The term metastasis encompasses specific biological traits that together enable the spread of aggressive tumour cells.
Different tumour types metastasize to distinct secondary organs, reflecting the influence of: the malignant cell of origin, aggressiveness of the primary tumour, the direction of circulation, and the capacity to co-opt supporting components of the microenvironment.
Underlying each of these factors are genetic determinants that are largely distinct from those that mediate malignant transformation.
Mediators of metastasis can be classified as metastasis initiation, metastasis progression and metastasis virulence genes, on the basis of the tumour stage, location in the body where they act, and their biological function.
By combining genome-wide technologies, functional experimentation in model systems and clinical validation, it is becoming possible to identify genetic alterations that are relevant to human metastatic disease.
These integrative approaches have uncovered genetic, epigenetic, somatic and inherited alterations, and serve as precedents for future metastasis gene discovery, prognosis and therapy.
Metastasis can be viewed as an evolutionary process, culminating in the prevalence of rare tumour cells that overcame stringent physiological barriers as they separated from their original environment and developmental fate. This phenomenon brings into focus long-standing questions about the stage at which cancer cells acquire metastatic abilities, the relationship of metastatic cells to their tumour of origin, the basis for metastatic tissue tropism, the nature of metastasis predisposition factors and, importantly, the identity of genes that mediate these processes. With knowledge cemented in decades of research into tumour-initiating events, current experimental and conceptual models are beginning to address the genetic basis for cancer colonization of distant organs.
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We apologize for omitting primary references and the work of those we could not cite owing to space limitations. We would like to thank A. Incassati, A. Chiang, P. Bos, D. Padua, G. Gupta and S.Tavazoie for insightful discussions. J.M. was funded by the National Institutes of Health, USA, grant P01-94060, and by a grant of the Keck Foundation, USA. D.X.N. is a Berlex postdoctoral fellow of the Damon Runyon Cancer Research Foundation, USA. J.M. is an Investigator of the Howard Hughes Medical Institute, USA.
The authors declare no competing financial interests.
- Primary tumour
Cancer that arises from the malignant conversion of cells from an initial organ site.
- Histological grade
Morphologically identifiable steps of tumour progression that are used to classify disease stage.
- Organ tropism
A predilection of a primary tumour to spread to specific secondary organs.
The pathological growth of new blood vessels to support tumour growth.
Entry of tumour cells into the bloodstream.
Exit of tumour cells out of capillary beds into the parenchyma of an organ.
The main functional portion of an organ.
Clumped tumour cells that typically lodge in blood vessels.
- Haematogenous dissemination
The spread of cancer cells through the bloodstream.
Skin cancer that is initiated by the transformation of melanocytes.
- Metastasis suppressor gene
A gene in which loss of function specifically enhances metastasis without affecting primary tumour growth.
- Mesenteric circulation
Blood flow from the intestines.
- Peritoneal cavity
The space within the abdomen that contains the intestines, the stomach and the liver.
- Palliative shunt
Diversion of malignant fluid to alleviate symptoms that arise from its accumulation in the body cavity.
A detectable accumulation of free fluid in the peritoneal cavity.
- Metastasis initiation genes
A gene that is engaged in the invasion and intravasation of metastatic cells.
- Metastasis progression gene
A gene that has dual functions in mediating primary tumorigenesis and metastatic colonization.
- Metastasis virulence gene
A gene that is exclusively involved in distant organ colonization.
- Focal contacts
Dynamic cell-adhesion structures.
A group of small signalling proteins (cytokines) that are usually secreted by immune cells.
- Neural crest cell
Highly motile cells that originate from the ectoderm during development.
Paediatric malignancy that arises from skeletal muscle cells.
- Stromal activation
Stimulation and mobilization of host cells in the microenvironment that surrounds a tumour.
The differentiation and activation of osteoclasts that mediates bone resorption.
Implantation of human tumour cells into an immunocompromized animal.
- Orthotopic site
Transplant of tumour cells into the anatomical location of an animal that best recapitulates the original source of primary tumorigenesis.
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Nguyen, D., Massagué, J. Genetic determinants of cancer metastasis. Nat Rev Genet 8, 341–352 (2007). https://doi.org/10.1038/nrg2101
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