The Met tyrosine kinase receptor as a therapeutic target and a potential cancer stem cell factor responsible for therapy resistance (Review)

  • Authors:
    • Katarzyna Miekus
  • View Affiliations

  • Published online on: December 7, 2016     https://doi.org/10.3892/or.2016.5297
  • Pages: 647-656
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

The MET tyrosine kinase receptor plays an important role during tumor development and progression being responsible for proliferation, morphogenetic transformation, cell motility and invasiveness. High expression of the MET receptor has been shown to correlate with increased tumor growth and metastasis, poor prognosis and resistance to radiotherapy. Moreover, MET expression and activation has been shown to be associated with therapy resistance. The occurrence of resistance to targeted therapy might be related to the presence of cancer stem cells (CSCs). CSCs are a subpopulation of cells in the tumor that possess the ability of self-renewal, clonogenicity, radioresistance and self-sustained protection from apoptosis. Recently, MET has been postulated as an essential factor supporting the functional stem cell phenotype in some tumors and as a CSC factor is believed to be responsible for therapy resistance. This review presents the results from recent studies identifying MET as a potential marker of CSCs and tumor initiating cells, demonstrating pivotal role of MET in supporting stem cell phenotype and indicating the role of MET in acquiring resistance to antitumor therapy.

Introduction

The major problem in the fight against cancer is metastatic disease and growing resistance to available therapies. Therefore, it is important to understand the mechanisms responsible for the emergence and development of tumors to establish novel molecular-based strategies to enable a more successful destruction of aggressive tumor disease.

One of the well-known factors connected with tumor growth and metastasis is the MET receptor (1). The MET tyrosine kinase receptor together with its ligand, hepatocyte growth factor (HGF) also known as scatter factor (SF), was identified to play a key role during embriogenesis (25). At the early stages of development, HGF and MET, are expressed in endoderm and mesoderm and act in an autocrine manner (2). Later, during organogenesis, MET is expressed in epithelial cells of many organs (liver, kidney, lung and skin), whereas HGF in mesenchymal cells (2). Moreover, MET is expressed in some myoblasts and neuronal precursors, and contributes to the development of muscular and nervous structures (2,5). Crucial role of MET during embryogenesis was confirmed in experiments with knockout mice that died in utero at E15 (4). HGF/MET axis is also important in the process of skin, liver and kidney regeneration (6,7).

Ligand-induced MET activation leads to phosphorylation of tyrosine residues (Tyr1230, Tyr1234 and Tyr1235) in the kinase domain of the receptor and allows binding of effector proteins, such as Gab1, Grb2, Shc, PI3K, Src, STAT3 or PLCγ (8). It activates mainly the RAS-MAPK and PI3K-AKT pathways leading to pleiotropic biological effects on various target cells including the induction of cell proliferation, morphogenetic transformation, cell motility and invasiveness under both normal and pathological conditions (911). The last findings also indicate that MET is able to act through c-Abl and p-38-MAPK to induce p53 phosphorylation and promotes cell survival (12).

The MET receptor is considered a good candidate for targeted therapies (13). However, although MET seems to be a very good target in development of new strategies, both in vitro and in vivo studies have shown that prolonged usage of tyrosine kinase inhibitors results in resistance to treatment and MET has been proposed as a new factor responsible for therapy resistance (14,15). Resistance to treatment is the major limitation and problem of contemporary oncology. This phenomenon may be partially related to the presence of cancer stem cells (CSCs).

The isolation and characterization of CSCs was begun by Lapidot and colleagues (16) who showed that a small population of human acute myeloid leukemic (AML) cells, were capable of initiating human AML after transplantation into severe combined immune-deficient (SCID) mice (16). CSCs as defined by the American Association for Cancer Research (AACR) workshop on CSCs, are a subpopulation of cells in the tumor that have self-renewal capacity and can give rise to heterogeneous cancer cells that comprise the tumor (17). CSCs are defined as cancer-initiating cells (CICs) as well, because of their property of retaining long-term self-renewal ability in vitro, and driving clonal expansion in xenotransplantation assays (18,19). CSCs are inherently resistant to radiochemotherapy owing to efficient DNA repair and self-sustained protection from apoptosis (18,20,21). Growing evidence shows that CSCs are responsible for resistance to conventional therapies, and thus, are the most likely cause of tumor recurrence (22). It has been postulated that stemness features of CSCs allow them to escape conventional antitumor therapy and maintain minimal residual disease, resulting in tumor relapse (23). Recently, it has been shown, in samples from patient tumors, that CSC marker expression is associated with a poorer clinical results and may have prognostic value (2426). However, identifying markers, that could better characterize and isolate a population of CSCs for some tumors, remains challenging and recently, several potential candidates have been proposed.

The MET receptor has been postulated as an essential factor responsible for the functional cancer stem cell phenotype in some tumors and as a CSC factor is believed to be responsible for therapy resistance. The present review provides examples that MET may be a potential cancer stem cell factor responsible for drug resistance and tumor relapse.

MET receptor in cancer

In the early 1990s it was shown that mouse and human cell lines with overexpression of HGF and/or MET become tumorigenic and metastatic in nude mice and the level of MET and HGF directly correlates with invasiveness and metastatic process (27). Nowadays, it is well documented that deregulation of MET expression and activity is characteristic for multiple cancer types and is a key event underlying tumor progression and metastasis (1). A large number of studies show that HGF and/or MET are frequently expressed in human carcinomas and in other types of solid tumors and in their metastases (1). MET overexpression has been demonstrated in a variety of tumors, including lung, breast, ovary, cervical, kidney, colon, thyroid, liver, gastric carcinomas, glioma and osteosarcoma (2841). Activating point mutations of MET occur in sporadic and inherited human renal carcinomas, hepatocellular carcinomas and several other cancer types (33,35,42).

Moreover, in case of MET and/or its ligand HGF, overexpression or misexpression often correlates with poor prognosis (1,31,33,37). MET was shown to be more frequently amplified in advanced stage of colorectal and gastric cancers suggesting its role in the metastatic process of malignant progression (33,43,44). It was demonstrated for human head and neck cancers that activating mutations of MET are clonally selected during the process of metastasis and its level increased from 2% in the primary tumors to 50% in the metastases (45). Interestingly enough, MET expression may vary within the same tumor. As Pennacchietti and colleagues showed (46) both in carcinoma and sarcoma cells hypoxia promotes the expression of met protooncogene and hypoxic areas overexpress the MET receptor leading to activation of invasive growth (46). It was also shown that MET-positive cells within glioblastoma are located close to the nearest blood vessels (47). MET positive cells co-express glioblastoma stem cell markers, CD133 and CD15, compared with MET-negative cells. Moreover, MET expression was efficient in inducing tumor formation regardless of CD133 expression (47). CD133 glycoprotein has been widely used to purify hematopoietic stem and progenitor cells and it was shown to define a subpopulation of brain tumor cells with significantly increased capacity for tumor initiation in xenograft models (48,49). The authors suggest that MET signaling was responsible for glioblastoma stem cell maintenance, migration and resistance to radiation (47).

The group of Comoglio (50) revealed that MET could be genetically selected for the long-term maintenance of the primary transformed phenotype, and some tumors were dependent on sustained MET activity for their growth and survival (51). Moreover, they proposed that MET overexpression in tumors is not only due to transcriptional induction at single-cell level but also expansion of the stem/progenitor subpopulation of cells inherently expressing MET (52). It has been also shown that cells displaying high MET copy number, overexpression of this receptor and ligand-independent constitutive activation, are addicted to this oncogene and responsive to anti-MET drugs (5356).

