Module notes from Imperial College London, Medical Biosciences BSc, 2nd year, Cancer Biology (CBIO) module
Cancer cells can break away from their site or organ of origin to invade surrounding tissue and spread (metastasise) to distant body parts.
At those new sites, cancer cells can form new tu...
Hallmark 6: tissue invasion & metastasis
- metastases = 90% of cancer deaths
Landmark discoveries
- 1st description in 1758 but relevance recognised in the 19th century
=> Paget’s ‘Seed and Soil’ theory: metastatic patterns do not follow blood flow distribution
=> ‘seeds’ (tumour cells) + ‘congenial soil’ (receptive metastatic microenvironment) interaction
=> non-random: preference of metastasis at distinct sites (lung, liver, bone)
- 1970: cancer cells travel through all organs BUT metastasis only develop in compatible organs
- stage by stage process
=> primary tumour growth (invasion of adjacent tissue)
=> angiogenesis = vascularisation => detachment
=> intravasation (blood vessel penetration)
=> transport through circulatory and/or lymphatic system - cell arrest at a secondary site
=> extravasation (escaping blood vessels)
=> growth in a secondary organ (micrometastasis - macrometastasis)
- metastasis in an organ is still the primary site cancer (ex: breast cancer in the lung)
Monoclonal & polyclonal metastasis
- genetic mutations => genomic instability => create cell subtypes: ‘clones’ => may be metastatic
- metastasis with further genetic alterations of clone = phenotypically heterogenic monoclonal
- metastasis containing many clones = polyclonal
- metastasis containing 1 clone = monoclonal
Clinical considerations
- metastatic tumour often indicates a terminal disease: survival is not improving (only breast cancer)
- cancer cells travelling in blood vessels = circulating tumour cells (CTCs)
=> blood also contains cell-free tumour DNA (ctDNA), RNA (ctRNA), proteins, vesicles (exosomes)
, - liquid biopsy = clinical test to detect circulating tumour cells or
tumour-derived material in the blood & other fluids (urine, saliva,
pleural effusions, cerebrospinal fluid CSF)
=> uses highly sensitive assays: CellSearch platform
(selection cells expressing EpCAM => distinguish CTCs
using cytokeratin monoclonal ab, DAPI stain, lack CD45 p)
=> non-invasive monitoring
=> BUT ctDNA is fragmented & very rare & CTCs are rare, w/ no universal surface marker
=> samples enriched for CTCs
=> negative enrichment: remove other blood cell
=> positive enrichment: select surface markers (ex: epithelial cell adhesion molecules EpCAM)
BUT do not distinguish malignant or not => characterise CTCs molecularly
Overview
- angiogenesis = formation of new blood vessel from existing vasculature
=> driven through pro-angiogenic molecules released by cancer cells (ex: VEGF)
=> around the tumour mass to provide nutrients & O2 to fast-growing cancer cells
=> role in intravasation & extravasation: leaky structures of the new vessel around the tumour
enter
blood
stream
- during intravasation + extravasation: degradation & remodelling of basement membrane (BM)
- BM produced by cells (epithelial, endothelial, stromal = mesenchymal)
=> separate epithelium/ endothelium from stroma & interstitial matrix
- ECM = BM + interstitial matrix
=> BM (w/ basal lamina underlying epithelium) more compact, less
porous, consists of collagen IV, laminin, fibronectin, nidogen, perlecan
=> I.M. consists of fibrillar collagen, proteoglycan (hyaluronan), fibronectin
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