Adenocarcinoma; Hepatocyte Growth Factor; Neoplastic
Stem Cells; Pancreatic Neoplasms
HGF hepatocyte growth factor; PDAC pancreatic ductal
Hepatocyte growth factor (HGF) is a multifunctional
gene. It was previously known for its role in the signaling
pathway especially in hepatocytes and described
as a heparin-binding polypeptide [1, 2, 3, 4]. HGF
acts in hepatocytes as a potential mitogen regulator,
stimulates DNA replication, controls organogenesis and
organ regeneration [3, 5, 6]. The roles of HGF in liver
regeneration following both drug induced liver injury and
partial hepatectomy have been already demonstrated [6, 7, 8, 9, 10]. However, previous studies showed that HGF
performs its numerous roles not only in hepatocytes, but
also in other cell types through activating its downstream
signalings and consequently stimulation of DNA synthesis
HGF is secreted by cells of mesenchymal origin, but
acts not only in cells of mesenchymal but also epithelial
origin. Its action is mediated by binding its receptor
c-Met (mesenchymal epithelial transition factor). This activation causes auto-phosphorylation of c-Met and
subsequent activation of downstream signaling pathways
such as mitogen-activated protein kinases (MAPKs),
phosphatidylinositol-3 kinase (PI3K), signal transducer
and activator of transcription (STAT), nuclear factorkappaB
(NF-κB) [1, 13, 14]. Therefore, activation of HGF/
c-Met signaling activates pathways which regulate cell
differentiation, proliferation, transformation, migration
and apoptosis [3, 14, 15, 16, 17, 18, 19, 20, 21]. An essential
role of this pathway in wound healing has been also
described [22, 23, 24, 25, 26].
In addition to the productive and protective roles of
the signaling pathway in fetal development, organogenesis
and organ regeneration [3, 4, 18, 22, 27, 28, 29, 30],
recent studies suggested an importance of HGF/c-Met
signaling pathway in cancerogenesis as it correlates with
poor prognosis and high metastasis rate [12, 31, 32, 33, 34]. Possible ways of action of the pleiotropic HGF/c-Met
signaling pathway in tumorigenesis include activation
of proliferation, cell de-differentiation and activation of
epithelial mesenchymal transition [13, 35, 36, 37].
Many clinical characteristics of cancers, like metastasis
rate, are meant to be dependent on the fraction of cancer
stem cells (CSCs) within the tumor [38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48]. CSCs are a small population of cancer cells
having ability of epithelial–mesenchymal transition (EMT),
self-renewal, aggressiveness, apoptosis resistance, invasive,
uncontrolled growth [37, 41, 47, 49, 50, 51, 52, 53, 54, 55, 56].
The cancer stem cells are defined by certain surface markers
. Recently, HGF/c-Met was also suggested as marker for
CSCs [46, 58, 59, 60, 61, 62, 63, 64, 65, 66].
Interestingly, overexpression of c-Met and its ligand
have been detected in PDAC and can be detected in
pancreatic cancer stem cells, too [56, 67, 68, 69, 70].
Increasing number of recent studies suggested an
association between high c-Met and HGF expression and
stem cell features of the tumor [34, 56, 59, 70, 71, 72, 73, 74]. However its definite role in PDAC still needs
to be thoroughly investigated and comprehensively
The HGF, also known as “scatter factor” (SF), was
initially found in the blood of hemihepatectomized rats
and described in 1984 as a mitogen protein for hepatocytes
[4, 14]. HGF is a cytokine belonging to the serine protease
family and known as a unique ligand of c-Met cell surface
marker. The gene is located on chromosome 7q21.1 in 70
kb length .
HGF is synthesized in mesenchymal cells as inactive
single chain protein and obtains its active heterodimer form
via cleaving catalysis by serine proteases in the extracellular
environment [1, 13] . An active form of HGF comprises α
and β chains with 69 and 34 kDa correspondingly. The
heavy α chain contains five domains: N-terminal domain
and four kringle domains. Kringle domains are responsible
for protein-protein interaction . The light β chain
constitutes a serine protease homology (SPH) domain and
has a catalytic feature (Figure 1) [75, 76]. The N-terminal
domain and the first Kringle domain of HGF (NK1 section)
are the essential receptor-binding fragment which
regulates receptor-ligand connection .
Figure 1. Maturation and domain structure of Hepatocyte growth factor (HGF).
c-Met is a pro-oncogenic protein, also called hepatocyte
growth factor receptor (HGFR) or receptor tyrosine kinase
(RTK). c-Met is a transmembrane tyrosine kinase which
is encoded by Met gene (Figure 2) [75, 76]. The gene
encoding c-Met is located on chromosome 7q21-31 in
120kb length . c-Met is composed of a 50-kDa, totally
extracellular α chain and a 140-kDa, transmembrane β
chain complex with disulfide link . Therefore, c-Met
has large extracellular, transmembrane and cytoplasmic
Figure 2. Structure of c-Met receptor.
The extracellular part of c-Met contains three domains:
semaphorin domain (SEMA); Met related sequence
domain (MRS) and immunoglobulin domain (Ig). The
SEMA domain constitutes of the whole α chain and the
N-terminal part of the β chain. This domain controls
protein-protein interaction. The SEMA domain is followed
by MRS domain, which is rich with cysteine and involved
in the right placing of the receptor during binding with
HGF receptor. These two domains create the semaphorin
homology region containing about 500 amino-acid. This
fragment is found almost in all Met receptor subfamily
. Finally, four Ig domains conclude the extracellular
The cytoplasmic part of c-Met comprises the
juxtamembrane domain, tyrosine kinase domain and the
C-terminal part [13, 75, 79, 80]. The former is responsible
for c-Met ubiquitination . Contrary, the kinase domain
has the ability to catalyze. The C-terminal part is a
multifunctional docking site and controls the enrollment
of downstream connectors [75, 76]. As mentioned before c-Met is expressed on various types of cells like epithelial,
endothelial, hematopoietic cells, neurons, hepatocytes,
melanocytes and cardiomyocytes .
Molecular Mechanisms of HGF/c-Met Signaling
The action of HGF is initiated upon binding to its
receptor c-Met (Figure 3). This results in dimerization
of the extracellular domain of the c-Met protein [83, 84, 85]. Subsequently, the intracellular part of c-Met is
phosphorylated which leads to the trans-phosphorylation
of the catalytic kinase domain and the C-terminal part of
c-Met [13, 79, 80]. The phosphorylation leads to activation
of diverse intracellular signaling pathways such as MAPKs,
PI3K, STAT, NF-κB [1, 13, 14].
Figure 3. Molecular mechanism of HGF signaling pathway.
The most important of these downstream pathways
are the MAPKs. MAPKs can be divided in three subgroupsextracellular
signal-regulated kinases (ERKs), p38, and Jun
NH2-terminal kinases (JNKs).
