gene of the month hgf

Gene of the month Gene of the month: HGF Ana Belen Fajardo-Puerta,1 Mireia Mato Prado,2 Adam E Frampton,1,2 Long R Jiao1 HPB Surgical Unit, Department of Surgery & Cancer, Imperial College, London, UK Division of Cancer, Department of Surgery & Cancer, Imperial College, London, UK Correspondence to Prof Long R Jiao, HPB Surgical Unit, Department of Surgery & Cancer, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London W12 0HS, UK; l.jiao@imperial.ac.uk Accepted 21 March 2016 Published Online First 12 April 2016 ABSTRACT Hepatocyte growth factor (HGF) is a multifunctional cytokine with important roles in cell proliferation, survival, motility and morphogenesis Secreted by cells of mesenchymal origin, HGF is the specific ligand for the tyrosine-kinase receptor c-MET (cellular mesenchymal-epithelial transition), also called MET, which is expressed in different types of epithelial, endothelial and haematopoietic progenitor cells The HGF/MET axis is involved in several biological processes, such as embryogenesis, organogenesis, adult tissue regeneration (including wound healing and liver regeneration) and carcinogenesis, for both solid and haematological malignancies.1 HGF and its particular interaction with the MET receptor have been extensively investigated in the last decades and remain the focus of numerous clinical trials.3–8 This short review focuses on HGF structure and function, as well as its roles in liver regeneration and different types of tumours HGF STRUCTURE To cite: Fajardo-Puerta AB, Mato Prado M, Frampton AE, et al J Clin Pathol 2016;69:575–579 HGF is mapped on the long arm of chromosome at q21.1 and it is formed by 18 exons, interrupted by 17 introns, spanning 71 433 bases of genomic DNA It encodes the inactive pre-pro-HGF, a single chain of 728 amino acids (83 134 Da), which includes a signal sequence (1–31), a heavy α chain (32–494; 69 kDa) and a light β chain (495–728; 34 kDa) The first exon contains the signal peptide and a 50 -untranslated region The following 10, 12 and remaining exons encode the α chain, with four kringle structures, the short spacer region between the α and β chains, and the β chain, respectively.9–11 The HGF primary structure was determined in 1989, but multiple transcript variants encoding different isoforms have been identified by alternative splicing of the gene since then.12 The inactive pre-pro-HGF becomes active after a two-cleavage process First, the signal peptide of the pre-pro-HGF is degraded, generating the pro-HGF, which is also cleaved between Arg494 and Val495 Several serum or cell-membrane proteases have been described to be involved, such as HGF activator (HGF-A), urokinase-type plasminogen activator, plasma kallikrein, coagulation factors XII and XI, matriptase and hepsin.13 Among them, HGF-A is the main protease responsible for the activation of pro-HGF in serum The activation process of HGF plays an important role in the regulation of tissue regeneration and susceptibility to pathological conditions Although HGF-A knockout mice showed normal development, they have impaired restitution of epithelia after mucosal injury.14 Similarly, fibroblasts from patients with idiopathic pulmonary fibrosis have been shown to have lower capacity to activate HGF compared with control fibroblasts.15 The final active heterodimeric molecule is produced by a disulfide bond between the α and β chains Although this multifunctional protein belongs to the plasminogen subfamily of S1 peptidases, no proteolytic activity has been detected, probably due to the substitution of two out of three amino acids required in the catalytic triad.16 It has been suggested that HGF could be evolutionally derived from those encoding proteases implicated in the coagulation cascade and fibrinolysis Indeed, its organisation is very similar, and so are its products The HGF α chain has 38% homology with plasmin, and the β chain is structurally similar to the catalytic domains of serine proteases, but with amino acid substitutions in the active site.1 In contrast to other growth factors and their receptors, HGF binds exclusively to the product of the c-MET proto-oncogene, also mapped on chromosome 