Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Hepatocyte Growth Factor Receptor

  • Simona Gallo
  • Paolo Maria Comoglio
  • Tiziana Crepaldi
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101684

Synonyms

 AUTS9;  c-MET;  DFNB97;  HGFR;  MET;  RCCP2

Historical Background

In the mid-1970s, Harold Varmus and Michael Bishop began the hunting for cancer genes in the cell genome. They provided evidence that the viral v-Src gene from avian sarcoma virus was taken up by the virus from host cells and incorporated in its genome. The v-Src was transforming since it encoded for a mutated tyrosine kinase protein. Like v-Src, oncogenes are mutant-activated versions of normal cellular genes, called “proto-oncogenes.” Harold Varmus and Michael Bishop’s theory of carcinogenesis explained how chemicals, X-rays, or other DNA injuries activated such endogenous proto-oncogenes, thus initiating cancer. The MET proto-oncogene was originally identified in 1984 in George Vande Woude’s lab, after a shiny decade of discoveries of cancer-causing genes. The treatment of a human osteogenic sarcoma cell line with a chemical carcinogen induced a chromosomal translocation of the TPR (translocated promoter region) sequences from chromosome 1 into the MET proto-oncogene on chromosome 7, generating the active Tpr-MET oncogene (Cooper et al. 1984). MET belongs to the tyrosine kinase growth factor receptor family and was an orphan receptor for a long time. The search for the MET ligand was run and successfully attained by Donald Bottaro’s and Paolo Comoglio’s labs in 1991. Both groups simultaneously discovered that the hepatocyte growth factor (HGF) is the ligand for the MET receptor (Bottaro et al. 1991; Naldini et al. 1991a). This growth factor is produced by mesenchymal cells and was originally identified as a powerful mitogen for hepatocytes (Nakamura et al. 1989), though it was later found as a growth factor for various cellular types. In normal hepatocytes, the MET receptor responds to HGF inciting cell proliferation and survival. Scatter factor (SF), initially identified as a fibroblast-derived cell motility factor, has the same coding sequences of HGF. Indeed, these two factors are identical high-affinity ligands for the MET receptor (Naldini et al. 1991b). Thus, ligand activation of MET incites – in epithelial cells – a phenomenon known as “cell scattering,” which involves cytoskeleton reorganization, loss of intercellular junctions, and cell–cell dissociation, followed by active migration. Next, a new and unique function of HGF/SF was enlightened in MDCK (Madin–Darby canine kidney) epithelial cells grown in a thick “three-dimensional” collagen gel. In this gel, these cells normally form a cyst consisting of a polarized epithelial monolayer surrounding a fluid-filled cavity. When HGF (or SF) is added, a group of cells in the cyst undergoes an “epithelial to mesenchymal” transition which involves the transformation of tightly polarized cells into invasive, spindle-shaped cells that migrate away from the central cavity in the surrounding matrix, forming solid cords of cells that become ramified epithelial tubules (Montesano et al. 1991). The tyrosine kinase receptor RON, which is MET homologous receptor for MSP, a ligand structurally related to HGF (Gaudino et al. 1994), elicits the same invasive growth program of MET. The extracellular regions of both MET and RON display structural similarities with semaphorins and plexins, together forming a wide family of ligand–receptor pairs originally identified as signals of cell–cell attraction or repulsion in the guidance of axon paths, which are typical aspects of the MET invasive growth program (Tamagnone et al. 1999). In the 1990s, the MET downstream signal transduction machinery was dissected, and specific intracellular cascades of biochemical events – which ultimately lead to invasive growth – were identified. The discovery of germ line mutations in the HGF receptor, which predispose individuals to papillary renal cell carcinoma (RCCP), offered the genetic proof for the oncogenic function of this signaling pathway (Schmidt et al. 1997). Subsequent to this study, intense research by many groups provided evidence that HGF–MET pair plays an important role in cancer and metastasis (Birchmeier et al. 2003). In the 2000s, a new paradigm emerged for oncogenes: the “oncogene addiction,” indicating that a cancer cell, despite its plethora of genetic alterations, is still dependent on a single oncogenic protein for its sustained proliferation or survival (Comoglio et al. 2008). Different types of tumors were shown to be MET addicted and to be halted in their growth by MET-targeted therapy, i.e., drugs inhibiting MET. Despite its promising translation into clinics, MET-targeted therapy still copes with mechanisms of drug resistance. Although the great body of studies dedicated to the role of HGF-MET in cancer, very little is known about how MET signaling affects other diseases. Here, it is worth mentioning the discovery of the MET receptor as an autism genetic risk (Campbell et al. 2006). As a result, the dissection of MET signaling in driving the cellular events that affect brain development and function are relevant for studying the pathogenesis of neurologic diseases (Maina and Klein 1999) (Fig. 1).
Hepatocyte Growth Factor Receptor, Fig. 1

