world cancer report - iarc
world cancer report - iarc
world cancer report - iarc
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INVASION AND METASTASIS<br />
SUMMARY<br />
> The ability of tumour cells to invade and<br />
colonize distant sites is a major feature<br />
distinguishing benign growths from<br />
malignant <strong>cancer</strong>.<br />
> Most human tumours lead to death through<br />
widespread metastasis rather than the<br />
adverse local effects of the primary neoplasm.<br />
> Often, metastatic spread first involves<br />
regional lymph nodes, followed by<br />
haematogenous spread throughout the<br />
body. Metastases may become clinically<br />
manifest several years after surgical resection<br />
of the primary tumour.<br />
> Current methods are inadequate for the<br />
routine detection of micrometastases and<br />
the search for effective, selective<br />
therapies directed toward metastatic<br />
growth remains a major challenge.<br />
Metastasis (from the Greek meaning<br />
“change in location”) refers to growth of<br />
secondary tumours at sites distant from a<br />
primary neoplasm. Metastasis thus distinguishes<br />
benign from malignant lesions<br />
and is the ultimate step in the multistage<br />
process of tumour progression.<br />
Metastatic growth is the major cause of<br />
treatment failure and the death of <strong>cancer</strong><br />
patients. Although secondary tumours<br />
may arise by shedding of cells within body<br />
cavities, the term metastasis is generally<br />
reserved for the dissemination of tumour<br />
cells via the blood or lymphatics. Spread<br />
in the cerebrospinal fluid and<br />
transcoelomic passage may also occur.<br />
Most (60-70%) <strong>cancer</strong> patients have overt<br />
or occult metastases at diagnosis, and<br />
the prognosis of the majority of these<br />
patients is poor (Box: TNM Classification<br />
of Malignant Tumours, p124).<br />
There is a critical need to identify reliable<br />
indicators of metastatic potential, since<br />
clinical detection of metastatic spread is<br />
synonymous with poor prognosis. Current<br />
methods of detecting new tumours,<br />
including computed tomography (CT)<br />
scans or magnetic resonance imaging<br />
(MRI), ultrasound, or measurement of circulating<br />
markers such as carcinoembryonic<br />
antigen (CEA), prostate-specific antigen<br />
(PSA) or <strong>cancer</strong> antigen 125 (CA125)<br />
are not sufficiently sensitive to detect<br />
micrometastases. A greater understanding<br />
of the molecular mechanisms of<br />
metastasis is required. It is clear that<br />
metastatic growth may reflect both gain<br />
and loss of function, and indeed the<br />
search for “metastasis suppressor” genes<br />
has been more fruitful than identification<br />
of genes which specifically and reliably<br />
potentiate metastasis [1].<br />
The genetics of metastasis<br />
With the publication of the human<br />
genome sequence, and various major initiatives<br />
such as the Cancer Genome<br />
Project in the UK and the Cancer Genome<br />
Anatomy Project in the USA, the search<br />
for genes selectively upregulated, mutat-<br />
• Growth • Angiogenesis<br />
• Protease activation<br />
• Selection<br />
1.Localized tumour 2.Breakthrough 3.Invasion<br />
4.Transport<br />
5.Lodgement<br />
• Adhesion<br />
• Protease production<br />
6.Extravasation<br />
Angiogenic<br />
factors<br />
Cytokines<br />
Growth<br />
factors<br />
Inflammatory<br />
cells<br />
Fig. 3.40 The hypoxia hypothesis suggests that<br />
the progression of malignant tumours to a<br />
metastatic phenotype is mediated by deficiency of<br />
oxygen and resulting tumour necrosis.<br />
• Decreased cell-cell adhesion<br />
• Increased protease production<br />
• Increased cell-matrix adhesion<br />
7.Metastasis<br />
• Proliferation • Angiogenesis<br />
• Protease activation/production<br />
• Metastasis of metastases<br />
Malignant tumour<br />
Growth<br />
Metastasis<br />
Viable cells<br />
Zone of sublethal<br />
hypoxia<br />
Necrosis<br />
Rapid accumulation<br />
of genetic damage<br />
in sublethal zone<br />
mediated by oxygen<br />
free radicals<br />
(NO= nitric oxide)<br />
Reperfusion of sublethal<br />
zone containing<br />
cells with varying<br />
degrees of genetic<br />
damage. Some have<br />
acquired a metastatic<br />
phenotype<br />
Fig. 3.41 The stages in the metastatic process, illustrated in relation to the spread of a primary tumour<br />
from a surface epithelium to the liver.<br />
Invasion and metastasis 119