world cancer report - iarc

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