Timeline of HGF receptor (MET) discovery

Structure and Biosynthesis

The MET receptor is classified as a member of the receptor tyrosine kinase (RTK) protein subfamily. It is a heterodimer composed of an entirely extracellular 50 kDa α-chain and a 140 kDa β-chain constituted by a large extracellular region, a transmembrane portion, and an intracellular tyrosine kinase domain. The two subunits are linked together by a disulfide bridge. The extracellular α-chain constitutes – with the N-terminus domain of the β-chain – a large semaphorin (SEMA) domain, which contains the HGF binding pocket. In addition, the β-chain includes (i) a plexin, semaphorin, and integrin (PSI)-rich domain; (ii) four immunoglobulin, plexin, and transcriptional factor (IPT) repeats; (iii) transmembrane (TM) and (iv) juxtamembrane (JM) domains; (v) intracellular tyrosine kinase (TK) domain; and (vi) the C-terminal tail containing a two-tyrosine multifunctional docking site (Tyr1349 and Tyr1356) that interacts with multiple SRC homology (SH2–3) containing intracellular signal transducers. In addition, intracellularly the β-chain includes: two phosphorylation sites (Ser985 and Tyr1003) for negative regulation in the juxtamembrane portion and two tyrosine residues (Tyr1234 and Tyr1235) in the TK domain with catalytic activity (Trusolino et al. 2010). The MET ligand HGF belongs to the plasminogen-related growth factor protein family. It is synthetized as an inactive single-chain pro-HGF and is extracellularly cleaved into a disulfide-linked α- and β-chain heterodimer. HGF contains two MET binding sites with different affinities. The α-chain bears the high-affinity site and recognizes the IPT3 and IPT4 domains of MET independently of HGF processing and maturation. The β-chain carries the low-affinity site, which is exposed only after HGF activation and interacts with the Sema domain of MET. Several serine proteases in the serum are able to cleave and activate pro-HGF, becoming a regulatory key point of the HGF/MET axis. Importantly, stimulation of pro-HGF activation has been evidenced in injured tissues. The α-chain of HGF is composed by an N-terminal hairpin loop (HL) followed by four kringle domains (K1–K4), while the β-chain contains a serine protease homology domain (SPH) without proteolytic activity (Trusolino et al. 2010) (Fig. 2).
Hepatocyte Growth Factor Receptor, Fig. 2

Schematic drawing of domain structures of HGF receptor (MET) and HGF

The gene encoding for the MET receptor is located on chromosome 7q31. The primary MET transcript produces a 150-kDa polypeptide, which constitutes the 170-kDa-precursor protein after glycosylation. This precursor is further glycosylated and then cleaved into the α- and β-chains. Moreover, the HGF encoding gene is located in the same chromosomal region of MET receptor (chromosome 7q21.1).