MET receptor as a prognostic marker

High MET expression pattern is currently associated with increased tumor growth rate and metastasis, poor prognosis and resistance to radiotherapy (5759). MET overexpression has been postulated as a prognostic factor in lung (60,61), breast (62), head and neck (63), gastric (64), ovarian (65) and clear cell renal cell carcinoma (66). MET overexpression is also associated with poor prognosis and tumor invasiveness in glioblastoma patients (67,68). It has been demonstrated that enhanced level of MET in primary colorectal cancer may predict tumor invasion and metastatic process (69). High MET protein level and its activation, resulting from MET amplification, have been reported as associated with a poor prognosis in colorectal and gastric cancers (33,44,64). It was also shown that MET overexpression was significantly associated with worse 3- and 5-year overall survival, progression-free survival and distant metastases in cervical cancer patients (70). Similar results were obtained after a follow-up of 50 months for multiple myeloma patients, where high MET mRNA expression characterized a worse progression-free and overall survival (71). Moreover, co-expression of the MET receptor together with CD47 was proposed as a novel prognostic factor for survival of patients suffering from luminal breast cancer (72). Another study proposed the MET receptor as independent predictor of decreased 5-year survival of patients with invasive ductal breast carcinoma (62). Similar results were obtained by the Edakuni group (73) and showed correlation between co-expression of HGF and MET in breast cancer, histologic grade and reduced patient survival (73). All these examples highlight MET as a prognostic factor whose presence and activity is important for the overall survival and development of metastatic disease in tumor patients.

Resistance to MET inhibitors

The HGF-MET pathway has been proven to be an attractive drug target for antitumor therapies. Several monoclonal antibodies or small molecules targeting HGF or MET have been discovered and used in monotherapy, in combination with other targeted therapy or with chemotherapy (13). Despite encouraging results involving the use of MET inhibitors in the laboratory and in clinical trials, as well as in studies with other RTK inhibitors, it has been suggested that resistance will develop even in the subset of cancers that initially derive clinical benefits (14,15). Several possible mechanisms of resistance to MET inhibitors such as, MET point mutations, amplification or MET gene overexpression, activation of MET parallel pathways or amplification of the KRAS gene, have been described (7476). Cepero and colleagues (74) established cell lines resistant to long-term treatment with MET inhibitors and showed that prolonged exposure to increasing doses of c-MET inhibitors leads to amplification, overexpression and activation of wild-type MET and KRAS in gastric cell lines. Furthermore, they observed strong activation of the mitogen-activated protein kinase (MAPK) pathway (74).

Another mechanism of resistance showed that cells developed resistance by acquired mutation in the MET activation loop or activated epidermal growth factor receptor pathway due to increased expression of transforming growth factor α (75). Two other studies showed that overexpression of HER family members in gastric carcinoma cells and non-small cell lung cancer cells are responsible for acquired resistance to MET kinase inhibitors (76,77). The authors concluded that cells carrying high MET copy number will undergo an oncogenic switch that will create an ERBB tyrosine kinase dependency (76,77).

A recent study revealed the acquisition of secondary resistance to MET monoclonal antibodies. In a very elegant study of Martin and coworkers (78), MET-addicted lung cancer cells continuously treated with MET monoclonal antibody became resistant to treatment, as a result of an increase of MET gene copy number and MET overexpression. However, MET antibody resistant cells were sensitive to MET-specific small tyrosine kinase inhibitors (TKIs) and acquired drug-dependence. Moreover, cells resistant to MET TKIs can still be sensitive to treatment with the antibody. The authors suggest that a discontinuous, combined treatment by antibodies and chemical kinase inhibitors may increase the clinical response and bypass resistance to anti-MET targeted therapies through synergistic effect on tumor cells (78). The results demonstrate that despite the acquired resistance to one type of inhibitors, it is possible to use another type and achieve good therapeutic effects. Furthermore, these results show the importance of MET as a therapeutic target.

MET inhibition overcomes drug resistance

Both in vitro and in vivo studies have shown that prolonged treatment with tyrosine kinases inhibitors (TKIs) results in resistance to treatment and MET receptor has been proposed as a new factor responsible for resistance to targeted therapies including epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), human epidermal receptor 2 (HER-2) and B-raf (BRAF) inhibitors (14,15). This phenomenon was demonstrated for the first time in lung cancers driven by mutations in the EGF receptor (79). In the study, 22% of patients who developed resistance to gefinitib, selective inhibitor of EGFR kinase, demonstrated amplification of the MET proto-oncogene. The amplification of MET driven ERBB3 (Erb-B2 receptor tyrosine kinase 3) dependent activation of PI3K, a pathway specific to the EGFR/ERBB family receptors, suggests that MET amplification may promote drug resistance in other ERBB-driven cancers (79). It is worth noting, that inhibition of MET signaling restored sensitivity to gefitinib (79,80). Another study reported that MET, as an RTK frequently coexpressed with Her2, in Her2 positive breast cancer, contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells through sustained AKT activation (81).

HGF-MET axis was also shown to be involved in resistance to anti-VEGR therapy. In tumors resistant to inhibitor of VEGF pathway, sunitinib, after treatment with highly selective MET inhibitor, PF-04217903, together with sunitinib, tumor growth was inhibited (82). The study on renal cell carcinoma model demonstrated that the MET receptor is involved in sunitinib acquired resistance (83). Combined treatment with the VEGF and MET inhibitors induced prolonged survival and inhibited tumor growth in mice giving hope for potential therapeutic use in the clinical treatment (83).

In light of these data MET seems to be a very good target for tumors resistant to tyrosine kinase targeted therapies. However, the activity and function of the receptor depend on the cell type and heterogeneity of tumors. Recent studies connect the presence of the MET receptor with cancer stem cell phenotype.

MET receptor and stem cells

It has been demonstrated that the MET receptor is expressed in stem/progenitor cells in various types of adult normal tissues and maintains stem cell properties. The MET receptor was considered as a putative pancreatic stem/progenitor cell marker in adult mouse pancreas (84,85). In the developing liver, cells expressing MET can form stem cell colonies in vitro and migrate and differentiate into liver parenchymal cells and cholangiocytes when they were transplanted into the spleen or liver of mice subjected to liver injury (86). The essential role of the HGF/MET axis in hepatocyte-mediated liver regeneration, was shown by Ishikawa and colleagues with the use of MET knockout mice (87). In the liver, the MET receptor supported survival, proliferation, sphere formation and differentiation properties of oval cells (87). Another study showed that MET, in cardiac stem cells and early committed cells, is responsible for proliferation, survival, migration and regeneration of the infracted myocardium and improvement of ventricular function (88).

The study by Chmielowiec et al (89) underlined a fundamental role of MET during regenerative process in the adult skin. The authors demonstrated that MET signaling not only controls growth and migration of keratinocytes during embryogenesis but is also essential for the generation of the hyperproliferative epithelium in skin wounds (89). It was also demonstrated that MET signaling is a key mechanism in maintaining stem cell niche in brain important for neural stem cell growth and self-renewal (90).