ERKs are activated by Ras kinase . Ras is one of
the guanosine triphosphate (GTP) binding proteins and
activated after trans-phosphorylation of C-terminal part
of c-Met in presence of secondary messengers such as
Growth Factor Receptor-Bound protein 2 (GRB2). GRB2
can interact directly with c-Met or indirectly via Srchomology-
2 domain-containing transforming protein
(SHC) . For this transduction c-Met needs intracellular
part of CD44v6 via an affiliation with ezrin, radixin,
moesin (ERM) proteins and subsequent activation of Raf
and MAPK/ERK kinase (MEK)-1,2 kinases [14, 72, 88]. ERKs activate and regulate biological processes such
as proliferation, differentiation, survival, migration,
angiogenesis, as well as chromatin remodeling in nuclear
level [86, 89, 90, 91, 92].
p38s and JNKs are activated by Rac, another GTP
binding protein, directly through Phosphatidylinositol-3
kinase (PI3K) or indirectly by the Ras-PI3K mediated way
[4, 93, 94, 95, 96]. Both p38s and JNKs Rac initiates MEKdepending
stimulation which leads to the phosphorylation
of MEK3/MEK6 and MEK4/MEK7 respectively . By
this signaling pathway cell differentiation, proliferation
migration and apoptosis is regulated [97, 98, 99, 100, 101].
The latter is also responsible for neurodegeneration, as
well as collagenase-3 expression and synthesis [91, 93, 95, 97].
PI3K can also activate protein kinase B (Akt) and
mechanistic target of rapamycin (mTOR) which regulates
anti-apoptotic processes [102, 103].
Transphosphorylation of c-Met also results in activation
of STATs. Especially, STAT3 is phosphorylated by binding
to the C-terminal end of c-Met via the Src-homology-2
domain (SH2 domain) and subsequently monomer STAT3s
dimerizes by recognizing their SH2 domain [15, 104].
Later, homodimer STAT3 is able to translocate to nucleus
and regulate cell proliferation, differentiation, remodeling,
migration and c-Met-dependent tubulogenesis as well [15, 23, 105, 106, 107].
Additionally, NF-κB is activated after c-Met stimulation
as well. This activation can occur through PI3K-Akt
signaling pathway and/or Src pathway. NF-κB controls proliferation, survival, and anti-apoptosis and apoptosis
[16, 108, 109].
Mechanisms of Action in Carcinogenesis
Latest insights suggest that HGF/c-Met signaling
plays a key role in carcinogenesis [13, 33, 79, 110, 111, 112]. Its pathophysiological role in tumorigenesis is
exerted via activating mutations, amplification, different
auto- and paracrine ligand-dependent mechanisms
and overexpression of c-Met which can cause ligandindependent
spontaneous initiation of the signaling
pathway [33, 113]. Interestingly, these findings are more
common in adenocarcinomas than sarcomas or other
types of cancer . Such pathophysiological findings
are detected in different types of cancers, especially in
pancreatic cancer [67, 114, 115, 116, 117, 118, 119].
Amplification of c-Met was frequently associated with
poor differentiation, poor prognosis and chemo- and
radiotherapy resistance [120, 121, 122, 123, 124]. c-Met
is rather involved in a late phase of tumor progression
as c-Met gene mutations are found in early lesions [125, 126, 127]. Its overexpression associates with cancers with
advanced stage, worse prognosis, high metastases, chemoand
radiotherapy resistance [72, 128, 129] .
In addition, HGF/c-Met signaling pathway plays a role
in tumor angiogenesis [31, 130, 131, 132, 133]. Several
experimental and clinical investigations demonstrated that
HGF/c-Met stimulates angiogenesis through stimulation of
vascular endothelial growth factor (VEGF) signal pathway
and its blockade causes downfall in vascularization of
tumors. On the other hand, overexpression of VEGF and
its receptor had a suppressive effect on HGF/c-Met [22, 134, 135, 136]. Accordingly, inhibition of VEGF activates
HGF/c-Met signaling pathway. One explanation might
be the anti-vascular effect of the therapy that causes cell
hypoxia. Cell hypoxia, however, induces the expression of
HGF and c-Met in tumor cells via HIF 1α factor [134, 137, 138, 139]. HGF/c-Met pathway stimulation can results in
reduced effect of antiangiogenic therapy. Therefore it was
suggested to use combination blocking therapy by using
both HGF/c-Met and VEGF inhibitors [130, 140, 141, 142, 143]. In the following we give a more detailed overview on
action of HGF/c-Met in pancreatic cancer.
HGF/c-Met in PDAC
PDAC is an aggressive tumor that is characterized by
aggressive infiltration, early metastases, chemoresistance
and a distinct desmoplastic reaction and all these
characteristics might be mediated by cancer stem cells,
which play an important role in pancreatic cancer [37, 72, 144, 145, 146, 147]. Recent evidences suggest that HGF/c-
Met signaling pathway has an importance in maintenance
of stem cell characteristics and tumorigenic features in
PDAC [34, 70, 148]. Overexpression of this stem cell marker
has been detected in PDAC CSCs and correlates with poor
survival rate and distant metastasis [56, 59, 66, 69, 70, 71, 149]. Furthermore, in vitro and in vivo investigations describe that inhibition of this pathway not only declines
metastasis, but also local tumor growth [36, 56, 116]. HGF/
c-Met signaling is also required for pancreatic CSCs survival,
since some in vivo studies showed that c-Met inhibition
decreased the population of CSCs and decelerated tumor
growth . Interestingly, Li et al. demonstrated this
pathway has a role in the sphere formation which is an
evidence of self-renewal ability of CSCs [53, 150]. This in
vitro experiment showed that c-Met+ cells formed spheres,
while c-Met- cells did not form spheres . Additionally,
the pathway also seems to mediate invasiveness in PDAC
[73, 82, 138, 151, 152, 153, 154].
It is known that the desmoplastic reactions of PDAC are
responsible for many of the tumors clinical characteristics
. Up to 90% of PDAC volume is stromal compartment,
which consists of extracellular matrix (ECM), pancreatic
stellate cells (PSCs), immune cells, endothelial cells and
neurons. [156, 157, 158, 159]. There is increasing interest
in the desmoplastic reaction as target for new therapies
[155, 160]. Latest reports show that HGF/c-Met signaling
pathway is also involved in the interaction between tumor
cells and stromal cells and thereby might contribute to
the desmoplastic reaction in PDAC [155, 158, 160, 161, 162]. Several studies showed that although PDAC cells do
express c-Met, they do not secrete HGF [36, 72]. On the
other hand it was demonstrated that cells of the stromal
compartment secret HGF and thereby might activate HGF/
c-Met signaling in PDAC cells [36, 161]. Interestingly, Niina et al. determined in vivo HGF expression in PSCs in chronic
pancreatitis which is a risk factor for PDAC . Yasui et
al. described that co-cultivation of fibroblasts and cancer
cells could elevate c-Met phosphorylation rate significantly
. Interestingly, desmoplastic reactions leads to
hypoxia in PDAC environment which also activates HGF/c-
Met pathway as already mentioned above [138, 139, 154].