Signal Transduction

Upon HGF binding, the MET receptor is subjected to different biochemical modifications: (i) receptor dimerization; (ii) autophosphorylation on the tyrosines Y1234 and Y1235 within the kinase catalytic domain, which is essential to enhance the intrinsic kinase activity of the receptor; and (iii) phosphorylation of the two tyrosines embedded in the degenerate sequence YVH/NV, which leads to activation of various downstream signaling substrates. The phosphorylated tyrosines (Tyr1349 and Tyr1356) in the tail are necessary docking sites to recruit the downstream signaling transducers and adapter proteins containing the SRC homology (SH) domain, such as Grb2 (growth factor receptor-bound protein 2), Gab1 (Grb2-associated binding protein 1), the p85 subunit of PI3K (phosphatidylinositol-3 kinase), PLCγ (phospholipase Cγ), Shc (Src homology and collagen homology), Src, and SHP-2 (tyrosine–protein phosphatase) (Ponzetto et al. 1994). Among the best characterized signal transducers, Grb2 and Gab1 emerge. Grb2 is involved in the recruitment and activation of the Ras (rat sarcoma) activator SOS (Son of Sevenless), which stimulates the downstream MAPK (mitogen-activated protein kinase) signaling cascades: ERK (extracellular signal-regulated kinase), p38MAPK, and JNK (c-Jun N-terminal protein kinase). Gab1 is a specific MET interactor (Weidner et al. 1996), which associates with the MET receptor either directly or indirectly through Grb2. Gab1 is then phosphorylated on multiple tyrosine residues, which provide additional sites for recruiting substrates containing SH2 or phosphotyrosine binding (PTB) domain, such as PI3K, SHP-2, and PLCγ. By converting the multifunctional docking site of the oncogenic form of MET into preferential binding motifs for Grb2 or PI3K, Bardelli et al. (1999) demonstrated that Ras signals are primarily involved in MET-triggered cell proliferation, whereas PI3K recruitment is required for the induction of cell motility and invasion. However, a fully metastatic phenotype was recapitulated only when both effectors were concomitantly associated with MET. The Ras signaling is also positively reinforced by Shc and SHP-2 and also activates Rac1 (Ra-related C3 botulinum toxin substrate 1), implicated in cell migration. The MAPK-ERK signaling pathway is associated with proliferation, while p38MAPK plays a fundamental role in cell migration and survival. On the other hand, PI3K/Akt pathway is implicated in cell survival and is involved in the regulation of protein synthesis and cell growth through the Akt-dependent stimulation of mTOR (mammalian target of rapamycin). PLCγ activity leads to the activation of protein kinase C (PKC) by 1,2-diacylglycerol and IP3-mediated release of Ca2+, with a role in receptor negative regulation (see below). In addition, Src binds to MET and induces the phosphorylation of Gab1 and of several downstream proteins, such as FAK (focal adhesion kinase). Indeed, Src takes part in the HGF-dependent induction of motility and transformation. In fact, FAK is the link between integrins and the growth factor signaling. In addition, FAK can be directly phosphorylated by MET reinforcing the motility response. Furthermore, in response to MET activation, the PI3K/Akt and Src pathway leads to IKK activation and destruction of IkBs (NF-κB inhibitors). As a consequence, NF-κB translocates into the nucleus and stimulates the transcription of various genes, including mitogenic and anti-apoptotic regulators (Trusolino et al. 2010). Finally, another transducer recruited by activated MET is STAT3 (signal transducer and activator of transcription 3). This transcription factor is tyrosine phosphorylated by MET and translocates into the nucleus leading to tubule formation. Interestingly, it has been demonstrated that MET can also enhance its downstream signaling pathways from endosomal compartments. In fact, after HGF binding, MET is internalized by clathrin-mediated endocytosis and recruited in early endosomes. From this point, MET stimulates the activity of ERK by PKC, which regulates cell migration through the localization in the focal adhesion complexes. From endosomes, MET reaches the perinuclear endomembrane by a PKC-dependent mechanism and regulates also the STAT3 nucleus translocation and activity. Hence, many transducers participate in MET signaling through multiple interactions with the receptor or with its scaffold adaptors. These molecular events stimulate multiple processes resulting in a plethora of biological and biochemical effects in the cell, known as “invasive-growth” program (Fig. 3).
Hepatocyte Growth Factor Receptor, Fig. 3

Summary of some of the identified MET-triggered transduction pathways and their role in MET signaling

