Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene

Pennacchietti, Selma; Michieli, Paolo; Galluzzo, Maria; Mazzone, Massimiliano; Giordano, Silvia; Comoglio, Paolo M.

doi:10.1016/s1535-6108(03)00085-0

Cited by 1,222 publications

(1,015 citation statements)

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“…In most tumours, MET is transcriptionally induced by hypoxia and inflammatory cytokines or pro-angiogenic factors that are abundant in the reactive stroma of full-blown tumours 34,136 . Hence, MET activation is a late event that aggravates the intrinsic malignant properties of already transformed cells by conveying proliferative, anti-apoptotic and promigratory signals (a biological situation that our group calls 'oncogene expedience') 23 .…”

Section: Met Signalling In Development and Diseasementioning

confidence: 99%

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

Trusolino

Bertotti

Comoglio

2010

Nat Rev Mol Cell Biol

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1,083

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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). ...

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Section: Met Signalling In Development and Diseasementioning

confidence: 99%

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

Trusolino

Bertotti

Comoglio

2010

Nat Rev Mol Cell Biol

Self Cite

1,083

1,076

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“…This induction in HCC cells may be attributed to different molecular mechanisms, such as genomic alterations (7q gains in 16.8%; Moinzadeh et al, 2005), tumor hypoxia (Pennacchietti et al, 2003) and growth factor-dependent transcriptional activation of MET (e.g. by HGF; Seol et al, 2000).…”

Section: Transforming Growth Factor B Signaling Axismentioning

confidence: 99%

Dysregulation of growth factor signaling in human hepatocellular carcinoma

2006

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“…The cmet gene is regulated by a high GC-content TATA-less promoter (Seol and Zarnegar, 1998); several transcription factors including Sp1, Smad, p53, Ets1, Pax3, AP1 were shown as positive regulators of this promoter (Epstein et al, 1996;Gambarotta et al, 1996;Seol et al, 1999;Zhang et al, 2005); HIF-1 activates c-met upon hypoxia (Pennacchietti et al, 2003), while oxidative stress and IFNa are negative regulators presumably via inhibition of Sp1 binding (Radaeva et al, 2002;Zhang and Liu, 2003). The complexity of c-met regulation, together with apparent correlation between c-Met protein level and carcinogenesis, points to the necessity of an additional study of c-met expression control.…”

Section: Introductionmentioning

confidence: 99%