Other studies also support that fibroblasts secrete high
amount of HGF in PDAC, subsequently increasing activation
of c-Met signaling . This suggests a possible effect of
novel cancer therapies that target the cancer environment
[155, 160, 161]. Whereas all these data suggest that HGF/
c-Met signaling pathway might play an important role
in tumor-stromal interaction, the molecular mechanism
of this interaction is still unclear and needs further
HGF/c-Met as a Target in PDAC Therapy
Recent investigations demonstrated that inhibition of
HGF/c-Met pathway can reduce metastasis in PDAC [36, 56, 116, 165, 166]. Pothula et al. showed that HGF inhibition
alone had a noteworthy reduction effect on metastases
of PDAC . Interestingly, HGF effect on metastasis
was not successful when used with gemcitabine. The
authors of this study explained this with the stimulating
effect of Gemcitabine on cancer cell stemness [36, 48].
Accordingly, it was shown that Gemcitabine treatment
increased the number of CSCs in PDAC [48, 167]. Li et al.
found that treatment with both c-Met inhibitor XL184 and gemcitabine reduced the cancer growth rate, while groups
treated with XL184 or gemcitabine only had the same
growth rate as controls .
In this regard, it was demonstrated that the inhibition
of HGF/c-Met signaling declined the amount of PDAC CSCs
and prevented sphere formation [56, 70, 82].
In conclusion, HGF/c-Met signaling might play an
important role in different characteristics of PDAC.
Accordingly, its inhibition might be an approach in cancer
treatment. Different preclinical studies could already
give evidence in this regard. Due to the complexity of this
pathway, combined therapies seem to have the best effect.
As our understanding of its molecular mechanisms is not
completely clear, further studies are needed.
Conflict of Interest
The authors declare that there is no conflict of interests
regarding the publication of this paper.
- Bardelli A, Ponzetto C, Comoglio PM. Identification of functional domains in the hepatocyte growth factor and its receptor by molecular engineering. J Biotechnol 1994; 37:109-22. [PMID: 7765452].
- Nakamura T, Nawa K, Ichihara A. Partial purification and characterization of hepatocyte growth factor from serum of hepatectomized rats. BiochemBiophys Res Commun 1984; 122:1450-9. [PMID: 6477569].
- Matsumoto K, Nakamura T. Hepatocyte growth factor: molecular structure and implications for a central role in liver regeneration. J Gastroenterol Hepatol 1991; 6:509-19. [PMID: 1834243].
- Trusolino L, Bertotti A,Comoglio PM. MET signalling: principles and functions in development, organ regeneration and cancer. Nat Rev Mol Cell Biol 2010; 11:834-48. [PMID: 21102609].
- Kost DP, Michalopoulos GK. Effect of 2% dimethyl sulfoxide on the mitogenic properties of epidermal growth factor and hepatocyte growth factor in primary hepatocyte culture. J Cell Physiol 1991; 147:274-80. [PMID: 1828251].
- Lindroos PM, Zarnegar R, Michalopoulos GK. Hepatocyte growth factor (hepatopoietin A) rapidly increases in plasma before DNA synthesis and liver regeneration stimulated by partial hepatectomy and carbon tetrachloride administration. Hepatology 1991; 13: 743-50. [PMID: 1826282].
- Fausto N. Hepatocyte growth factor receptor and the c-met oncogene. Hepatology 1991; 14: 738-40.
- Gohda E, Tsubouchi H, Nakayama H, Hirono S, Arakaki N, Yamamoto I, et al. Human hepatocyte growth factor in blood of patients with fulminant hepatic failure. Basic aspects. Dig Dis Sci 1991; 36: 785-90. [PMID: 1827762].
- Kinoshita T, Hirao S, Matsumoto K, Nakamura T. Possible endocrine control by hepatocyte growth factor of liver regeneration after partial hepatectomy. BiochemBiophys Res Commun 1991; 177: 330-5. [PMID: 1828341].
- Zarnegar R, DeFrances MC, Kost DP, Lindroos P, Michalopoulos GK. Expression of hepatocyte growth factor mRNA in regenerating rat liver after partial hepatectomy. Biochem Biophys Res Commun 1991; 177: 559-65. [PMID: 1828343].
- Kaido T, Imamura M. Hepatocyte growth factor: clinical implications in hepatobiliary pancreatic surgery. J Hepatobiliary Pancreat Surg 2001; 8: 65-75. [PMID: 11294292].
- Furukawa T, Duguid WP, Kobari M, Matsuno S, Tsao MS. Hepatocyte growth factor and Met receptor expression in human pancreatic carcinogenesis. Am J Pathol 1995; 147: 889-95. [PMID: 7573364].
- Garajová I, Giovannetti E, Biasco G, Peters GJ. c-Met as a Target for Personalized Therapy. Transl Oncogenomics 2015; 7: 13-31. [PMID: 26628860].
- Ponzetto C, Bardelli A, Zhen Z, Maina F, dallaZonca P, Giordano S, et al. A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Cell 1994; 77: 261-71. [PMID: 7513258].
- Levy DE, Lee CK. What does Stat3 do. J Clin Invest 2002; 109: 1143-8. [PMID: PMC150972].
- Fan S, Gao M, Meng Q, Laterra JJ, Symons MH, Coniglio S, et al. Role of NF-kappaB signaling in hepatocyte growth factor/scatter factor-mediated cell protection. Oncogene 2005; 24: 1749-66. [PMID: 15688034].
- Nakamura T, Nishizawa T, Hagiya M, Seki T, Shimonishi M, Sugimura A, et al. Molecular cloning and expression of human hepatocyte growth factor. Nature 1989; 342: 440-3. [PMID: 2531289].
- Nakamura T. Hepatocyte growth factor as mitogen, motogen and morphogen, and its roles in organ regeneration. Princess Takamatsu Symp 1994; 24: 195-213. [PMID: 8983076].
- Huh CG, Factor VM, Sánchez A, Uchida K, Conner EA, Snorri S. Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc Natl Acad Sci U S A 2004; 101: 4477-82. [ PMID: PMC384772].
- Alvarez-Perez JC, Ernst S, Demirci C, Casinelli GP, Mellado-Gil JM, Rausell-Palamos F, et al. Hepatocyte growth factor/c-Met signaling is required for beta-cell regeneration. Diabetes 2014; 63:216-23. [PMID: PMC3868042].
- Bussolino F, Di Renzo MF, Ziche M, Bocchietto E, Olivero M, Naldini L, Gaudino G, et al. Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth. J Cell Biol 1992; 119:629-41. [PMID: PMC2289675].