MET receptor and cancer stem cells

Recently, the MET receptor has been postulated as an essential factor responsible for the functional CSCs phenotype in some tumors. It was reported that MET expression was associated with glioblastoma stem cells (GSCs) identified by prospective isolation from fresh tumors (47) or with neurospheres endowed with specific genetic/molecular features (91). Furthermore, MET was considered to play a central role in maintaining CSC populations in human glioblastoma multiforme (GBM), suggesting a link between MET signaling and CSCs (91,92). Other studies, on GBM cell subpopulations, showed that only cells expressing high level of MET retained clonogenic, tumorigenic and radioresistant properties, features of CSCs (47,91). The authors demonstrated pivotal role of MET in supporting the pool of GBM SCs (47). They used freshly isolated patient-derived GBM cells and provided evidence suggesting that MET plays critical role in SC maintenance, migration and resistance to radiation (47). Subpopulation with high MET level displayed enhanced kinetics growth and was highly tumorigenic in vivo as well (47,91). Moreover, only small population of GBM cells has been shown to be positive for the MET receptor and to contain amplification of MET, independent of other RTKs (93,94). The study by Li et al (95) involved MET as a novel, functional, stem cell marker for pancreatic adenocarcinoma. The authors identified the population with a high expression of MET and suggested that the receptor regulates SCs proliferation, cell renewal and has the ability to form tumors in NOD/SCID mice (95). This study also showed that the use of the MET inhibitor or small hairpin RNAs in pancreatic adenocarcinoma significantly inhibited tumor sphere formation and self-renewal capacity (95). In pancreatic tumors established in NOD SCID mice, MET inhibition decreased tumor growth, reduced the population of CSCs and prevented the development of metastases (95). The study of Sun and Wang (96) on human head and neck squamous cell carcinoma (HNSCC) demonstrated that MET expressing cells have the capacity for self-renewal (96). Furthermore, the MET receptor was responsible for tumor formation and metastatic process in NOD/SCID mice and cisplatin resistance (96). It was also shown that the HGF/MET axis regulates stem- like phenotype in human prostate cancer (97). The study of Gastaldi and coworkers (98) emphasized the role of MET in breast tumorigenesis. The authors showed that MET acts as a critical regulator of luminal cell proliferation and differentiation in the context of murine mammary morphogenesis (98). Moreover, the authors presented that MET is preferentially expressed in luminal progenitors and its activation stimulates clonogenic activity in vitro, confers repopulating potential in vivo and promotes aberrant branching morphogenesis (98). Table I summarizes the data with reference to MET expression correlated with cancer stem cell phenotype.

Table I.

MET expression and cancer stem cell phenotype.

Table I.

MET expression and cancer stem cell phenotype.

Tumor typeRefs.
Breast cancer(98)
Colon cancer(115)
Glioblastoma(47,91,92,103)
Head and neck(96)
Pancreatic adenocarcinoma(95)
Prostate cancer(97)

[i] Association of MET expression with the stem/progenitor status.

Our study on rhabdomyosarcoma showed that silencing of the MET receptor stimulates tumor cell differentiation and activation of MET signaling may be the cause of its development and progression (99,100). We have also demonstrated that cervical cancer cells depend on sustained MET activity for their growth and survival and downregulation of MET decreased tumor growth and forced tumor differentiation in vivo (101). Our observation on cervical cancer patient samples revealed that low level of MET accompanied low-grade squamous intraepithelial lesion, whereas increased heavily in high-grade squamous intraepithelial lesion and invasive carcinoma (101) (Fig. 1).

MET receptor and stem cell markers

The MET receptor not only supports stem-like phenotype of cancer cells but also affects the expression and activity of stem cell markers. It has been shown that MET signaling can regulate glioma subpopulations and expand the pool of stem-like cells. The study of Li and colleagues (92) revealed that MET positively correlates with stem cell marker expression and the neoplastic stem cell phenotype in glioblastoma neurospheres, as well as in clinical glioblastoma specimens. MET expression and activation influences the expression of reprogramming transcription factors known to support embryonic stem cells, Sox2, Klf4, c-Myc, Oct4 and Nanog, known to induce stem-like properties in differentiated cells (92,102). Moreover, MET enhances stem cell characteristics of neurosphere formation and neurosphere cell self-renewal (92). The MET receptor supports the GBM SC phenotype by involving an endogenous dynamic mechanism analogous to cellular reprogramming (92). It was shown that MET-positive cells expressed high levels of stemness transcriptional regulators, Oct4, Nanog and Klf4, when compared to MET-negative cells and the activation of MET signaling increases the expression of the Oct4, Nanog and Klf4 (103). The expression returned to basal levels in response to MET inhibition (103). It was also shown that MET induces a stem-like phenotype in prostate cancer and is expressed together with stem-like markers CD49b and CD49f and (97). Another study reported that cabozantinib, a novel inhibitor of MET, downregulated CSC markers, SOX2 and CD133, induced apoptosis and increased efficacy of gemcitabine, currently used in standard therapy for advanced pancreatic cancer (104).

In our study, we have reported that blocking of the MET receptor could influence expression and function of the chemokine CXCR4 receptor in rhabdomyosarcoma and cervical carcinoma cells (99,101). Cells with decreased MET expression had impaired intracellular signaling and chemotaxis toward SDF-1 gradient, a ligand of the CXCR4 receptor, which was in accordance with decreased expression of CXCR4 (99,101). CXCR4 overexpression and hyperactivation was shown for the first time to correlate with the metastatic ability of breast cancer cells (105). Since that time, the SDF-1-CXCR4 axis has been shown to be involved in the regulation of metastasis to organs that highly express SDF-1 (e.g., lymph nodes, lungs, liver and bones) (106). It was postulated that cancer stem cells and trafficking of normal stem cells involve similar mechanisms regulated partially by CXCR4 (107).

Table II summarizes the study of the correlation between the MET receptor and cancer stem cell markers.

Table II.

MET expression and cancer stem cell factors.

Table II.

MET expression and cancer stem cell factors.

Stem cell markerFunctionTumor typeRefs.
Sox2Transcription factorGlioblastoma pancreatic cancer(92,104)
Klf4Transcription factorGlioblastoma(92,103)
c-MycTranscription factorGlioblastoma(92)
Oct4Transcription factorGlioblastoma(92,103)
NanogTranscription factorGlioblastoma(92,103)
CD49bα2 integrinProstate cancer(97)
CD49fα6 integrin subunitProstate cancer(97)
CD133Stem cell biomarkerPancreatic cancer(104)
CXCR4Chemokine receptorRhabdomyosarcoma, cervical carcinoma(99,101)

[i] Correlation of MET receptor and stem/progenitor factors.

MET as a CSC factor responsible for therapy resistance

Growing evidence shows that CSCs are responsible for resistance to conventional therapies, and thus, are the most likely cause of tumor recurrence (22). It has been postulated that stemness features of CSCs would allow them to escape conventional antitumor therapy and maintain minimal residual disease, leading to tumor relapse (23). It has been shown for breast cancer (108) and glioma (21) that CSCs survived after radiation, repaired their damaged DNA more efficiently than their non-CSC counterparts and began the process of self-renewal (21,108). Recently, it has been shown, in samples from patient tumors, that CSC marker expression is associated with a poor clinical outcome and may have prognostic value (2426,109).

