Key Points
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Invasive growth is a complex genetic programme in which cell proliferation combines with cell–cell dissociation and movement, matrix degradation and survival. It occurs under physiological conditions — during organ development and regeneration, axon guidance or wound healing — and in carcinoma progression, in which it is instrumental in tumour invasion and metastasis.
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Scatter factors (mainly hepatocyte growth factor, HGF) and their receptors (the MET tyrosine kinase receptor) are the main mediators of normal and neoplastic invasive growth. Data are emerging that two other families of molecules that are structurally related to MET — semaphorins (acting as ligands) and plexins (acting as receptors) — are involved in the control of invasive growth.
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MET activity is deregulated in many human cancers owing to genetic mutations, gene amplification, protein overexpression or production of HGF-dependent autocrine circuits. Some semaphorins are overexpressed in clinically aggressive and metastatic tumours.
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Scatter factors induce invasive growth by affecting the expression, topographical localization or activity of cadherins, integrins and matrix metalloproteinases. This results in disruption of intercellular junctions, dissolution of the epithelial basement membrane and integrin-dependent interaction with extracellular matrix components that are not commonly recognized by quiescent cells, which in turn supports cell survival and invasion through stromal surroundings.
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MET signals are channelled by an unconventional multi-docking site that consists of two tyrosines that, when phosphorylated, recruit a wide spectrum of transducers and adaptors (phosphatidylinositol 3-kinase (PI3K), SRC, GRB2, SHC, GAB1 and STAT3), as well as by the α6β4 integrin, which forms a complex with MET and whose cytoplasmic domain provides additional docking sites for PI3K and SHC. Enhanced activation of the SHC–GRB2–SOS–RAS pathway results in stimulation of cell proliferation and transformation, whereas selective recruitment of PI3K promotes cell migration and survival.
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Plexins do not display an intrinsic catalytic activity, but can be phosphorylated by means of associated tyrosine kinases. They crucially control the dynamics of actin microfilaments by impinging on the RHO and RAC small GTPases.
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The specificity of the biological response that is evoked by scatter factors is likely to result from the integration of quantitative and qualitative regulation of signalling outputs. To elicit invasive growth, activation of 'public' downstream effectors must be sustained over time, and this can be achieved by combinatorial association of MET with 'private' partners that tune MET signalling potential by functioning as scaffolds for controlled recruitment of specific subsets of transducers.
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Some variants of scatter factors can behave, both in vitro and in vivo, as partial agonists, thereby retaining some of the biological properties of the parental ligands, while being deprived of others, or as pure antagonists, completely inhibiting the function of the parental ligands. These activities might be exploited therapeutically to promote cell survival and organ regeneration without inducing cell invasion, or to hamper metastases during progression of cancers in which the HGF–MET system is deregulated.
Abstract
Malignant disease occurs when neoplastic cells abandon their primary site of accretion, cross tissue boundaries and penetrate the vasculature to colonize distant sites. This process —metastasis — is the aberrant counterpart of a physiological programme for organ regeneration and maintenance. Scatter factors and semaphorins, together with their receptors, help to orchestrate this programme. What are the differences between physiological and pathological activation of these signalling molecules, and can we exploit them therapeutically to prevent metastasis?
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Acknowledgements
We thank A. Bertotti for discussion, critical reading of the manuscript and help with the artwork, and E. Wright for editing the manuscript. Work in the authors' laboratory is supported by AIRC (Associazione Italiana per la Ricerca sul Cancro) and Armenise–Harvard Foundation for Advanced Scientific Research.
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Glossary
- MYOTOME
-
A block of cells that is derived from the somite that, during embryogenesis, gives rise to some sets of skeletal muscles.
- GROWTH CONE
-
Exploratory tip of an extending neuronal process such as an axon.
- INTEGRINS
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A family of more than 20 heterodimeric cell-surface extracellular matrix (ECM) receptors. They connect the structure of the ECM with the cytoskeleton and can transmit signalling information bidirectionally.
- ADHERENS JUNCTIONS
-
Cell–cell or cell–matrix adhesive junctions that are linked to microfilaments.
- CADHERINS
-
(For example, E-, N-, P- and R-cadherin.) A subfamily of cadherins that share a common primary structure and bind to catenins by conserved cytoplasmic domains.
- CATENINS
-
A family of submembraneous proteins (α-, β-, and γ-catenin, also known as plakoglobin) that are enriched at adherens junctions and connect the cytoplasmic domains of transmembrane cadherins to the actin microfilament cytoskeleton.
- MATRIX METALLOPROTEINASES
-
A family of proteolytic enzymes that degrade the extracellular matrix and have important roles in tissue remodelling and tumour metastasis.
- STATS
-
A family of cytoplasmic transcription factors (signal transducers and activators of transcription) that dimerize following phosphorylation, and translocate to the nucleus to activate transcription of target genes.
- E3 UBIQUITIN PROTEIN LIGASE
-
The third enzyme in a series — the first two are designated E1 and E2 — that are responsible for ubiquitylation of target proteins. E3 enzymes provide platforms for binding E2 enzymes and specific substrates, thereby coordinating ubiquitylation of the selected substrates.
- LAMELLIPODIUM
-
A thin sheet-like cell extension that is found at the leading edge of crawling cells or growth cones.
- FILOPODIUM
-
A finger-like exploratory cell extension that is found in crawling cells and growth cones.
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Trusolino, L., Comoglio, P. Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat Rev Cancer 2, 289–300 (2002). https://doi.org/10.1038/nrc779
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DOI: https://doi.org/10.1038/nrc779
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