- Wojta J, Kaun C, Breuss JM, Koshelnick Y, Beckmann R, Hattey E, et al. Hepatocyte growth factor increases expression of vascular endothelial growth factor and plasminogen activator inhibitor-1 in human keratinocytes and the vascular endothelial growth factor receptor flk-1 in human endothelial cells. Lab Invest 1999; 79:427-38. [PMID: 10211995].
- Sano S1, Itami S, Takeda K, Tarutani M, Yamaguchi Y, Miura H, et al. Keratinocyte-specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis. EMBO J 1999; 18:4657-68. [PMID: 10469645] .
- Chmielowiec J, Borowiak M, Morkel M, Stradal T, Munz B, Werner S, et al. c-Met is essential for wound healing in the skin. J Cell Biol 2007; 177: 151-62. [PMID: PMC2064119].
- Nakamura T. Structure and function of hepatocyte growth factor. Prog Growth Factor Res 1991; 3:67-85. [PMID: 1838014].
- Jin Z. Increased c-Met phosphorylation is related to keloid pathogenesis: implications for the biological behaviour of keloid fibroblasts. Pathology 2014; 46:25-31. [PMID: 24300717].
- Organ SL, Tsao MS. An overview of the c-MET signaling pathway. TherAdv Med Oncol 2011; 3:S7-S19. [PMID: 22128289].
- Liu Y, Yang J. Hepatocyte growth factor: new arsenal in the fights against renal fibrosis. Kidney Int 2006; 70: 238-40. [PMID: 16838037].
- Watanabe M, Ebina M, Orson FM, Nakamura A, Kubota K, Koinuma D, et al. Hepatocyte growth factor gene transfer to alveolar septa for effective suppression of lung fibrosis. Mol Ther 2005; 12: 58-67. [PMID: 15963921].
- Ueki T, Kaneda Y, Tsutsui H, Nakanishi K, Sawa Y, Morishita R, et al. Hepatocyte growth factor gene therapy of liver cirrhosis in rats. Nat Med 1999; 5: 226-30. [PMID: 9930873].
- Qin L, Bromberg-White JL, Qian CN. Opportunities and challenges in tumor angiogenesis research: back and forth between bench and bed. Adv Cancer Res 2012; 113: 191-239. [PMID: 22429856].
- Gholamin S, Fiuji H, Maftouh M, Mirhafez R, Shandiz FH, Avan A. Targeting c-MET/HGF signaling pathway in upper gastrointestinal cancers: rationale and progress. Curr Drug Targets 2014; 15: 1302-11. [PMID: 25382190].
- Scagliotti GV, Novello S, von Pawel J. The emerging role of MET/HGF inhibitors in oncology. Cancer Treat Rev 2013; 39: 793-801. [PMID: 23453860].
- Delitto D, Vertes-George E, Hughes SJ, Behrns KE, Trevino JG. c-Metsignaling in the development of tumorigenesis and chemoresistance: potential applications in pancreatic cancer. World J Gastroenterol 2014; 20: 8458-70. [PMID: PMC4093697].
- Jung KH, Park BH, Hong SS. Progress in cancer therapy targeting c-Met signaling pathway. Arch Pharm Res 2012; 35: 595-604. [PMID: 22553051].
- Pothula SP, Xu Z, Goldstein D, Biankin AV, Pirola RC, Wilson JS. Hepatocyte growth factor inhibition: a novel therapeutic approach in pancreatic cancer. Br J Cancer 2016; 114: 269-80. [PMID: 26766740].
- Boccaccio C, Comoglio PM. Invasive growth: a MET-driven genetic programme for cancer and stem cells. Nat Rev Cancer 2006; 6: 637-45. [PMID: 16862193].
- Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, et al. Identification of pancreatic cancer stem cells. Cancer Res 2007; 67: 1030-7. [PMID: 17283135].
- Adikrisna R, Tanaka S, Muramatsu S, Aihara A, Ban D, Ochiai T, et al. Identification of pancreatic cancer stem cells and selective toxicity of chemotherapeutic agents. Gastroenterology 2012; 143: 234-45 e7. [PMID: 22510202].
- De Bacco F, Casanova E, Medico E, Pellegatta S, Orzan F, Albano R, et al. The MET oncogene is a functional marker of a glioblastoma stem cell subtype. Cancer Res 2012; 72: 4537-50. [PMID: 22738909].
- Li Y, Kong D, Ahmad A, Bao B, Sarkar FH. Pancreatic cancer stem cells: emerging target for designing novel therapy. Cancer Lett 2013; 338: 94-100. [PMID: 22445908].
- Lim YC, Kang HJ, Moon JH. C-Met pathway promotes self-renewal and tumorigenecity of head and neck squamous cell carcinoma stem-like cell. Oral Oncol 2014; 50: 633-9. [PMID: 24835851].
- Luraghi P, Reato G, Cipriano E, Sassi F, Orzan F, Bigatto V, et al. MET signaling in colon cancer stem-like cells blunts the therapeutic response to EGFR inhibitors. Cancer Res 2014; 74: 1857-69. [PMID: 24448239].
- Peng Z, Zhu Y, Wang Q, Gao J, Li Y, Li Y, Ge S, et al. Prognostic significance of MET amplification and expression in gastric cancer: a systematic review with meta-analysis. PLoS One 2014; 9: e84502. [PMID: 24416238].
- Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003; 63: 5821-8. [PMID: 14522905].
- Todaro M, Gaggianesi M, Catalano V, Benfante A, Iovino F, Biffoni M, et al. CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis. Cell Stem Cell 2014; 14: 342-56. [PMID: 24607406].
- Codony-Servat J, Rosell R. Cancer stem cells and immunoresistance: clinical implications and solutions. Transl Lung Cancer Res 2015; 4: 689-703. [PMID: 26798578].
- Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, et al. Distinct populations of cancer stem cells determinetumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cel 2007; 1: 313-23. [PMID: 18371365].
- Yu S, Yu Y, Zhao N, Cui J, Li W, Liu T. C-Met as a prognostic marker in gastric cancer: a systematic review and meta-analysis. PLoS One 2013; 8: e79137. [PMID: 24223894].
- Xia J, Chen C, Chen Z, Miele L, Sarkar FH, Wang Z. Targeting pancreatic cancer stem cells for cancer therapy. Biochim Biophys Acta 2012; 1826: 385-99. [PMID: 22728049].
- Abbaszadegan MR, Bagheri V, Razavi MS, Momtazi AA, Sahebkar A, Gholamin M. Isolation, identification, and characterization of cancer stem cells: A review. J Cell Physiol 2017; 232:2008-2018. [PMID: 28019667].
- Doherty MR, Smigiel JM, Junk DJ, Jackson MW. Cancer Stem Cell Plasticity Drives Therapeutic Resistance. Cancers (Basel) 2016; 8. [PMID: 26742077].
- Cao L, Zhou Y, Zhai B, Liao J, Xu W, Zhang R, Li J, Zhang Y, et al. Sphere-forming cell subpopulations with cancer stem cell properties in human hepatoma cell lines. BMC Gastroenterol 2011; 11: 71. [PMID: 21669008].
- Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T. Opinion: migrating cancer stem cells - an integrated concept of malignant tumour progression. Nat Rev Cancer 2005; 5: 744-9. [PMID: 16148886].
- Reya T1, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 2001; 414: 105-11. [PMID: 11689955].
- Herreros-Villanueva M, Zubia-Olascoaga A, Bujanda L. c-Met in pancreatic cancer stem cells: therapeutic implications. World J Gastroenterol 2012; 18:5321-3. [PMID: PMC3471099].
- DallaPozza E, Dando I, Biondani G, Brandi J, Costanzo C, Zoratti E, et al. Pancreatic Ductal Adenocarcinoma Stem Cells. Pancreatic Disorders & Therapy 2015; 5(s5). [PMID: 25502497].
- Lau EY, Lo J, Cheng BY, Ma MK, Lee JM, Ng JK, et al. Cancer-Associated Fibroblasts Regulate Tumor-Initiating Cell Plasticity in Hepatocellular Carcinoma through c-Met/FRA1/HEY1 Signaling. Cell Rep 2016; 15: 1175-89. [PMID: 27134167].
- Hideo Tomihara, Daisaku Yamada, HidetoshiEguchi, Yoshifumi Iwagami, Takehiro Noda, TadafumiAsaoka, MiR-181b-5p, ETS1 and c-Met pathway exacerbates the prognosis of pancreatic ductal adenocarcinoma after radiation therapy. Cancer Sci 2017; 108: 398–407. [PMID: 23082047].
- Berger L, Shamai Y, Skorecki KL, Tzukerman M. Tumor Specific Recruitment and Reprogramming of Mesenchymal Stem Cells in Tumorigenesis. Stem Cells 2016; 34: 1011-26. [PMID: 26676563].
- Dang H, Steinway SN, Ding W, Rountree CB. Induction of tumor initiation is dependent on CD44s in c-Met(+) hepatocellular carcinoma. BMC Cancer 2015; 15: 161. [PMID: 25886575].
- Sattler M, Salgia R. c-Met and hepatocyte growth factor: potential as novel targets in cancer therapy. Curr Oncol Rep 2007; 9: 102-8. [PMID: 17288874].
- Sattler M, Salgia R. Role of c-MET in upper aerodigestive malignancies--from biology to novel therapies. J Environ Pathol Toxicol Oncol 2005; 24: 149-62. [PMID: 17288874].
- Maulik G, Shrikhande A, Kijima T, Ma PC, Morrison PT, Salgia R. Role of the hepatocyte growth factor receptor, c-Met, in oncogenesis and potential for therapeutic inhibition. Cytokine Growth Factor Rev 2002; 13: 41-59. [PMID: 11750879].
- Hass R, Jennek S, Yang Y, Friedrich K. c-Met expression and activity in urogenital cancers - novel aspects of signal transduction and medical implications. Cell Commun Signal 2017; 15: 10. [PMID: 28212658].
- Zhu GH, Huang C, Qiu ZJ, Liu J, Zhang ZH, Zhao N, et al. Expression and prognostic significance of CD151, c-Met, and integrin alpha3/alpha6 in pancreatic ductal adenocarcinoma. Dig Dis Sci 2011; 56: 1090-8. [PMID: 20927591].
- Di Renzo MF, Poulsom R, Olivero M, Comoglio PM, Lemoine NR. Expression of the Met/hepatocyte growth factor receptor in human pancreatic cancer. Cancer Res 1995; 55: 1129-38. [PMID: 7866999].
- Tan XG, Yang ZL. Expression of Ezrin, HGF, C-met in pancreatic cancer and non-cancerous pancreatic tissues of rats. Hepatobiliary Pancreat Dis Int 2010; 9: 639-44. [PMID: 21134835].
- Fitzgerald TL, McCubrey JA. Pancreatic cancer stem cells: association with cell surface markers, prognosis, resistance, metastasis and treatment. Adv Biol Regul 2014; 56: 45-50. .
- Li C, Wu JJ, Hynes M, Dosch J, Sarkar B, Welling TH, et al. c-Met is a marker of pancreatic cancer stem cells and therapeutic target. Gastroenterology 2011; 141: 2218-2227 e5. [PMID: 21864475].
- Neuzillet C, Couvelard A, Tijeras-Raballand A, de Mestier L, de Gramont A, Bédossa P, et al. High c-Met expression in stage I-II pancreatic adenocarcinoma: proposal for an immunostaining scoring method and correlation with poor prognosis. Histopathology 2015; 67: 664-76. [PMID: 25809563].
- Heiler S, Wang Z, Zöller M. Pancreatic cancer stem cell markers and exosomes - the incentive push. World J Gastroenterol 2016; 22: 5971-6007. [PMID: 27468191].
- Matsuda Y, Kure S, Ishiwata T. Nestin and other putative cancer stem cell markers in pancreatic cancer. Med Mol Morphol 2012; 45: 59-65. [PMID: 22718289].
- Salnikov AV, Liu L, Platen M, Gladkich J, Salnikova O, Ryschich E, et al. Hypoxia induces EMT in low and highly aggressive pancreatic tumor cells but only cells with cancer stem cell characteristics acquire pronounced migratory potential. PLoS One 2012; 7: e46391. [PMID: 23050024].
- Ma PC, Maulik G, Christensen J, Salgia R. c-Met: structure, functions and potential for therapeutic inhibition. Cancer Metastasis Rev 2003; 22: 309-25. [PMID: 12884908].
- Birchmeier C, Birchmeier W, Gherardi E, VandeWoude GF. Met, metastasis, motility and more. Nat Rev Mol Cell Biol 2003; 4: 915-25. [PMID: 14685170].
- Pons E, Uphoff CC, Drexler HG. Hepatocyte growth factor and its receptor, the tyrosine kinase encoded by the c-MET proto-oncogene. Cell Mol Biol (Noisy-le-grand) 1994; 4: 597-604. [PMID: 9716011].
- Kozlov G, Perreault A, Schrag JD, Park M, Cygler M, Gehring K, et al. Insights into function of PSI domains from structure of the Met receptor PSI domain. Biochem Biophys Res Commun 2004; 321: 234-40. [PMID: 15358240].
- Smyth EC, Sclafani F, Cunningham D. Emerging molecular targets in oncology: clinical potential of MET/hepatocyte growth-factor inhibitors. Onco Targets Ther 2014; 7:1001-14. [PMID: 24959087].
- Sheth PR, Hays JL, Elferink LA, Watowich SJ. Biochemical basis for the functional switch that regulates hepatocyte growth factor receptor tyrosine kinase activation. Biochemistry 2008; 47:4028-38. [PMID: 18324780].