The study of Bardelli and colleagues (110) with the use of human colorectal cancer metastases xenografted in mice, demonstrated that amplification of the MET oncogene is a mechanism of both primary and secondary resistance to anti-EGFR therapies. In the study by Jun et al (103) the authors used a mouse model of GBM and demonstrated that treatment of EGFR-positive GBM with gefitinib, a TKI, results in the induction of MET expression in a subset of cells that have GSC characteristics. MET signaling was a requisite for initiation and maintenance of the GSC features. The results emphasized the capacity for MET to support the GSC phenotype that involves an endogenous dynamic mechanism analogous to cellular reprogramming (103). It was also presented that MET amplification mediates in developing of EGFR tyrosine kinase inhibitors resistance in EGFR-mutant lung cancer cells (111,112). The authors showed that small population of cells carrying MET amplification may pre-exist in EGFR-mutated lung cancers. These cells, not driven by EGFR mutations, can be positively selected by therapy with EGFR inhibitors and sustain resistance to EGFR inhibitors (111). It was demonstrated that the response to specific inhibitors was efficiently counteracted by a variety of growth factors with prominent role of the MET receptor ligand HGF (111,112). BRAF-mutant melanomas or ERBB2-driven carcinomas have been also rescued from drug sensitivity by exposing them to HGF (113,114). Recent study of Luraghi and coworkers (115), showed that effects of EGFR inhibition in sensitive colorectal cancer initiating cells (CCIC) could be counteracted by HGF supporting in vitro CCIC proliferation and resistance to EGFR inhibition. It was also shown, for colon cancer, that HGF, secreted by tumor microenvironment, activates β-catenin-dependent transcription and thereby influences CSC clonogenicity and restores the CSC phenotype in more differentiated tumor cells both in vitro and in vivo (116,117).

All the observations are clinically appealing because combined treatment with an EGFR and MET inhibitor, specifically in patients with evidence of MET amplification at baseline, may lead to extended progression and better outcome.

A study showed that MET amplification together with EMT, and stem cell-like features are observed in non-small cell lung cancer cells with acquired resistance to Afatinib, an EGFR-TKI (118). It was also demonstrated that resistance of non-small lung cancer patients to EGFR inhibitors is due to EGFR T790M mutation and MET amplification (119). Moreover, the patients acquired resistance to the MET receptor inhibitors used as a therapeutic approach in clinical trials. The mechanism of the resistance involved ABCB1 overexpression, which was associated with CSC properties and EMT (119).

Taken together, MET involved in enhancing and maintaining cancer stem cell properties may be responsible for resistance to antitumor therapy (Fig. 2).

Conclusions

Targeted therapies with compounds inhibiting a specific target molecule opened a new direction in the treatment of cancer. The development of targeted therapies requires the identification of good targets that are known to play a key role in tumor cell growth and survival and are more effective and less toxic than previous standards of care involving cytotoxic therapies (120). Targeted therapy relies on the concept of ‘oncogene addiction’ that reveals a possible ‘Achilles heel’ of cancer cells, wherein they depend on a single oncogenic pathway for sustained proliferation and/or survival (121,122). This means that the inhibition of a single pathway, gene or protein to which they are addicted results in the inhibition of their growth or even their death (121). Unfortunately, targeted therapeutics in cancer has not yet met the high expectations of patients and physicians because some patients relapsed following treatment with specific inhibitors as a result of acquired resistance mechanisms (120,123). CSCs have been shown to be largely responsible for chemoresistant phenotypes in various tumors, thus, the development of new, targeted, effective therapies has become focused on identifying factors that drive and sustain CSCs. The CSC hypothesis predicts that only therapies that efficiently eliminate population of CSCs are able to induce long-term response and stop tumor recurrence. The activation of the MET receptor axis has been directly implicated in acquiring chemoresistance, maintaining clonogenicity and ability to self-renew in various tumor cell populations. In the light of our knowledge MET seems to have two faces: acts as a promising factor for developing personalized cancer therapy and as a factor responsible for cancer stem cell properties and therapy resistance.

Acknowledgements

The present study was supported by a grant from the National Science Centre (no. 2013/09/D/NZ5/00249) to K.M. The Faculty of Biochemistry, Biophysics and Biotechnology of the Jagiellonian University is a beneficiary of the structural funds from the European Union and the Polish Ministry of Science and Higher Education (grants nos. POIG.02.01.00-12-064/08 and 02.02.00-00-014/08) and is a partner of the Leading National Research Center (KNOW) supported by the Ministry of Science and Higher Education. I am very grateful to Mikolaj Przywara for language editing, proofreading and suggestions.

Glossary

Abbreviations

Abbreviations:

AML

acute myeloid leukemia

CCIC

colorectal cancer initiating cells

CICs

cancer-initiating cells

CSCs

cancer stem cells

EGFR

epidermal growth factor receptor

GBM

glioblastoma multiforme

GSCs

glioblastoma stem cells

HER

human epidermal receptor

HGF

hepatocyte growth factor

HNSCC

human head and neck squamous cell carcinoma

NOD/SCID

non-obese diabetic/severe combined immunodeficiency

NSCLC

non-small cell lung cancer

RTKs

receptor tyrosine kinases

SCs

stem cells

SCID

severe combined immune-deficient

SF

scatter factor

TKIs

tyrosine kinase inhibitors

References

1 

Birchmeier C, Birchmeier W, Gherardi E and Vande Woude GF: Met, metastasis, motility and more. Nat Rev Mol Cell Biol. 4:915–925. 2003. View Article : Google Scholar : PubMed/NCBI

2 

Andermarcher E, Surani MA and Gherardi E: Co-expression of the HGF/SF and c-met genes during early mouse embryogenesis precedes reciprocal expression in adjacent tissues during organogenesis. Dev Genet. 18:254–266. 1996. View Article : Google Scholar : PubMed/NCBI

3 

Schmidt C, Bladt F, Goedecke S, Brinkmann V, Zschiesche W, Sharpe M, Gherardi E and Birchmeier C: Scatter factor/hepatocyte growth factor is essential for liver development. Nature. 373:699–702. 1995. View Article : Google Scholar : PubMed/NCBI

4 

Uehara Y, Minowa O, Mori C, Shiota K, Kuno J, Noda T and Kitamura N: Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor. Nature. 373:702–705. 1995. View Article : Google Scholar : PubMed/NCBI

5 

Maina F, Hilton MC, Ponzetto C, Davies AM and Klein R: Met receptor signaling is required for sensory nerve development and HGF promotes axonal growth and survival of sensory neurons. Genes Dev. 11:3341–3350. 1997. View Article : Google Scholar : PubMed/NCBI

6 

Borowiak M, Garratt AN, Wüstefeld T, Strehle M, Trautwein C and Birchmeier C: Met provides essential signals for liver regeneration. Proc Natl Acad Sci USA. 101:10608–10613. 2004. View Article : Google Scholar : PubMed/NCBI

7 

Huh CG, Factor VM, Sánchez A, Uchida K, Conner EA and Thorgeirsson SS: Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc Natl Acad Sci USA. 101:4477–4482. 2004. View Article : Google Scholar : PubMed/NCBI

8 

Furlan A, Kherrouche Z, Montagne R, Copin MC and Tulasne D: Thirty years of research on met receptor to move a biomarker from bench to bedside. Cancer Res. 74:6737–6744. 2014. View Article : Google Scholar : PubMed/NCBI

