Biology of Tumour Growth
Natural History of Tumour Growth
A single tumour stem cell must undergo in excess of thirty divisions before a clinically detectable mass ( > 1 gm) is formed. A further ten divisions would lead to a mass of over 1 kg, incompatible with life. This statement is only true if all the cells produced in a division survive and continue to replicate themselves. Also, the growth of tumours may also be dependent on endocrine influences. Leiomyomas of the uterus may change size dependent on the menstrual cycle, and during pregnancy may become much larger before shrinking in menopause
In general, the less differentiated a tumour is, the less restrictions it has on cell division and the rate of growth is usually faster. As malignant tumours tend to be less differentiated, they also trend towards more rapid growth. This generalisation is not always true as some benign tumours (eg. keratoacanthoma) may grow more rapidly than malignant equivalents (eg. squamous cell carcinoma of skin).
The natural history of malignant tumours includes invasion and metastasis, which are not seen in benign tumours.
Biological Features of Tumour Growth
Benign tumours typically grow more slowly, do not infiltrate into surrounding tissues and do not metastasise to distant sites. In some locations they may still cause deleterious effects due to compression of critical structures (eg. skull base meningioma). Benign tumours are typically well differentiated, and may produce hormones or other products similar to their parent tissue.
Malignant tumours will often grow rapidly and infiltrate surrounding structures. They may also grow with a ‘pushing border’ similar to benign tumours. They can cause symptoms through direct invasion, metastatic spread or through paraneoplastic syndromes such as hypercalcaemia or cachexia.
The rate at which a tumour grows may be measured as a volume doubling time, the time taken for the tumour to double in size. This is dependent on the number of cycling cells (growth fraction, GF) and the speed of the cell cycle. By multiplying these two figures, it is possible to obtain the potential doubling time Tpot. The actual doubling time is significantly longer than the potential time due to loss of cells to senescence, necrosis or apoptosis.
Features of Neoplasms
Neoplasia is ‘new growth’. A neoplasm is “an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after cessation of the stimuli which evoked the change”. Neoplasia may be benign (non-invasive) or malignant (invades other tissues and spreads throughout the body).
Differentiation is the degree to which neoplastic cells resemble their cell of origin, both functionally and morphologically. Less differentiated tumours tend to behave more aggressively and have a poorer prognosis.
Anaplasia describes cells that show no differentiation. Anaplastic features include pleomorphism, abnormal nuclear morphology, increased mitoses, and loss of cellular polarity. Malignant tumours show varying degrees of anaplasia; a synonym for undifferentiated is anaplastic.
Aneuploidy is the presence of too few or too many chromosomes within the nucleus of a cell, relative to the usual number for that cell. It is commonly seen in malignancy due to genomic instability.
Cancer Stem Cells and Lineages
Cancer Stem Cells
Cancer stem cells, or tumour clonagens, are a concept of either:
- The initial cell which gives initially gives rise to a neoplasm
- The population of cells within a tumour which drives the production of new cancer cells, each of which is able to completely regenerate the primary tumour in the event of sterility of all other stem cells.
Cancer Cell Lineage
In classic tumourigenesis, all cancer cells arise from a single progenitor (the first cancer stem cell). Therefore, a single stem cell gives rise to progeny that, if charted, form a cancer cell lineage.
The descendants of a single cancer stem cell are said to monoclonal, descended from the same ‘clone’. For instance, a myeloma will often produce a specific immunoglobulin, giving a 'monoclonal band' on protein electrophoresis.
Tumour heterogeneity refers to that despite the proposed origin from a single cancer stem cell, neoplasms contain a variety of different cell types. These may include cancer stem cells, terminally differentiated cancer cells, and supporting cells such as endothelium and fibrocytes. Tumour cells themselves may have different genomes and epigenetic changes, brought about by different environmental stimuli (eg. hypoxia in the tumour core) and genomic instability.
Pathways of Spread
Malignant cells can spread in numerous ways:
- Local invasion into adjacent tissues
- Spread in the lymphatic system to distant sites (usually regional lymph nodes)
- Spread in the vascular system to distant sites (usually vascular organs such as the brain, liver, lungs and bone marrow)
- Spread along nerves (perineural spread)
- Spread throughout body cavities (transcoelomic spread)
- Seeding due to medical procedures (eg biopsy)
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