Receptor Desensitization

The HGF/MET axis is tightly controlled and regulated through different mechanisms involving the MET receptor (reviewed in Trusolino et al. 2010): (i) de/phosphorylation, (ii) ubiquitination, (iii) internalization, and (iv) proteolysis. The MET kinase activity can be switched off by the phosphorylation of Ser985 site by PKC or calcium calmodulin-activated serine kinase III in the juxtamembrane domain. On the other hand, several protein-tyrosine phosphatases (PTPs) stimulate the dephosphorylation of tyrosines in either the catalytic and docking domain, leading to negative regulation of receptor activity. The MET signal depends also from the levels of receptor expression at the cell surface. In fact, MET can be removed from the plasma membrane through shedding, intracellular cleavage, and ubiquitin-mediated degradation. Although the MET receptor stimulates its downstream signals from endosomial and perinuclear compartments, its internalization is exploited to reduce – through lysosomal degradation – its protein levels and activity. The signal addressing MET to the lysosomes is triggered by Cbl (casitas b-lineage lymphoma), an E3 ubiquitin–protein ligase, which is recruited to the juxtamembrane domain on the phosphorylated Tyr1003 site. Moreover, the Cbl-MET association is sustained by decorin, an extracellular proteoglycan. Once recruited by MET, Cbl ubiquinates the receptor at multiple sites. Then, MET is recognized by endocytic adaptors, transported into clathrin-coated areas, and delivered to endosomes. These vesicles fuse with lysosomes and MET undergoes proteolytic demolition. In addition, Cbl recruits, through CiN85 (Cbl-interacting protein 85), endophilins, a family of proteins that assist the negative curvature and invagination of the plasma membrane during endocytosis. Moreover, MET downregulation can be induced by proteolytic cleavages. One mechanism induces the cleavage of the HGFR extracellular domain by a disintegrin and metalloprotease called ADAM, which produces a soluble N-terminal fragment anchored to the membrane through a cytoplasmic tail. This mechanism of extracellular shedding leads to the reduction of plasma membrane receptor and to the generation of a decoy, which interacts with HGF ligand and MET receptor. Subsequently, the γ-secretase cleaves the remaining cytoplasmic peptide, and the intracellular portion is degraded in the proteasome (Fig. 4).
Hepatocyte Growth Factor Receptor, Fig. 4

Mechanisms of MET receptor desensitization (Adapted from Trusolino et al. 2010)

Finally, the production of active HGF ligand is also controlled and limited. In particular, inhibitors of the HGF proteases, which are involved in the maturation of HGF ligand, have been identified.

Physiological Function

Tissue Homeostasis and Morphogenesis

The HGF receptor is expressed at the cell surface in the epithelial cells of many organs, including the skin, liver, mammary gland, pancreas, prostate, kidney, muscle, and bone marrow. Targeted deletion of either HGF or MET receptor gene during embryonic development has showed that HGF mediates a signal exchange between mesenchymal and epithelial cells, which is essential for placental trophoblasts and hepatocytes (Schmidt et al. 1995; Uehara et al. 1995; Bladt et al. 1995). In addition, MET plays an essential role in the migration and survival of migratory muscle progenitors which colonize long distance sites such as limbs, diaphragm, and tongue, giving rise to the hypaxial muscles (Bladt et al. 1995). Knock-in mice bearing phenylalanine substitutions in place of the tyrosines in the multifunctional docking site display a loss-of-function phenotype similar to that of mice entirely lacking HGF or MET (Maina et al. 1996), indicating that the docking site is essential to transduce the HGF signal in vivo. The Gab1 knockout phenocopied the defects that were observed in HGF and MET null embryos, confirming the Gab1 essential role in MET-based signal transduction pathways (Sachs et al. 2000). Finally, the process of axon guidance in the developing nervous system is driven by both HGF and their cousins, semaphorins (Trusolino and Comoglio 2002). Tissue-specific MET conditional knockouts have shown that MET contributes to the homeostasis of liver, skeletal and cardiac muscle, pancreas, kidney, and brain also in adulthood (for a review, see Matsumoto et al. (2014)). In endothelial cells, HGF promotes the formation of capillary-like structures during angiogenesis (Bussolino et al. 1992). These apparently different functions may be reunified in the complex events orchestrated by HGF-MET axis for branching morphogenesis, which involves – besides survival and proliferation – cell shape changes, cytoskeleton reorganization, asymmetric polarization of the cells in the direction of branching, cell elongation, cell–cell contact dissociation and reassociation, extracellular matrix (ECM) remodeling, basement membrane, matrigel or collagen invasion, and cell motility.