- Peschard P, Fournier TM, Lamorte L, Naujokas MA, Band H, Langdon WY, et al. Mutation of the c-Cbl TKB domain binding site on the Met receptor tyrosine kinase converts it into a transforming protein. Mol Cell 2001; 8:995-1004. [PMID: 11741535].
- Sierra JR. c-MET as a potential therapeutic target and biomarker in cancer. Ther Adv Med Oncol 2011; 3:S21-35. [PMID: PMC3225018].
- Orian-Rousseau V, Chen L, Sleeman JP, Herrlich P, Ponta H. CD44 is required for two consecutive steps in HGF/c-Met signaling. Genes Dev 2002; 16: 3074-86. [PMID: 12464636].
- Orian-Rousseau V, Morrison H, Matzke A, Kastilan T, Pace G, Herrlich P, et al. Hepatocyte growth factor-induced Ras activation requires ERM proteins linked to both CD44v6 and F-actin. MolBiol Cell 2007; 18:76-83. [PMID: 17065554].
- Ponta H, Sherman L, Herrlich PA.CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 2003; 4: 33-45. [PMID: 12511867].
- Yoon S, Seger R. The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors 2006; 2: 21-44. [PMID: 16393692].
- Pelicci G, Giordano S, Zhen Z, Salcini AE, Lanfrancone L, Bardelli A, et al. The motogenic and mitogenic responses to HGF are amplified by the Shc adaptor protein. Oncogene 1995; 10: 1631-8. [PMID: 7731718].
- Hasenauer S, Malinger D, Koschut D, Pace G, Matzke A, von Au A, et al. Internalization of Met requires the co-receptor CD44v6 and its link to ERM proteins. PLoS One 2013; 8: e62357. [PMID: 23626807].
- Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene 2007; 26: 3279-90. [PMID: 17496922].
- Dunn KL, Espino PS, Drobic B, He S, Davie JR. The Ras-MAPK signal transduction pathway, cancer and chromatin remodeling. Biochem Cell Biol 2005; 83: 1-14. [PMID: 15746962].
- Schramek H, Schumacher M, Pfaller W. Sustained ERK-2 activation in rat glomerular mesangial cells: differential regulation by protein phosphatases. Am J Physiol 1996; 271: F423-32. [PMID: 8770175].
- Traverse S, Gomez N, Paterson H, Marshall C, Cohen P. Sustained activation of the mitogen-activated protein (MAP) kinase cascade may be required for differentiation of PC12 cells. Comparison of the effects of nerve growth factor and epidermal growth factor. Biochem J 1992; 288: 351-5. [PMID: 1334404].
- Reboul P, Pelletier JP, Tardif G, Benderdour M, Ranger P, Bottaro D, et al. Hepatocyte growth factor induction of collagenase 3 production in human osteoarthritic cartilage: involvement of the stress-activated protein kinase/c-Jun N-terminal kinase pathway and a sensitive p38 mitogen-activated protein kinase inhibitor cascade. Arthritis Rheum 2001; 44:73-84.
- Kyriakis JM, Banerjee P, Nikolakaki E, Dai T, Rubie EA, Ahmad MF, Avruch J, et al. The stress-activated protein kinase subfamily of c-Jun kinases. Nature 1994; 369: 156-60. [PMID: 8177321].
- Vlahopoulos S, Zoumpourlis VC. JNK: a key modulator of intracellular signaling. Biochemistry (Mosc) 2004; 69: 844-54. [PMID: 15377263].
- Rodrigues GA, Park M, Schlessinger J. Schlessinger, Activation of the JNK pathway is essential for transformation by the Met oncogene. EMBO J 1997; 16: 2634-45. [PMID: PMC1169874].
- Recio JA, Merlino G. Hepatocyte growth factor/scatter factor activates proliferation in melanoma cells through p38 MAPK, ATF-2 and cyclin D1. Oncogene 2002; 21:1000-8. [PMID: 11850817] .
- Perdiguero E, Ruiz-Bonilla V, Serrano AL, Muñoz-Cánoves P. Genetic deficiency of p38alpha reveals its critical role in myoblast cell cycle exit: the p38alpha-JNK connection. Cell Cycle 2007; 6:1298-303. [PMID: 17534150].
- Cuenda A, Rousseau S. p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta 2007; 1773: 1358-75. [PMID: 17481747].
- Chatterjee B, Wolff D, Jothi M, Mal M, Mal A, et al. p38alpha MAPK disables KMT1A-mediated repression of myogenic differentiation program. Skelet Muscle 2016; 6:28.
- Hui L, Bakiri L, Stepniak E, Wagner EF. p38alpha: a suppressor of cell proliferation and tumorigenesis. Cell Cycle 2007; 6: 2429-33. [PMID: 17957136].
- Guo JR, Li W, Wu Y, Wu LQ, Li X, Guo YF, et al. Hepatocyte growth factor promotes proliferation, invasion, and metastasis of myeloid leukemia cells through PI3K-AKT and MAPK/ERK signaling pathway. Am J Transl Res 2016; 8: 3630-3644. [PMID: 27725846].
- Togo S, Sugiura H, Nelson A, Kobayashi T, Wang X, Kamio K, et al. Hepatic growth factor (HGF) inhibits cigarette smoke extract induced apoptosis in human bronchial epithelial cells. Exp Cell Res 2010; 316: 3501-11. [PMID: 20850432].
- Pedranzini L, Leitch A, Bromberg J. Stat3 is required for the development of skin cancer. J Clin Invest 2004; 114: 619-22. [PMID: 15343379].
- Boccaccio C, Andò M, Tamagnone L, Bardelli A, Michieli P, Battistini C, et al. Induction of epithelial tubules by growth factor HGF depends on the STAT pathway. Nature 1998; 391: 285-8. [PMID: 9440692].
- Kermorgant S, Parker PJ. Receptor trafficking controls weak signal delivery: a strategy used by c-Met for STAT3 nuclear accumulation. J Cell Biol 2008; 182: 855-63. [PMID: 18779368].
- Cramer A, Kleiner S, Westermann M, Meissner A, Lange A, Friedrich K. Activation of the c-Met receptor complex in fibroblasts drives invasive cell behavior by signaling through transcription factor STAT3. J Cell Biochem 2005; 95: 805-16. [PMID: 15838885].
- Müller M, Morotti A, Ponzetto C. Activation of NF-kappaB is essential for hepatocyte growth factor-mediated proliferation and tubulogenesis. Mol Cell Biol 2002; 22:1060-72. [PMID: 1809798].
- DeMeester SL, Buchman TG, Cobb JP. Cobb, The heat shock paradox: does NF-kappaB determine cell fate. FASEB J 2001; 15: 270-274. [PMID: 11149915].
- Cecchi F, Rabe DC, Bottaro DP. Targeting the HGF/Met signaling pathway in cancer therapy. Expert OpinTher Targets 2012; 16:553-72. [PMID: 22530990].