7.17–19 The MET receptor is a 190 kDa protein, comprising a ligand-binding extracellular domain, a transmembrane region and a cytoplasmic domain with tyrosine kinase activity Although the HGF α chain has a higher affinity for MET, it is the β chain which activates the receptor.20 21 Upon MET dimerisation, kinase activation results in autophosphorylation of tyrosines Y1349 and Y1356, and recruitment of several substrates, including growth factor receptor-bound protein 2, Shc, p85 subunit of phosphatidylinositol 30 kinase, phospholipase C γ, signal transducer and activator of transcription and Grb2-associated binding protein The downstream signalling pathways generate diverse cellular responses, such as proliferation, survival, motility, invasion and stimulation of angiogenesis (figure 1).22–34 Several growth factors, cytokines and prostaglandins upregulate HGF gene expression: basic fibroblast growth factor, oncostatin M, hypoxiainducible factor α and nuclear factor κ-B Its main inhibitor is tumour growth factor β.35 HGF FUNCTION AND ITS RECEPTOR In 1984, HGF was purified for the first time in rat platelets, and years later in humans It was described as a potent mitogenic factor for mature rat hepatocytes in vitro.36–39 The HGF/MET pathway has diverse biological and physiological roles in organogenesis, morphogenesis, tissue regeneration and carcinogenesis that have been discovered using conditional knockout of MET in mice.8 In 1991, a fibroblast-derived factor for epithelial cells, the scatter factor, involved in increasing cell migration during embryogenesis and tumour progression, together with the human lung fibroblast-derived mitogen, were found to be identical proteins Both are encoded by the same chromosome bands as HGF and are ligands for the MET receptor.40–44 Soon after, a tumour cytotoxic Fajardo-Puerta AB, et al J Clin Pathol 2016;69:575–579 doi:10.1136/jclinpath-2015-203575 575 Gene of the month Figure The hepatocyte growth factor/mesenchymal-epithelial transition (HGF/MET) axis Once HGF is activated by a two-cleavage process in the extracellular matrix, it binds to the MET receptor on epithelial cells, promoting its dimerisation and autophosphorylation of tyrosine residues The recruitment of adaptor proteins generates different downstream signalling pathways which evoke diverse cellular responses as shown C-Cbl, casitas b-lineage lymphoma; Erk1-2, extracellular signal-regulated kinases; Gab1, Grb2-associated binding protein 1; Grb2, growth factor receptor bound protein 2; Gsk3β, glycogen synthetase kinase 3β; IKK, inhibitor of nuclear factor κ-B kinase; MEK, mitogen-activated protein kinase/ERK kinase; mTor, mammalian target of rapamycin; NF-kβ, nuclear factor κ-B; PI3K, phosphatidylinositol 30 kinase; Plcγ, phospholipase C-γ; Stat3, signal transducer and activator of transcription (Adapted from Boissinot et al35) factor derived from fibroblasts, which induces cell death in several cancer types, was also found to be an identical molecule to HGF.45 These results had important consequences for further studies on the involvement of HGF as a modulator of cellular growth and motility during embryogenesis, tissue regeneration and carcinogenesis Interestingly, targeted disruption of HGF or MET results in embryonically lethal knockouts with impaired development of the liver and placenta.46 47 Overexpression, mutations and amplification of the receptor, and/or changes in its kinase activity have been implicated in different types of cancer.48 It has been suggested that because of the proximity between HGF and MET on chromosome 7, a polysomy of this chromosome could lead to malignancy secondary to overproduction of both molecules.49 The one-to-one ligand-receptor relationship makes the HGF/MET axis an attractive target for drug development, either by activation or inhibition of this pathway Three pharmacological approaches are currently being developed as inhibitors of MET signalling with promising results: anti-HGF antibodies, anti-MET antibodies and MET kinase inhibitors.50 HGF AND LIVER REGENERATION The liver has the ability to regenerate to almost its optimal volume after liver resection.51 HGF is one of two complete mitogens