself is not mutagenic, but it creates an environment where chronic inflammation and cell turnover can occur, increasing the risk of cancer. It is solely a promoter.
Examples of carcinogens and their function as initiators or promoters.
Adapted from Environ Res. 2007 Nov;105(3):414-29.
|Alcohol||(only indirect role)||P (mostly as promoter)|
|Metals (e.g. nickel, chromium)||M|
|Nitrites, nitrates (N-nitroso compounds)||M|
|Polycyclic aromatic hydrocarbons||M (>5 rings)||P (|
|Epstein-Barr virus||M (genomic instability)||P (increase proliferation and survival of infected cells)|
|Hepatitis B and C viruses||M||P|
|Human papillomavirus||M (genomic instability)||P (increase proliferation and survival of infected cells)|