Tissue Repair and Organ Regeneration

Tissue fibrosis is the final common outcome of organs withstanding chronic and sustained injury. In response to stress and damage, a wound-healing process starts to repair and recover the affected tissue. These reparative mechanisms include induction of the inflammatory response, activation of fibroblasts to produce ECM, and regeneration of damaged tissue through stimulation of stem/progenitor cells proliferation, migration, and differentiation. However, chronic injuries may lead to a maladaptive response with overproduction of ECM causing fibrotic lesions and tissue scar. Growing evidence indicates that HGF possesses a potent anti-fibrotic activity in different pathological contexts, such as ischemic cardiac damage and chronic renal and liver fibrosis. In vivo deletion of MET receptor in renal tubular cells increases apoptosis and interstitial fibrosis after kidney injury. MET deletion in hepatocytes causes defective liver regeneration and increased susceptibility to fibrosis and inflammation after hepatectomy or liver injury. Thus, MET signaling provides anti-apoptotic stimuli for organ repair. The anti-fibrotic activity of HGF-MET axis is largely due to its ability to antagonize TGF-β, the principal culprit of fibrosis, which is secreted in the damaged organ and stimulates myofibroblasts to deposit collagen in the ECM.

Stem cells are found in the adult organism and act as a repair system for the body. These stem/progenitor cells may remain quiescent (nondividing) for long periods of time until they are activated by a normal need for more cells to maintain tissues or by a disease or a tissue injury. The MET receptor is expressed in these cells. HGF, which is released by the injured ECM, activates them (oval cells in the liver, satellite cells in skeletal muscle, etc.) in their “niches,” guides their migration into the site of injury, and stimulates their expansion, survival, and differentiation. Thus, stem cells or progenitor cells, in damaged organs, exploit the MET-driven morphogenetic program, which is active during embryogenesis, and enhance tissue regeneration. Monocytes, macrophages, and monocyte-derived dendritic cells also express the MET receptor, while platelets, neutrophils, and mast cells produce HGF during regenerative processes, indicating a role of HGF-MET in immune regulation and inflammation. The protective action of HGF is at most explained by its ability to prevent cell death against various types of stress and injury, but it also seems to be associated with suppression of inflammation. Thus, enhancement of MET-mediated signaling may have a therapeutic meaning for the treatment of different types of diseases involving tissue injury in the liver and gastrointestinal, kidney, respiratory, cardiovascular, musculoskeletal, skin, and nervous system diseases (for a review, see Matsumoto et al. (2014)) (Fig. 5).

Function in Diseases

Cancer

Missense mutations in the MET proto-oncogene and a nonrandom duplication of the chromosome bearing the mutated MET were initially found in inherited RCCP, implicating MET as a cancer-causing gene in human (Schmidt et al. 1997). With the advent of precision medicine, different tumors have been found to harbor mutations or – more often – amplification of the MET proto-oncogene and to rely on MET activation for their sustained proliferation (reviewed in Corso and Giordano (2013)). When identified as a clear driver for tumor growth, MET has become a biological drug candidate for targeted therapy in cancer. Several MET inhibitors have been introduced in the clinic to be proven for their efficacy against some types of cancer. Unfortunately, resistance to the inhibitor inevitably emerges. On the other hand, amplification of the MET proto-oncogene is associated with acquired resistance in colorectal metastatic tumors during anti-epidermal growth factor receptor (EGFR) therapy (Bardelli et al. 2013). Indeed, MET association with EGFR and their reciprocal transphosphorylation have been found in different systems, and they appear to substitute for each other in many tumors. Switching from EGFR to MET inhibition may thus result in clinical benefit after the occurrence of MET-driven acquired resistance, offering novel opportunities to design clinical studies with combined EGFR/MET inhibitors. Several aspects of the “invasive growth” program are also recapitulated and exacerbated in cancer. Tumor cells with autocrine or paracrine (by stromal cells) secretion of HGF may take advantage from a more convenient environment for survival and migration (Comoglio et al. 2008) (Fig. 5).
Hepatocyte Growth Factor Receptor, Fig. 5