which induce hepatocyte DNA synthesis and mitosis along with epidermal growth factor receptor (EGFR) Activation of the HGF/MET axis generates a cascade of intracellular signalling for the G1-S progression of hepatocytes Available evidence has shown that immediately after different liver injuries, such as partial hepatectomy, ischaemia or hepatitis, there is an intense 576 remodelling of the extracellular matrix, with increased activity of proteinases and intense intracellular signalling.52 The levels of active HGF rise rapidly in the liver secondary to its production by Kupffer, stellate and sinusoidal endothelial cells, and subsequently activation by urokinases.53–55 Since HGF also increases in plasma, an endocrine mechanism has been suggested In addition, HGF transcript levels and HGF activity have been found to be markedly higher in other intact organs like the lung, kidney or spleen after injuries of the liver.56 Overall, this results in balanced liver growth and regeneration HGF AND HEPATOCELLULAR CARCINOMA Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality worldwide with a multifactorial aetiology and extensive molecular and phenotypical heterogeneity.57 Several signalling pathways have been described in which the HGF/MET axis may play a crucial role.58–60 Patients with HCC have significantly higher serum levels of HGF compared with healthy controls52 61 and overexpression of HGF and c-MET has been detected in 33% and 20%–48% of HCC tissues, respectively.62–66 Upregulation of MET has also been associated with tumour migration, vascular invasion, neoangiogenesis and, therefore, poor patient outcomes.67 In contrast, other studies have shown contradictory results with regard to their impact on survival in patients with HCC.68–73 Nonetheless, clinical trials using pharmacological inhibitors of this axis for both HCC and other solid malignancies are currently being performed These targeted therapies could be a promising second line option to treat patients with advanced HCC.60 74 75 A recent study has demonstrated that the Fajardo-Puerta AB, et al J Clin Pathol 2016;69:575–579 doi:10.1136/jclinpath-2015-203575 Gene of the month mixed-lineage leukaemia protein (MLL), in association with HGF/MET, promotes cell invasion and metastasis in HCC Theoretically, the inhibition of this interaction could potentially reduce the incidence of distant metastasis, although it may not affect the tumour load or its proliferative capacity.76 HGF IN OESOPHAGOGASTRIC CANCER Oesophagogastric cancer (OGC) is the fifth most common malignancy worldwide and the fourth and fifth most common type of cancer death in men and women in UK, respectively A clear geographical difference has been observed in overall survival with 70% surviving years in Japan, compared with 25% in Europe, suggesting that the implementation of screening tools might allow earlier detection and treatment of this cancer OGC has a diverse molecular landscape and exhibits alterations in various different oncogenes and kinase pathways Activation of the HGF/MET axis promoting tumourigenesis and metastasis in gastric cancer is mainly secondary to MET overexpression and/ or amplification, which was observed in 75%–90% of cases and in 1.5%–20% of the patients, respectively.77–79 However, mutations of HGF or MET are extremely rare in OGC.80 81 Different drugs targeting the axis include tyrosine kinase inhibitors (crizotinib, a dual c-MET and ALK (anaplastic lymphoma kinase) inhibitor), and monoclonal antibodies that neutralise HGF (rilotumumab) or MET (onartuzumab) are currently being trialled.82–86 HGF IN COLORECTAL CANCER Colorectal cancer (CRC) is the third most common cancer in men and the second in women worldwide,87 and around 30% of the patients will develop metastasis even after curative surgery It has been suggested that the HGF/MET axis is involved in the metastatic progression and potential invasiveness of the cancer cells by regulating the expression of cadherins and extracellular membrane proteases.88 Besides, MET amplification seems to be a late event in CRC progression MET amplification is more common in advanced tumour stages89 and its expression has been found to be higher in