MET signalling: principles and functions in development, organ regeneration and cancer

Abstract

The MET tyrosine kinase receptor (also known as the HGF receptor) promotes tissue remodelling, which underlies developmental morphogenesis, wound repair, organ homeostasis and cancer metastasis, by integrating growth, survival and migration cues in response to environmental stimuli or cell-autonomous perturbations. The versatility of MET-mediated biological responses is sustained by qualitative and quantitative signal modulation. Qualitative mechanisms include the engagement of dedicated signal transducers and the subcellular compartmentalization of MET signalling pathways, whereas quantitative regulation involves MET partnering with adaptor amplifiers or being degraded through the shedding of its extracellular domain or through intracellular ubiquitylation. Controlled activation of MET signalling can be exploited in regenerative medicine, whereas MET inhibition might slow down tumour progression.Throughout embryogenesis, cells bud off from developing tissues and move outwards to shape and pattern the complex architecture of prospective organs 1 . A similar process occurs in adult life during wound healing and tissue repair, when lingering cells migrate into injury sites to recreate the pre-existing structures 2 . The acquisition of cell motility is necessary, but not sufficient, for this event. Cells that detach from their neighbours must elude anoikis, a form of apoptotic cell death that occurs when cells lose adhesion with the extracellular matrix 3 . Moreover, migratory cells undergo extensive mitotic divisions to produce 'founder populations', which settle in newly forming organs during development or colonize worn tissues during repair 4,5 . The normal phases of embryogenesis and organ regeneration strongly resemble the pathological process of tumour invasiveness: similarly to cells at the wound edge, cells at the tumour's leading front disrupt intercellular contacts and infiltrate the adjacent surroundings, where they resist anoikis and grow before lodging in the blood vessels for systemic dissemination 6 . This resemblance is not simply a biological correlate, it has a common mechanistic basis: cancer cells resurrect the latent schemes of cellular reorganization, which are usually confined to embryonic development and damaged adult organs, and leverage them to become competent for metastasization 7 . The activities -motility, survival and proliferation -that occur in developing, injured and neoplastic tissues embody a biological programme that is defined as 'invasive growth' 8 . This is triggered by extracellular stimuli that regulate the activity of several transcription factors that, in turn, modulate the expression of a number of proteins, ranging from cytoskeletal and cell-cell junctional components to cell cycle regulators and anti-apoptotic effectors 9, 10 . One major environmental inducer of invasive growth is hepatocyte growth factor (HGF, also known as scatter factor), the ligand for the MET tyrosine kinase receptor (also known as the HGF receptor) 11,12,13,14,15,16,17,18,19,20 (Box 1). ...

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of HGF/MET–Driven Resistance to Targeted Therapies: From Basic Research to a Clinical Perspective

“…Many studies have focused on the specifi c role played by each of these pathways in different MET-induced biologic activities (for a review, see ref. 5 ).…”

Tumor MET Expression and Gene Amplification in Chinese Patients with Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Cancer

“…Activation of the HGF/MET signaling pathway promotes the proliferation, migration, and survival of tumor cells (10). It has also been shown to be associated with cancer pathogenesis, invasion, and metastasis (11).…”

“…Cancer stage may be an important factor when studying the prognostic effect of MET, as MET is associated with tumor invasion (11). Moreover, prior studies primarily evaluated samples from resected tissue (13)(14)(15)(16)(17)(18)(19)(20).…”

Vascular-targeted agents for the treatment of angiosarcoma

“…Through the receptor tyrosine kinase MET, HGF promotes cell proliferation, migration and invasion, and protects cells from apoptosis [222]. Hypoxia increases MET transcription, and it has therefore been postulated that increased tumour hypoxia, as a consequence of anti-angiogenic therapy, promotes MET signalling and thus increases tumour invasion and metastasis [223].…”