- Blumenschein GR Jr, Mills GB, Gonzalez-Angulo AM. Targeting the hepatocyte growth factor-cMET axis in cancer therapy. J Clin Oncol 2012; 30: 3287-96. [PMID: 22869872].
- Yap TA, Sandhu SK, Alam SM, de Bono JS. HGF/c-MET targeted therapeutics: novel strategies for cancer medicine. Curr Drug Targets 2011; 12: 2045-58. [PMID: 21777195].
- Ghiso E, Giordano S. Targeting MET: why, where and how. Curr Opin Pharmacol 2013; 13: 511-8. [PMID: 23797036].
- Lee J, Seo JW, Jun HJ, Ki CS, Park SH, Park YS, et al. Impact of MET amplification on gastric cancer: possible roles as a novel prognostic marker and a potential therapeutic target. Oncol Rep 2011; 25: 1517-24. [PMID: 21424128].
- Liang H, Wang M. Mechanism of c-MET in Non-small Cell Lung Cancer and Its Treatment and Testing. Zhongguo Fei Ai ZaZhi 2015; 18: 745-51.
- Kiehne K, Herzig KH, Fölsch UR. c-met expression in pancreatic cancer and effects of hepatocyte growth factor on pancreatic cancer cell growth. Pancreas 1997; 15: 35-40. [PMID: 9211490].
- Gao H, Guan M, Sun Z, Bai C. High c-Met expression is a negative prognostic marker for colorectal cancer: a meta-analysis. Tumour Biol 2015; 36: 515-20. [PMID: 25636446].
- Thayaparan T, Spicer JF, Maher J. The role of the HGF/Met axis in mesothelioma. BiochemSoc Trans 2016; 44: 363-70. [PMID: 27068941] .
- Macher-Goeppinger S, Keith M, Endris V, Penzel R, Tagscherer KE1, Pahernik S, et al. MET expression and copy number status in clear-cell renal cell carcinoma: prognostic value and potential predictive marker. Oncotarget 2017; 8: 1046-1057. [PMID: 27894094].
- Jardim DL, Tang C, GagliatoDde M, Falchook GS, Hess K, Janku F, et al. Analysis of 1,115 patients tested for MET amplification and therapy response in the MD Anderson Phase I Clinic. Clin Cancer Res 2014; 20: 6336-45. [PMID: 25326232].
- Lengyel E, Prechtel D, Resau JH, Gauger K, Welk A, Lindemann K, et al. C-Met overexpression in node-positive breast cancer identifies patients with poor clinical outcome independent of Her2/neu. Int J Cancer 2005; 113: 678-82. [PMID: 15455388].
- Yamamoto S, Tsuda H, Miyai K, Takano M, Tamai S, Matsubara O. Gene amplification and protein overexpression of MET are common events in ovarian clear-cell adenocarcinoma: their roles in tumor progression and prognostication of the patient. Mod Pathol 2011; 24: 1146-55. [PMID: 21478826].
- An X, Wang F, Shao Q, Wang FH, Wang ZQ, Wang ZQ, et al. MET amplification is not rare and predicts unfavorable clinical outcomes in patients with recurrent/metastatic gastric cancer after chemotherapy. Cancer 2014; 120: 675-82. [PMID: 24804300].
- Graziano F, Galluccio N, Lorenzini P, Ruzzo A, Canestrari E, D'Emidio S, et al. Genetic activation of the MET pathway and prognosis of patients with high-risk, radically resected gastric cancer. J ClinOncol 2011; 29: 4789-95. [IMPT: 22042954].
- Lorenzato A, Olivero M, Patanè S, Rosso E, Oliaro A, Comoglio PM, et al. Novel somatic mutations of the MET oncogene in human carcinoma metastases activating cell motility and invasion. Cancer Res 2002; 62: 7025-30. [PMID: 12460923].
- Park WS, Oh RR, Kim YS, Park JY, Shin MS, Lee HK, Lee SH, et al. Absence of mutations in the kinase domain of the Met gene and frequent expression of Met and HGF/SF protein in primary gastric carcinomas. APMIS 2000; 108: 195-200. [PMID: 10752688].
- Moon YW, Weil RJ, Pack SD, Park WS, Pak E, Pham T, et al. Missense mutation of the MET gene detected in human glioma. Mod Pathol 2000; 13: 973-7. [PMID: 11007037].
- Tang SC, Chen YC. Novel therapeutic targets for pancreatic cancer. World J Gastroenterol 2014; 20: 10825-44. [PMID: 25152585].
- D'Amico L, Belisario D, Migliardi G, Grange C, Bussolati B, D'Amelio P et al. C-met inhibition blocks bone metastasis development induced by renal cancer stem cells. Oncotarget 2016; 7 45525-45537. [PMID: 27322553].
- Patel MB, Pothula SP, Xu Z, Lee AK, Goldstein D, Pirola RC, et al. The role of the hepatocyte growth factor/c-MET pathway in pancreatic stellate cell-endothelial cell interactions: antiangiogenic implications in pancreatic cancer. Carcinogenesis 2014; 35: 1891-900. [PMID: 24876152].
- Patel MB, Pothula SP, Xu Z, Lee AK, Goldstein D, Pirola RC, et al. The hepatocyte growth factor/c-Met signaling pathway as a therapeutic target to inhibit angiogenesis. BMB Rep 2008; 41: 833-9. [PMID: 24876152].
- Matsumoto K, Nakamura T. NK4 gene therapy targeting HGF-Met and angiogenesis. Front Biosci 2008; 13: 1943-51. [PMID: 17981681].
- Tomioka D, Maehara N, Kuba K, Mizumoto K, Tanaka M, Matsumoto K, et al. Inhibition of growth, invasion, and metastasis of human pancreatic carcinoma cells by NK4 in an orthotopic mouse model. Cancer Res 2001; 61: 7518-24. [PMID: 11606388].
- Giordano S, Columbano A. Met as a therapeutic target in HCC: facts and hopes. J Hepatol 2014. 60: 442-52. [PMID: 24045150].
- Lu KV, Chang JP, Parachoniak CA, Pandika MM, Aghi MK, Meyronet D, et al. VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer Cell 2012; 22: 21-35.[PMID: 22789536].
- Sengupta S, Gherardi E, Sellers LA, Wood JM, Sasisekharan R, Fan TP. Hepatocyte growth factor/scatter factor can induce angiogenesis independently of vascular endothelial growth factor. Arterioscler Thromb Vasc Biol 2003; 23: 69-75. [PMID: 12524227].
- Ide T, Kitajima Y, Miyoshi A, Ohtsuka T, Mitsuno M, Ohtaka K, et al. The hypoxic environment in tumor-stromal cells accelerates pancreatic cancer progression via the activation of paracrine hepatocyte growth factor/c-Met signaling. Ann Surg Oncol 2007; 14: 2600-7. [PMID: 17534684].