Role of MET in tissue repair, organ regeneration, and cancer

One of the main mechanisms for the metastatic behavior relies on the hypoxia-induced genes, which regulate angiogenesis, tumor vascularization, invasion, drug resistance, and metastasis. In 2003, Pennacchietti et al. discovered that the MET promoter contains several responsive elements that bind the hypoxia inducible factor (HIF), a transcription factor activated by low oxygen tension. Thus, in metabolically active tumors, the adaptation to low oxygen induces MET overexpression and promotes tumor migration and invasion as a mechanism of escape in search of oxygen. Another expedient used by tumor cells to disseminate in the body utilizes blood coagulation, as fibrin provides a scaffold for anchorage and invasion. In 2005, Boccaccio et al. showed that the MET oncogene activation leads to the hemostasis perturbation by upregulation of plasminogen activator inhibitor type 1 and cyclooxygenase-2, which induces migratory routes for invasive growth. In the majority of tumors, MET is overexpressed to help cells survive in conditions of stress, as it happens in tissue or organ injury. The cancer antiproliferative-targeted therapies, radiotherapy or anti-angiogenic agents, may select MET-amplified cancer cells or MET-expressing stem/progenitor cells which repair the cancer tissue damage. In cancer stem cells, not only amplification but also MET physiological expression inherited from the cell of origin (a stem/progenitor) can contribute to tumorigenesis and therapeutic resistance, by sustaining the inherent self-renewing, self-preserving, and invasive growth phenotype (Boccaccio and Comoglio 2014).

Autism

A polymorphism in the promoter region of the MET gene, known to decrease MET expression, was found to be genetically linked with autism (Campbell et al. 2006). Much less is known about the function of MET in brain diseases than about its role in cancer biology. HGF-MET axis promotes survival and migration of sensory neuron, motor neurons, and sympathetic neurons in embryonic development (Maina and Klein 1999). In addition, a role played by MET in the migration and survival of specialized interneurons of the cerebral cortex, cerebellum, and olfactory bulb has been shown (Powell et al. 2001; Giacobini et al. 2007; Ieraci et al. 2002). Thus, it is plausible that MET alteration leads to disturbed neuronal migration during early gestation. In cultured neuronal cells, HGF enhances neurite extension and branching, maturation of the dendritic spine and synaptic plasticity in the hippocampus, as well as synaptic long-term potentiation (LTP) in the CA1 region of the hippocampus (Akimoto et al. 2004; Qiu et al. 2014). Accordingly, the HGF-MET axis contributes to the activity-dependent regulation of physiological learning and memory performance in the adult brain (Kato et al. 2012). Genetic deletion of MET in pyramidal neurons showed alteration of synaptic development in specific excitatory hyperconnectivity circuits that may underlie social behavior and communication (Qiu et al. 2011). However, the exact mechanism of action of MET in these neurons remains elusive.

Summary

Stimulation of HGF receptor (MET) evokes a unique set of biological responses known as “invasive growth,” which are exploited during embryonic development, organ regeneration, and cancer. Although the MET downstream intracellular signaling events have been identified, they are not MET specific, since they have been found activated also by other growth factor receptors. It appears that the synchronous activation of the various pathways is critical for the completion of the invasive growth program. Moreover, spatial and temporal differences in signal intensity and duration may account for the specific biological outcome. Indeed, the subcellular compartmentalization of activated MET and the multiple regulatory systems used by the cell to downregulate MET may finely tune the RTK action and define the duration of the signal.

Over the last two decades, HGF receptor has become one of the most highly investigated cancer genes. In cancer, enhanced activation of MET is achieved through strategies such as activating point mutations, oncogenic translocation, and gene amplification. These strategies lead to constitutive activated forms of MET that escape regulatory mechanisms, which normally modulate signaling intensity and duration. Different MET inhibitors have been approved for clinical use in cancer and are being evaluated for their efficacy in MET-driven tumors. MET-targeted therapy may also benefit patients whose tumors have selected MET amplification as a mechanism of resistance to therapies attacking other regulators of cell proliferation such as EGFR. Whether MET inhibitors will be efficacious against tumors treated with radiotherapy or conventional chemotherapy in cases where MET is activated as an adaptive response to stressful conditions is still an outstanding question. On the other side of the coin based on studies using cell-/tissue-specific disruption of functional MET and preclinical disease models in experimental animals, there is evidence that HGF or agents with MET agonistic activity may have beneficial effects to contrast fibrosis and repair organs after injury damage in various clinical contexts. The challenge for the therapeutic use of MET-activating compounds in regenerative medicine is to envision bioactive molecules able to uncouple MET intrinsic ability of wound healing from those properties promoting full-blown invasive growth.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Simona Gallo
    • 1
    • 2
  • Paolo Maria Comoglio
    • 2
  • Tiziana Crepaldi
    • 1
    • 2
  1. 1.Department of OncologyUniversity of TurinCandiolo, TurinItaly
  2. 2.Candiolo Cancer Institute - IRCCSCandiolo, TurinItaly