9 

Kermorgant S, Aparicio T, Dessirier V, Lewin MJ and Lehy T: Hepatocyte growth factor induces colonic cancer cell invasiveness via enhanced motility and protease overproduction. Evidence for PI3 kinase and PKC involvement. Carcinogenesis. 22:1035–1042. 2001. View Article : Google Scholar : PubMed/NCBI

10 

Weidner KM, Sachs M and Birchmeier W: The Met receptor tyrosine kinase transduces motility, proliferation, and morphogenic signals of scatter factor/hepatocyte growth factor in epithelial cells. J Cell Biol. 121:145–154. 1993. View Article : Google Scholar : PubMed/NCBI

11 

Trusolino L, Bertotti A and Comoglio PM: MET signalling: Principles and functions in development, organ regeneration and cancer. Nat Rev Mol Cell Biol. 11:834–848. 2010. View Article : Google Scholar : PubMed/NCBI

12 

Furlan A, Stagni V, Hussain A, Richelme S, Conti F, Prodosmo A, Destro A, Roncalli M, Barilà D and Maina F: Abl interconnects oncogenic Met and p53 core pathways in cancer cells. Cell Death Differ. 18:1608–1616. 2011. View Article : Google Scholar : PubMed/NCBI

13 

Vigna E and Comoglio PM: Targeting the oncogenic Met receptor by antibodies and gene therapy. Oncogene. 34:1883–1889. 2015. View Article : Google Scholar : PubMed/NCBI

14 

Engelman JA and Settleman J: Acquired resistance to tyrosine kinase inhibitors during cancer therapy. Curr Opin Genet Dev. 18:73–79. 2008. View Article : Google Scholar : PubMed/NCBI

15 

Sierra JR, Cepero V and Giordano S: Molecular mechanisms of acquired resistance to tyrosine kinase targeted therapy. Mol Cancer. 9:752010. View Article : Google Scholar : PubMed/NCBI

16 

Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA and Dick JE: A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 367:645–648. 1994. View Article : Google Scholar : PubMed/NCBI

17 

Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL and Wahl GM: Cancer stem cells - perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 66:9339–9344. 2006. View Article : Google Scholar : PubMed/NCBI

18 

OBrien CA, Pollett A, Gallinger S and Dick JE: A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 445:106–110. 2007. View Article : Google Scholar : PubMed/NCBI

19 

Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C and De Maria R: Identification and expansion of human colon-cancer-initiating cells. Nature. 445:111–115. 2007. View Article : Google Scholar : PubMed/NCBI

20 

Chen J, Li Y, Yu TS, McKay RM, Burns DK, Kernie SG and Parada LF: A restricted cell population propagates glioblastoma growth after chemotherapy. Nature. 488:522–526. 2012. View Article : Google Scholar : PubMed/NCBI

21 

Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD and Rich JN: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 444:756–760. 2006. View Article : Google Scholar : PubMed/NCBI

22 

Kreso A and Dick JE: Evolution of the cancer stem cell model. Cell Stem Cell. 14:275–291. 2014. View Article : Google Scholar : PubMed/NCBI

23 

Ghiaur G, Gerber J and Jones RJ: Concise review: Cancer stem cells and minimal residual disease. Stem Cells. 30:89–93. 2012. View Article : Google Scholar : PubMed/NCBI

24 

Maeda S, Shinchi H, Kurahara H, Mataki Y, Maemura K, Sato M, Natsugoe S, Aikou T and Takao S: CD133 expression is correlated with lymph node metastasis and vascular endothelial growth factor-C expression in pancreatic cancer. Br J Cancer. 98:1389–1397. 2008. View Article : Google Scholar : PubMed/NCBI

25 

Vogler T, Kriegl L, Horst D, Engel J, Sagebiel S, Schäffauer AJ, Kirchner T and Jung A: The expression pattern of aldehyde dehydrogenase 1 (ALDH1) is an independent prognostic marker for low survival in colorectal tumors. Exp Mol Pathol. 92:111–117. 2012. View Article : Google Scholar : PubMed/NCBI

26 

Zeppernick F, Ahmadi R, Campos B, Dictus C, Helmke BM, Becker N, Lichter P, Unterberg A, Radlwimmer B and Herold-Mende CC: Stem cell marker CD133 affects clinical outcome in glioma patients. Clin Cancer Res. 14:123–129. 2008. View Article : Google Scholar : PubMed/NCBI

27 

Rong S, Segal S, Anver M, Resau JH and Woude GF Vande: Invasiveness and metastasis of NIH 3T3 cells induced by Met-hepatocyte growth factor/scatter factor autocrine stimulation. Proc Natl Acad Sci USA. 91:4731–4735. 1994. View Article : Google Scholar : PubMed/NCBI

28 

Tokunou M, Niki T, Eguchi K, Iba S, Tsuda H, Yamada T, Matsuno Y, Kondo H, Saitoh Y, Imamura H, et al: c-MET expression in myofibroblasts: Role in autocrine activation and prognostic significance in lung adenocarcinoma. Am J Pathol. 158:1451–1463. 2001. View Article : Google Scholar : PubMed/NCBI

29 

Tsao MS, Liu N, Chen JR, Pappas J, Ho J, To C, Viallet J, Park M and Zhu H: Differential expression of Met/hepatocyte growth factor receptor in subtypes of non-small cell lung cancers. Lung Cancer. 20:1–16. 1998. View Article : Google Scholar : PubMed/NCBI

30 

Olivero M, Rizzo M, Madeddu R, Casadio C, Pennacchietti S, Nicotra MR, Prat M, Maggi G, Arena N, Natali PG, et al: Overexpression and activation of hepatocyte growth factor/scatter factor in human non-small-cell lung carcinomas. Br J Cancer. 74:1862–1868. 1996. View Article : Google Scholar : PubMed/NCBI

31 

Lengyel E, Prechtel D, Resau JH, Gauger K, Welk A, Lindemann K, Salanti G, Richter T, Knudsen B, Woude GF Vande, et al: C-Met overexpression in node-positive breast cancer identifies patients with poor clinical outcome independent of Her2/neu. Int J Cancer. 113:678–682. 2005. View Article : Google Scholar : PubMed/NCBI

32 

Di Renzo MF, Olivero M, Katsaros D, Crepaldi T, Gaglia P, Zola P, Sismondi P and Comoglio PM: Overexpression of the Met/HGF receptor in ovarian cancer. Int J Cancer. 58:658–662. 1994. View Article : Google Scholar : PubMed/NCBI

33 

Di Renzo MF, Olivero M, Giacomini A, Porte H, Chastre E, Mirossay L, Nordlinger B, Bretti S, Bottardi S, Giordano S, et al: Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer. Clin Cancer Res. 1:147–154. 1995.PubMed/NCBI

34 

Natali PG, Prat M, Nicotra MR, Bigotti A, Olivero M, Comoglio PM and Di Renzo MF: Overexpression of the met/HGF receptor in renal cell carcinomas. Int J Cancer. 69:212–217. 1996. View Article : Google Scholar : PubMed/NCBI

35 

Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, Scherer SW, Zhuang Z, Lubensky I, Dean M, et al: Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet. 16:68–73. 1997. View Article : Google Scholar : PubMed/NCBI

36 

Knowles LM, Stabile LP, Egloff AM, Rothstein ME, Thomas SM, Gubish CT, Lerner EC, Seethala RR, Suzuki S, Quesnelle KM, et al: HGF and c-Met participate in paracrine tumorigenic pathways in head and neck squamous cell cancer. Clin Cancer Res. 15:3740–3750. 2009. View Article : Google Scholar : PubMed/NCBI

