Definitions: neoplasia, dysplasia, (proto)oncogenes, TSGs Monoclonal nature of neoplasms Features of benign vs malignant: growth, histology, cytology

Development of neoplasia Carcinogenesis Invasion and metastasis Local and systemic effects Paraneoplastic effects

---

Neoplasia

'Irreversible changes in genetic material of cells leading to abnormal cellular growth patterns.'



Dysplasia

Dysplastic changes precede, and may develop into neoplastic changes. Dysplastic cells show increased rates of cell division, and incomplete maturation. There may be histological abnormalities consistent with neoplasia:

• increased nuclear:cytoplasm ratio
• altered cellular architecture
• increased mitoses

Dysplasia often arises in epithelial tissues exposed to chronic irritation, so there is often an associated inflammatory response. Removal of the chronic irritation often restores tissue to normal. Dysplastic tissue may be removed surgically to reduce risk of malignancy.

Areas where dysplastic changes may develop into neoplastic changes are:

• Epidermis of sun-exposed skin
• Gastric mucosa after long-term gastritis
• Squamocolumnar junction of the uterine cervix.

Distinguish between in situ neoplasia, and invasive neoplasia

Carcinoma in situ is an early stage of neoplasia, preceding spread to other tissue. Although the cells are cytologically malignant, i.e. have nuclear and cellular pleomorphism, they are confined to one area, e.g. within a duct or lobe of a tissue. It is important to identify and treat these tumors before they spread, as at this early stage treatment may be curative.


The path from dysplasia to neoplasia summarised

Normal <--> dysplasia --> in situ neoplasia --> invasive neoplasia



Oncogenes and proto-oncogenes

• A proto-oncogene is a gene coding for one of the proteins involved in control of cell growth - the products of these genes are normally functional proteins.
• An oncogene is a proto-oncogene that has become damaged / changed and produces an abnormal product that pre-disposes to neoplasia. Genetic alterations passed on to successive cell generations in neoplasm and further changes may occur in other genes. Oncogenes may be cellular in origin or may come from a viral source. These act in a dominant fashion - only one damaged gene is needed.

There are two main processes may lead to a proto-oncogene becoming an oncogene:

• Mutation in gene leading to a mutant protein product (abnormal product)
• Gene amplification leading to excess protein product (the gene is normal but there is too much of the product)
• e.g. mutation in a promotor, viral promotor insertion, gene translocation to proximity of a more active promotor (sometimes occurs with chromosmal translocations

Usually, multiple oncogene abnormalities are seen in a single tumour.



Tumour Suppressor Genes

A tumour suppressor gene is a gene that produces a product that prevents neoplasia. It may do this by reapiring damaged DNA, halting the cell cycle or killing the cell with the damaged DNA. These act in a recessive fashion - both copies of the gene in question must be dysfunctional. Important TSGs include:

• retinoblastoma (Rb): Rb is a binding protein that sequesters another protein called E2F-1. Without free E2F-1 the cell cannot move from G1 phase to S phase (DNA synthesis). In this way Rb holds the cell at what is known as the G1 checkpoint – the cell is not allowed to proceed into DNA synthesis until all is known to be well within the cell. If RB is damaged then E2F-1 is available and the checkpoint does not work – the cell can proceed into DNA replication before all is ready and this may result in damage to DNA (mutation).
• p53: This gene is encoded in the presence of DNA damage – the p53 protein is a CDK inhibitor – it prevents phosphorylation of cyclins (needed for progression of the cell through its cycle) and results in arrested progress through the cycle and cessation of replication. If p53 gene is damaged then this important regulatory system is lost and replication can occur when DNA is damaged – resulting in daughter cells that have the same damage.
  

---

The clonality of neoplasms

• Tumours develop from a single cell – they are monoclonal
• Normal tissue is polyclonal

Contrast benign and malignant neoplasms

	Benign	Malignant
Growth Characteristics	Expands only Local growth	Expands and may invade local tissues May metastasise
Histology	Organised tissue Cells uniform throughout Few mitoses	Disorganised tissue appearance Cellular / nuclear pleomorphism* High mitotic count - many abnormal
Cytology	Normal / slightly increased nucleus : cytoplasm Diploid Resembles cell of origin May retain original functions	High nucleus : cytoplasm ratio Range of ploidy Failure of differentialisation Loss of original function(s)

* multiple differeing appearances of cells and/or nuclei

Some tissues fall into neither of these categories – they are described as dysplastic or In-situ carcinoma.

---

Describe the alterations to DNA which cause neoplasia

The altered cells (neoplastic cells) do not respond normally to cell signalling controlling growth, and proliferate uncontrollably into a neoplasm (a mass of neoplastic tissue, 'tumour').

Basically: due to the following genetic changes:

• Abnormal expression of the genes (oncogenes) that produce products that normally control growth
• Loss of activity of genes that normally protect against neoplasia (tumour suppressor genes)
• Over-expression of genes which normally prevent cell death, so lengthening life-span of cells.
• Loss of activity of gene products which normally repair damaged DNA.