- Ide T, Kitajima Y, Miyoshi A, Ohtsuka T, Mitsuno M, Ohtaka K, et al. Tumor-stromal cell interaction under hypoxia increases the invasiveness of pancreatic cancer cells through the hepatocyte growth factor/c-Met pathway. Int J Cancer 2006; 119: 2750-9. [PMID: 16998831].
- Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 2003; 3: 347-61. [PMID: 12726861].
- Loges S, Mazzone M, Hohensinner P, Carmeliet P. Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited. Cancer Cell 2009; 15: 167-70. [PMID: 19249675].
- You WK, Sennino B, Williamson CW, Falcón B, Hashizume H, Yao LC, et al. VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer. Cancer Res 2011; 71: 4758-68. [PMID: 21613405 ].
- Zhao Y, Adjei AA. Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular Endothelial Growth Factor. Oncologist 2015; 20: 660-73. [PMID: 26001391].
- Choi HJ, Armaiz Pena GN, Pradeep S, Cho MS, Coleman RL, Sood AK. Anti-vascular therapies in ovarian cancer: moving beyond anti-VEGF approaches. Cancer Metastasis Rev 2015; 34: 19-40.
- Hidalgo M. Pancreatic cancer. N Engl J Med 2010; 362:1605-17.
- Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014. 74: 2913-21. [PMID: 24840647].
- Carrato, A., et al., A Systematic Review of the Burden of Pancreatic Cancer in Europe: Real-World Impact on Survival, Quality of Life and Costs. J Gastrointest Cancer, 2015. 46(3): p. 201-11.
- Haberle, L., et al., [Metastasis of pancreatic tumors]. Pathologe, 2015. 36 Suppl 2: p. 176-80.
- Perugini RA, McDade TP, Vittimberga FJ Jr, Callery MP. The molecular and cellular biology of pancreatic cancer. Crit Rev Eukaryot Gene Expr 1998; 8: 377-93. [PMID: 9807701].
- Hage C, Rausch V, Giese N, Giese T, Schönsiegel F, Labsch S, et al. The novel c-Met inhibitor cabozantinib overcomes gemcitabine resistance and stem cell signaling in pancreatic cancer. Cell Death Dis 2013 4: e627. [PMID: 23661005].
- Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, et al. Identification of human brain tumour initiating cells. Nature 2004; 432: 396-401. [PMID: 15549107].
- Matsushita A, Götze T, Korc M. Gotze, and M. Korc, Hepatocyte growth factor-mediated cell invasion in pancreatic cancer cells is dependent on neuropilin-1. Cancer Res 2007; 67: 10309-16. [PMID: 17974973].
- Hasegawa Y, Yamamoto M, Maeda S, Saitoh Y. Hepatocyte growth-factor and its receptor C-met regulate both cell-growth and invasion of human pancreatic-cancer. Int J Oncol 1995; 7: 877-81. [PMID: 21552917].
- Jin H, Yang R, Zheng Z, Romero M, Ross J, Bou-Reslan H, et al. MetMAb, the one-armed 5D5 anti-c-Met antibody, inhibits orthotopic pancreatic tumor growth and improves survival. Cancer Res 2008; 68: 4360-8. [PMID: 18519697].
- Kitajima Y, Ide T, Ohtsuka T, Miyazaki K. Induction of hepatocyte growth factor activator gene expression under hypoxia activates the hepatocyte growth factor/c-Met system via hypoxia inducible factor-1 in pancreatic cancer. Cancer Sci 2008; 99: 1341-7. [PMID: 18422749].
- Apte MV, Xu Z, Pothula S, Goldstein D, Pirola RC, Wilson JS. Pancreatic cancer: The microenvironment needs attention too! Pancreatology 2015; 15: S32-8. [PMID: 25845856].
- Aghamaliyev U, Hajiyeva Y, Rückert F. Desmoplastic Reaction In Pancreatic Ductal Adenocarcinoma. Pancreas - Open Journal 2016; 1:22-29.
- Neesse A, Michl P, Frese KK, Feig C, Cook N, Jacobetz MA, et al. Stromal biology and therapy in pancreatic cancer. Gut 2011; 60: 861-8. [PMID: 20966025].
- Yasui T, Ohuchida K, Zhao M, Onimaru M, Egami T, Fujita H, et al. Tumor-stroma interactions reduce the efficacy of adenoviral therapy through the HGF-MET pathway. Cancer Sci 2011; 102: 484-91. [PMID: 21105966].
- Apte MV, Park S, Phillips PA, Santucci N, Goldstein D, Kumar RK, et al. Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells. Pancreas 2004; 29: 179-87. .
- Whatcott CJ, Diep CH, Jiang P, Watanabe A, LoBello J, Sima C, et al. Desmoplasia in Primary Tumors and Metastatic Lesions of Pancreatic Cancer. Clin Cancer Res 2015; 21: 3561-8. [PMID: 25695692].
- Qian LW, Mizumoto K, Maehara N, Ohuchida K, Inadome N, Saimura M, et al. Co-cultivation of pancreatic cancer cells with orthotopictumor-derived fibroblasts: fibroblasts stimulate tumor cell invasion via HGF secretion whereas cancer cells exert a minor regulative effect on fibroblasts HGF production. Cancer Lett 2003; 190: 105-12. [PMID: 12536083].
- Rizwani W, Allen AE, Trevino JG. Trevino, Hepatocyte Growth Factor from a Clinical Perspective: A Pancreatic Cancer Challenge. Cancers (Basel) 2015; 7: 1785-805. [PMID: 26404380].
- Niina Y, Ito T, Oono T, Nakamura T, Fujimori N, Igarashi H, et al. A sustained prostacyclin analog, ONO-1301, attenuates pancreatic fibrosis in experimental chronic pancreatitis induced by dibutyltin dichloride in rats. Pancreatology 2014; 14: 201-10. [PMID: 24854616 ].
- Xu D, Matsuo Y, Ma J, Koide S, Ochi N, Yasuda A, et al. Cancer cell-derived IL-1alpha promotes HGF secretion by stromal cells and enhances metastatic potential in pancreatic cancer cells. J Surg Oncol 2010; 102: 469-77. [PMID: 20872950].
- Sennino B, Ishiguro-Oonuma T, Schriver BJ, Christensen JG, McDonald DM. Inhibition of c-Met reduces lymphatic metastasis in RIP-Tag2 transgenic mice. Cancer Res 2013; 73: 3692-703. [PMID: 23576559].
- Matzke-Ogi A, Jannasch K, Shatirishvili M, Fuchs B, Chiblak S, Morton J, et al., Inhibition of Tumor Growth and Metastasis in Pancreatic Cancer Models by Interference With CD44v6 Signaling. Gastroenterology 2016; 150:513-25.e10. [PMID: 26597578].
- Shah AN, Summy JM, Zhang J, Park SI, Parikh NU, Gallick GE. Development and characterization of gemcitabine-resistant pancreatic tumor cells. Ann Surg Oncol 2007; 14: 3629-37. [PMID: 17909916].