37 

Ramirez R, Hsu D, Patel A, Fenton C, Dinauer C, Tuttle RM and Francis GL: Over-expression of hepatocyte growth factor/scatter factor (HGF/SF) and the HGF/SF receptor (cMET) are associated with a high risk of metastasis and recurrence for children and young adults with papillary thyroid carcinoma. Clin Endocrinol (Oxf). 53:635–644. 2000. View Article : Google Scholar : PubMed/NCBI

38 

Soman NR, Correa P, Ruiz BA and Wogan GN: The TPR-MET oncogenic rearrangement is present and expressed in human gastric carcinoma and precursor lesions. Proc Natl Acad Sci USA. 88:4892–4896. 1991. View Article : Google Scholar : PubMed/NCBI

39 

Koochekpour S, Jeffers M, Rulong S, Taylor G, Klineberg E, Hudson EA, Resau JH and Woude GF Vande: Met and hepatocyte growth factor/scatter factor expression in human gliomas. Cancer Res. 57:5391–5398. 1997.PubMed/NCBI

40 

Ferracini R, Di Renzo MF, Scotlandi K, Baldini N, Olivero M, Lollini P, Cremona O, Campanacci M and Comoglio PM: The Met/HGF receptor is over-expressed in human osteosarcomas and is activated by either a paracrine or an autocrine circuit. Oncogene. 12:1697–1705. 1996.PubMed/NCBI

41 

Di Renzo MF, Poulsom R, Olivero M, Comoglio PM and Lemoine NR: Expression of the Met/hepatocyte growth factor receptor in human pancreatic cancer. Cancer Res. 55:1129–1138. 1995.PubMed/NCBI

42 

Ma PC, Tretiakova MS, MacKinnon AC, Ramnath N, Johnson C, Dietrich S, Seiwert T, Christensen JG, Jagadeeswaran R, Krausz T, et al: Expression and mutational analysis of MET in human solid cancers. Genes Chromosomes Cancer. 47:1025–1037. 2008. View Article : Google Scholar : PubMed/NCBI

43 

Zeng ZS, Weiser MR, Kuntz E, Chen CT, Khan SA, Forslund A, Nash GM, Gimbel M, Yamaguchi Y, Culliford AT IV, et al: c-Met gene amplification is associated with advanced stage colorectal cancer and liver metastases. Cancer Lett. 265:258–269. 2008. View Article : Google Scholar : PubMed/NCBI

44 

Tsugawa K, Yonemura Y, Hirono Y, Fushida S, Kaji M, Miwa K, Miyazaki I and Yamamoto H: Amplification of the c-met, c-erbB-2 and epidermal growth factor receptor gene in human gastric cancers: Correlation to clinical features. Oncology. 55:475–481. 1998. View Article : Google Scholar : PubMed/NCBI

45 

Di Renzo MF, Olivero M, Martone T, Maffe A, Maggiora P, Stefani AD, Valente G, Giordano S, Cortesina G and Comoglio PM: Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas. Oncogene. 19:1547–1555. 2000. View Article : Google Scholar : PubMed/NCBI

46 

Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S and Comoglio PM: Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell. 3:347–361. 2003. View Article : Google Scholar : PubMed/NCBI

47 

Joo KM, Jin J, Kim E, Ho Kim K, Kim Y, Gu Kang B, Kang YJ, Lathia JD, Cheong KH, Song PH, et al: MET signaling regulates glioblastoma stem cells. Cancer Res. 72:3828–3838. 2012. View Article : Google Scholar : PubMed/NCBI

48 

Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J and Dirks PB: Identification of a cancer stem cell in human brain tumors. Cancer Res. 63:5821–5828. 2003.PubMed/NCBI

49 

Bidlingmaier S, Zhu X and Liu B: The utility and limitations of glycosylated human CD133 epitopes in defining cancer stem cells. J Mol Med (Berl). 86:1025–1032. 2008. View Article : Google Scholar : PubMed/NCBI

50 

Comoglio PM, Giordano S and Trusolino L: Drug development of MET inhibitors: Targeting oncogene addiction and expedience. Nat Rev Drug Discov. 7:504–516. 2008. View Article : Google Scholar : PubMed/NCBI

51 

Benvenuti S, Lazzari L, Arnesano A, Li Chiavi G, Gentile A and Comoglio PM: Ron kinase transphosphorylation sustains MET oncogene addiction. Cancer Res. 71:1945–1955. 2011. View Article : Google Scholar : PubMed/NCBI

52 

Boccaccio C and Comoglio PM: The MET oncogene in glioblastoma stem cells: Implications as a diagnostic marker and a therapeutic target. Cancer Res. 73:3193–3199. 2013. View Article : Google Scholar : PubMed/NCBI

53 

Corso S, Migliore C, Ghiso E, De Rosa G, Comoglio PM and Giordano S: Silencing the MET oncogene leads to regression of experimental tumors and metastases. Oncogene. 27:684–693. 2008. View Article : Google Scholar : PubMed/NCBI

54 

Lennerz JK, Kwak EL, Ackerman A, Michael M, Fox SB, Bergethon K, Lauwers GY, Christensen JG, Wilner KD, Haber DA, et al: MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib. J Clin Oncol. 29:4803–4810. 2011. View Article : Google Scholar : PubMed/NCBI

55 

Lutterbach B, Zeng Q, Davis LJ, Hatch H, Hang G, Kohl NE, Gibbs JB and Pan BS: Lung cancer cell lines harboring MET gene amplification are dependent on Met for growth and survival. Cancer Res. 67:2081–2088. 2007. View Article : Google Scholar : PubMed/NCBI

56 

Smolen GA, Sordella R, Muir B, Mohapatra G, Barmettler A, Archibald H, Kim WJ, Okimoto RA, Bell DW, Sgroi DC, et al: Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. Proc Natl Acad Sci USA. 103:2316–2321. 2006. View Article : Google Scholar : PubMed/NCBI

57 

De Bacco F, Luraghi P, Medico E, Reato G, Girolami F, Perera T, Gabriele P, Comoglio PM and Boccaccio C: Induction of MET by ionizing radiation and its role in radioresistance and invasive growth of cancer. J Natl Cancer Inst. 103:645–661. 2011. View Article : Google Scholar : PubMed/NCBI

58 

Matsui S, Osada S, Tomita H, Komori S, Mori R, Sanada Y, Takahashi T, Yamaguchi K and Yoshida K: Clinical significance of aggressive hepatectomy for colorectal liver metastasis, evaluated from the HGF/c-Met pathway. Int J Oncol. 37:289–297. 2010.PubMed/NCBI

59 

Navab R, Liu J, Seiden-Long I, Shih W, Li M, Bandarchi B, Chen Y, Lau D, Zu YF, Cescon D, et al: Co-overexpression of Met and hepatocyte growth factor promotes systemic metastasis in NCI-H460 non-small cell lung carcinoma cells. Neoplasia. 11:1292–1300. 2009. View Article : Google Scholar : PubMed/NCBI

60 

Cai YR, Zhang HQ, Qu Y, Mu J, Zhao D, Zhou LJ, Yan H, Ye JW and Liu Y: Expression of MET and SOX2 genes in non-small cell lung carcinoma with EGFR mutation. Oncol Rep. 26:877–885. 2011.PubMed/NCBI