Describe alterations in growth control

• Cellular proliferation and growth occur in the absence of continuing external stimulus, compare this with hyperplasia in which abnormal growth occurs but ceases when stimulus stops. Progression through the cell cycle occurs more rapidly in neoplastic cells – possibly resulting in the accumulation of yet more errors during DNA replication.
• There is decreased cell death in neoplastic cells
• The lifespan of neoplastic cells is vastly prolonged – cells that may have a short lifespan in normal form may become effectively immortal when they become neoplastic – one theory to account for this is a difference in the enzyme telomerase. This enzyme is responsible for the repair of the chromosomal telomeres that are normally shortened with each round of cell division.
• Neoplasic cells may show altered receptors for growth factors, or normal receptors may be under- or over-produced. Neoplastic cells may produce their own growth factors that act in a paracrine (on nearby cells) or autocrine (on themselves) manner.
• Neoplastic cells show altered interactions with neighbouring cells and basement membrane – the anchoring proteins to these structures may become altered allowing cells to escape the tissue they are in.

---

Radiation

• UV radiation damages epidermal cells and is a factor in the development of several malignant skin tumour including malignant melanoma and basal cell carcinoma. Melanin has a protective effect so Caucasians may be especially at risk.
• Ionising radiation: This causes direct damage to DNA by removing electrons from the atoms of tissues it passes through and generating free radicals. These interact with DNA and cause strand breaks, base alterations or abnormal cross-linking.If this does not lead to cell death immediately or at next division then alteration in the genome may result, predisposing to neoplasia.
• Radon gas released from hard rock such as granite. May reach high concentrations in some buildings
• Industrial or military sources
• Radiation therapy (high dose, localised). Ionising radiation has most effect on rapidly dividing tissues – this is the basis of radiotherapy – the tumour cells will be more rapidly dividing than the tissues around them.

Chemicals
Only genotoxic chemicals are considered here – these work by forming covalent adducts to DNA. These chemicals all have electrophilic regions (or regions that are converted to electrophilic in metabolism) that react with DNA (which is negatively charged). In non-proliferating DNA the strands  form a double helix that is protected from these chemicals but in DNA synthesis, bases are vulnerable to adduct formation which distorts the structure of DNA and disrupts replication. If this is not repaired than an inappropriate base (a mutation) is incorporated into the new strand.

• Polycyclic aromatic hydrocarbons: generated from tobacco, whisky, grilled meat and incomplete combustion of coal and petrol.
• Aromatic amines: were used in the dye and rubber industries and in colouration of magarine (now all discontinued!). Causative of bladder cancer and possibly liver ca.
• Nitrosamines: Their most significant presence is in tobacco but also in grilled meats and fish.

Viruses:

• Epstein-Barr virus (EBV): Burkitts lymphoma, Nasopharyngeal carcinoma, Other B cell lymphomas and some cases of Hodgekin’s disease
• Human papillomavirus (HPV): Cervical carcinoma (HPV types 16, 18 and – rarely - some others), some carcinomas of the skin.
• Hepatitis B virus (HBV): Hepatocellular carcinoma (in about 1% of cases, after many years). HBV infects a major part of the third world population.

Others:

• Hormones
• Aflatoxins
• Parasites

---

The difference between invasion and metastasis Invasion is the spread into adjacent tissues – may occur along natural tissue planes such as along nerves Metastasis is the spread of cells to distant parts of the body – there are several mechanisms for this (see fig 1) Vascular – cells travel through the arterial or venous system. GI tumours often spread to liver via portal vein while systemic spread often leads to secondaries in lung, bone marrow, brain and adrenal glands Lymphatic spread usually results in secondaries in lymph nodes. Coelemic – cells can travel through either the pleural or peritoneal space to organs or tissues adjacent to this space.

Describe the mechanisms facilitating invasion and metastasis

For metastasis to occur several changes need to take place within cells – these will occur in only a very small proportion of cells within a tumour by way of random mutational events.

• The cell must acquire the ability to bind to basement membrane – esp surface integrins binding to laminin and fibronectin.
• The cell must become motile – usually by autocrine secretion of motility factors
• The cell must be able to attach to the extracellular matrix
• The cell must be able to degrade the extracellular matrix – this is done by way of metaloproteinases which degrade collagen IV. However, stromal cells secrete proteinase inhibitors so the malignant cell must be able to overcome this defence (an inhibitor inhibitor!).

Once the cell has escaped its site of origin it will travel to a distant site (see fig 1) and must be able to grow at that site. Some cancers can only survive at a narrow range of sites while others (e.g. malignant melanoma) can spread to a very wide range of tissues.



Describe the local effects of benign and malignant neoplasms

• Pressure
• Invasion
• Ulceration
• Obstruction

Describe the systemic effects of neoplasms
The most frequent systemic symptoms of neoplams are

• Weight loss (cachexia)
• Loss of appetite (anorexia)
• Fever
• Anaemia
• General Malaise

In many cases cause is unknown but probably due to TNF and IL-1 from inflammatory cells within the tumour.

Tumours of endocrine cells may secrete excess hormone – upsetting the normal hormonal balances. Some tumours not of endocrine origin may spontaneously gain this function.

Paraneoplastic effects are syndromes that are not directly the effect of the tumour concerned – it is thought that they may arose due to autoantibodies to the tumour cells that cross-react with normal tissues causing damage:

• Weakness of muscle (myopathy)
• Malfunction of peripheral nerves (neuropathy)
• Cerebellar ataxia

Updated March 2010