metastatic tissue than in primary tumour.90 Although survival of patients with unresectable metastatic CRC (mCRC) has improved in the last years with the introduction of agents targeting EGFR, such as cetuximab, its response rate range varies from 10% to 20%.91 92 HGF-induced MET activation has been described as a novel mechanism for cetuximab resistance Dual activation of both EGFR and MET receptors in CRC cells synergistically increases cell proliferation.93 Cetuximab could inhibit this cell growth by 60%–80% However, addition of HGF to cetuximab-treated cells phosphorylated MET, but not EGFR, restoring cell proliferation Inhibition of the HGF/MET axis may therefore improve response to EGFR inhibitors in CRC, and combination therapy should be further investigated.93 A recent study revealed that high levels of serum HGF and epiregulin (EREG) before treatment with anti-EGFR antibodies were associated with poor survival in KRAS (Kirsten rat sarcoma viral oncogene homolog) wild type patients with mCRC, suggesting that serum HGF and EREG may be associated with resistance to anti-EGFR treatment HGF might be a potential biomarker for predicting response and prognosis in dual target therapy with anti-EGFR antibodies and HGF/MET inhibitors.94 Handling editor Runjan Chetty Contributors Study concept and design: ABF-P and AEF; literature review, analysis and interpretation of literature, drafting of the manuscript: MMP and ABF-P; revision of manuscript, supervision of work: AEF and LRJ Competing interests None declared Provenance and peer review Commissioned; internally peer reviewed REFERENCES 10 11 12 13 Take home messages 14 ▸ HGF is a multifunctional cytokine produced by cells of mesenchymal origin and is involved in cell proliferation, survival, motility and morphogenesis ▸ Mesenchymal-epithelial transition (MET) is a tyrosine kinase receptor physiologically expressed on cells of epithelial origin and HGF is its unique binding factor ▸ The HGF/MET axis plays important roles in embryogenesis, organogenesis, adult tissue regeneration and carcinogenesis ▸ Both HGF and MET genes are overexpressed, mutated, and/ or amplified in several types of cancers, including haematological malignancies ▸ The HGF/MET axis has become the candidate target of numerous therapeutic clinical 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Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012 Secondary Globocan 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012 2012 http://globocan.iarc fr/Pages/fact_sheets_cancer.aspx Gao D, Vahdat LT, Wong S, et al Microenvironmental regulation of epithelial-mesenchymal transitions in cancer Cancer Res 2012;72:4883–9 Zeng ZS, Weiser MR, Kuntz E, et al c-Met gene amplification is associated with advanced stage colorectal cancer and liver metastases Cancer Lett 2008;265:258–69 Di Renzo MF, Olivero M, Giacomini A, et al Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer Clin Cancer Res 1995;1:147–54 Jonker DJ, O’Callaghan CJ, Karapetis CS, et al Cetuximab for the treatment of colorectal cancer N Engl J Med 2007;357:2040–8 Arnold D, Seufferlein T Targeted treatments in colorectal cancer: state of the art and future perspectives Gut 2010;59:838–58 Liska D, Chen CT, Bachleitner-Hofmann T, et al HGF rescues colorectal cancer cells from EGFR inhibition via MET activation Clin Cancer Res 2011;17:472–82 Takahashi N, Yamada Y, Furuta K, et al Serum levels of hepatocyte growth factor and epiregulin are associated with the prognosis on anti-EGFR antibody treatment in KRAS wild-type metastatic colorectal cancer Br J Cancer 2014;110:2716–27 579 ... further studies on the involvement of HGF as a modulator of cellular growth and motility during embryogenesis, tissue regeneration and carcinogenesis Interestingly, targeted disruption of HGF. .. cells of epithelial origin and HGF is its unique binding factor ▸ The HGF/ MET axis plays important roles in embryogenesis, organogenesis, adult tissue regeneration and carcinogenesis ▸ Both HGF. .. (HGF) stimulates the tyrosine kinase activity of the receptor encoded by the proto-oncogene c-MET Oncogene 1991;6:501–4 Dean M, Park M, Le Beau MM, et al The human met oncogene is related to the