61 

Masuya D, Huang C, Liu D, Nakashima T, Kameyama K, Haba R, Ueno M and Yokomise H: The tumour-stromal interaction between intratumoral c-Met and stromal hepatocyte growth factor associated with tumour growth and prognosis in non-small-cell lung cancer patients. Br J Cancer. 90:1555–1562. 2004. View Article : Google Scholar : PubMed/NCBI

62 

Ghoussoub RA, Dillon DA, DAquila T, Rimm EB, Fearon ER and Rimm DL: Expression of c-met is a strong independent prognostic factor in breast carcinoma. Cancer. 82:1513–1520. 1998. View Article : Google Scholar : PubMed/NCBI

63 

Qian CN, Guo X, Cao B, Kort EJ, Lee CC, Chen J, Wang LM, Mai WY, Min HQ, Hong MH, et al: Met protein expression level correlates with survival in patients with late-stage nasopharyngeal carcinoma. Cancer Res. 62:589–596. 2002.PubMed/NCBI

64 

Nakajima M, Sawada H, Yamada Y, Watanabe A, Tatsumi M, Yamashita J, Matsuda M, Sakaguchi T, Hirao T and Nakano H: The prognostic significance of amplification and overexpression of c-met and c-erb B-2 in human gastric carcinomas. Cancer. 85:1894–1902. 1999. View Article : Google Scholar : PubMed/NCBI

65 

Sawada K, Radjabi AR, Shinomiya N, Kistner E, Kenny H, Becker AR, Turkyilmaz MA, Salgia R, Yamada SD, Woude GF Vande, et al: c-Met overexpression is a prognostic factor in ovarian cancer and an effective target for inhibition of peritoneal dissemination and invasion. Cancer Res. 67:1670–1679. 2007. View Article : Google Scholar : PubMed/NCBI

66 

Gibney GT, Aziz SA, Camp RL, Conrad P, Schwartz BE, Chen CR, Kelly WK and Kluger HM: c-Met is a prognostic marker and potential therapeutic target in clear cell renal cell carcinoma. Ann Oncol. 24:343–349. 2013. View Article : Google Scholar : PubMed/NCBI

67 

Nabeshima K, Shimao Y, Sato S, Kataoka H, Moriyama T, Kawano H, Wakisaka S and Koono M: Expression of c-Met correlates with grade of malignancy in human astrocytic tumours: An immunohistochemical study. Histopathology. 31:436–443. 1997. View Article : Google Scholar : PubMed/NCBI

68 

Kong DS, Song SY, Kim DH, Joo KM, Yoo JS, Koh JS, Dong SM, Suh YL, Lee JI, Park K, et al: Prognostic significance of c-Met expression in glioblastomas. Cancer. 115:140–148. 2009. View Article : Google Scholar : PubMed/NCBI

69 

Takeuchi H, Bilchik A, Saha S, Turner R, Wiese D, Tanaka M, Kuo C, Wang HJ and Hoon DS: c-MET expression level in primary colon cancer: A predictor of tumor invasion and lymph node metastases. Clin Cancer Res. 9:1480–1488. 2003.PubMed/NCBI

70 

Refaat T, Donnelly ED, Sachdev S, Parimi V, El Achy S, Dalal P, Farouk M, Berg N, Helenowski I, Gross JP, et al: c-Met overexpression in cervical cancer, a prognostic factor and a potential molecular therapeutic target. Am J Clin Oncol. Jun 10–2015.(Epub ahead of print). View Article : Google Scholar

71 

Rocci A, Gambella M, Aschero S, Baldi I, Trusolino L, Cavallo F, Gay F, Larocca A, Magarotto V, Omedè P, et al: MET dysregulation is a hallmark of aggressive disease in multiple myeloma patients. Br J Haematol. 164:841–850. 2014. View Article : Google Scholar : PubMed/NCBI

72 

Baccelli I, Stenzinger A, Vogel V, Pfitzner BM, Klein C, Wallwiener M, Scharpff M, Saini M, Holland-Letz T, Sinn HP, et al: Co-expression of MET and CD47 is a novel prognosticator for survival of luminal breast cancer patients. Oncotarget. 5:8147–8160. 2014. View Article : Google Scholar : PubMed/NCBI

73 

Edakuni G, Sasatomi E, Satoh T, Tokunaga O and Miyazaki K: Expression of the hepatocyte growth factor/c-Met pathway is increased at the cancer front in breast carcinoma. Pathol Int. 51:172–178. 2001. View Article : Google Scholar : PubMed/NCBI

74 

Cepero V, Sierra JR, Corso S, Ghiso E, Casorzo L, Perera T, Comoglio PM and Giordano S: MET and KRAS gene amplification mediates acquired resistance to MET tyrosine kinase inhibitors. Cancer Res. 70:7580–7590. 2010. View Article : Google Scholar : PubMed/NCBI

75 

Qi J, McTigue MA, Rogers A, Lifshits E, Christensen JG, Jänne PA and Engelman JA: Multiple mutations and bypass mechanisms can contribute to development of acquired resistance to MET inhibitors. Cancer Res. 71:1081–1091. 2011. View Article : Google Scholar : PubMed/NCBI

76 

Corso S, Ghiso E, Cepero V, Sierra JR, Migliore C, Bertotti A, Trusolino L, Comoglio PM and Giordano S: Activation of HER family members in gastric carcinoma cells mediates resistance to MET inhibition. Mol Cancer. 9:1212010. View Article : Google Scholar : PubMed/NCBI

77 

McDermott U, Pusapati RV, Christensen JG, Gray NS and Settleman J: Acquired resistance of non-small cell lung cancer cells to MET kinase inhibition is mediated by a switch to epidermal growth factor receptor dependency. Cancer Res. 70:1625–1634. 2010. View Article : Google Scholar : PubMed/NCBI

78 

Martin V, Corso S, Comoglio PM and Giordano S: Increase of MET gene copy number confers resistance to a monovalent MET antibody and establishes drug dependence. Mol Oncol. 8:1561–1574. 2014. View Article : Google Scholar : PubMed/NCBI

79 

Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J, et al: MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 316:1039–1043. 2007. View Article : Google Scholar : PubMed/NCBI

80 

Bean J, Brennan C, Shih JY, Riely G, Viale A, Wang L, Chitale D, Motoi N, Szoke J, Broderick S, et al: MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci USA. 104:20932–20937. 2007. View Article : Google Scholar : PubMed/NCBI

81 

Shattuck DL, Miller JK, Carraway KL III and Sweeney C: Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells. Cancer Res. 68:1471–1477. 2008. View Article : Google Scholar : PubMed/NCBI

82 

Shojaei F, Lee JH, Simmons BH, Wong A, Esparza CO, Plumlee PA, Feng J, Stewart AE, Hu-Lowe DD and Christensen JG: HGF/c-Met acts as an alternative angiogenic pathway in sunitinib-resistant tumors. Cancer Res. 70:10090–10100. 2010. View Article : Google Scholar : PubMed/NCBI

83 

Ciamporcero E, Miles KM, Adelaiye R, Ramakrishnan S, Shen L, Ku S, Pizzimenti S, Sennino B, Barrera G and Pili R: Combination strategy targeting VEGF and HGF/c-met in human renal cell carcinoma models. Mol Cancer Ther. 14:101–110. 2015. View Article : Google Scholar : PubMed/NCBI

84 

Teng C, Guo Y, Zhang H, Zhang H, Ding M and Deng H: Identification and characterization of label-retaining cells in mouse pancreas. Differentiation. 75:702–712. 2007. View Article : Google Scholar : PubMed/NCBI

85 

Oshima Y, Suzuki A, Kawashimo K, Ishikawa M, Ohkohchi N and Taniguchi H: Isolation of mouse pancreatic ductal progenitor cells expressing CD133 and c-Met by flow cytometric cell sorting. Gastroenterology. 132:720–732. 2007. View Article : Google Scholar : PubMed/NCBI

86 

Kamiya A, Gonzalez FJ and Nakauchi H: Identification and differentiation of hepatic stem cells during liver development. Front Biosci. 11:1302–1310. 2006. View Article : Google Scholar : PubMed/NCBI

87 

Ishikawa T, Factor VM, Marquardt JU, Raggi C, Seo D, Kitade M, Conner EA and Thorgeirsson SS: Hepatocyte growth factor/c-met signaling is required for stem-cell-mediated liver regeneration in mice. Hepatology. 55:1215–1226. 2012. View Article : Google Scholar : PubMed/NCBI

88 

Urbanek K, Rota M, Cascapera S, Bearzi C, Nascimbene A, De Angelis A, Hosoda T, Chimenti S, Baker M, Limana F, et al: Cardiac stem cells possess growth factor-receptor systems that after activation regenerate the infarcted myocardium, improving ventricular function and long-term survival. Circ Res. 97:663–673. 2005. View Article : Google Scholar : PubMed/NCBI

89 

Chmielowiec J, Borowiak M, Morkel M, Stradal T, Munz B, Werner S, Wehland J, Birchmeier C and Birchmeier W: c-Met is essential for wound healing in the skin. J Cell Biol. 177:151–162. 2007. View Article : Google Scholar : PubMed/NCBI

90 

Nicoleau C, Benzakour O, Agasse F, Thiriet N, Petit J, Prestoz L, Roger M, Jaber M and Coronas V: Endogenous hepatocyte growth factor is a niche signal for subventricular zone neural stem cell amplification and self-renewal. Stem Cells. 27:408–419. 2009. View Article : Google Scholar : PubMed/NCBI

91 

De Bacco F, Casanova E, Medico E, Pellegatta S, Orzan F, Albano R, Luraghi P, Reato G, DAmbrosio A, Porrati P, et al: The MET oncogene is a functional marker of a glioblastoma stem cell subtype. Cancer Res. 72:4537–4550. 2012. View Article : Google Scholar : PubMed/NCBI

92 

Li Y, Li A, Glas M, Lal B, Ying M, Sang Y, Xia S, Trageser D, Guerrero-Cázares H, Eberhart CG, et al: c-Met signaling induces a reprogramming network and supports the glioblastoma stem-like phenotype. Proc Natl Acad Sci USA. 108:9951–9956. 2011. View Article : Google Scholar : PubMed/NCBI

93 

Snuderl M, Fazlollahi L, Le LP, Nitta M, Zhelyazkova BH, Davidson CJ, Akhavanfard S, Cahill DP, Aldape KD, Betensky RA, et al: Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell. 20:810–817. 2011. View Article : Google Scholar : PubMed/NCBI

94 

Szerlip NJ, Pedraza A, Chakravarty D, Azim M, McGuire J, Fang Y, Ozawa T, Holland EC, Huse JT, Jhanwar S, et al: Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response. Proc Natl Acad Sci USA. 109:3041–3046. 2012. View Article : Google Scholar : PubMed/NCBI

95 

Li C, Wu JJ, Hynes M, Dosch J, Sarkar B, Welling TH, di Magliano M Pasca and Simeone DM: c-Met is a marker of pancreatic cancer stem cells and therapeutic target. Gastroenterology. 141:2218–2227.e5. 2011. View Article : Google Scholar : PubMed/NCBI

96 

Sun S and Wang Z: Head neck squamous cell carcinoma c-Met+ cells display cancer stem cell properties and are responsible for cisplatin-resistance and metastasis. Int J Cancer. 129:2337–2348. 2011. View Article : Google Scholar : PubMed/NCBI

97 

van Leenders GJ, Sookhlall R, Teubel WJ, de Ridder CM, Reneman S, Sacchetti A, Vissers KJ, van Weerden W and Jenster G: Activation of c-MET induces a stem-like phenotype in human prostate cancer. PLoS One. 6:e267532011. View Article : Google Scholar : PubMed/NCBI

98 

Gastaldi S, Sassi F, Accornero P, Torti D, Galimi F, Migliardi G, Molyneux G, Perera T, Comoglio PM, Boccaccio C, et al: Met signaling regulates growth, repopulating potential and basal cell-fate commitment of mammary luminal progenitors: Implications for basal-like breast cancer. Oncogene. 32:1428–1440. 2013. View Article : Google Scholar : PubMed/NCBI

99 

Miekus K, Lukasiewicz E, Jarocha D, Sekula M, Drabik G and Majka M: The decreased metastatic potential of rhabdomyosarcoma cells obtained through MET receptor downregulation and the induction of differentiation. Cell Death Dis. 4:e4592013. View Article : Google Scholar : PubMed/NCBI

100 

Skrzypek K, Kusienicka A, Szewczyk B, Adamus T, Lukasiewicz E, Miekus K and Majka M: Constitutive activation of MET signaling impairs myogenic differentiation of rhabdomyosarcoma and promotes its development and progression. Oncotarget. 6:31378–31398. 2015.PubMed/NCBI

101 

Miekus K, Pawlowska M, Sekuła M, Drabik G, Madeja Z, Adamek D and Majka M: MET receptor is a potential therapeutic target in high grade cervical cancer. Oncotarget. 6:10086–10101. 2015. View Article : Google Scholar : PubMed/NCBI

102 

Takahashi K and Yamanaka S: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 126:663–676. 2006. View Article : Google Scholar : PubMed/NCBI

103 

Jun HJ, Bronson RT and Charest A: Inhibition of EGFR induces a c-MET-driven stem cell population in glioblastoma. Stem Cells. 32:338–348. 2014. View Article : Google Scholar : PubMed/NCBI

104 

Hage C, Rausch V, Giese N, Giese T, Schönsiegel F, Labsch S, Nwaeburu C, Mattern J, Gladkich J and Herr I: The novel c-Met inhibitor cabozantinib overcomes gemcitabine resistance and stem cell signaling in pancreatic cancer. Cell Death Dis. 4:e6272013. View Article : Google Scholar : PubMed/NCBI

105 

Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, et al: Involvement of chemokine receptors in breast cancer metastasis. Nature. 410:50–56. 2001. View Article : Google Scholar : PubMed/NCBI

106 

Zlotnik A, Burkhardt AM and Homey B: Homeostatic chemokine receptors and organ-specific metastasis. Nat Rev Immunol. 11:597–606. 2011. View Article : Google Scholar : PubMed/NCBI

107 

Kucia M, Reca R, Miekus K, Wanzeck J, Wojakowski W, Janowska-Wieczorek A, Ratajczak J and Ratajczak MZ: Trafficking of normal stem cells and metastasis of cancer stem cells involve similar mechanisms: Pivotal role of the SDF-1-CXCR4 axis. Stem Cells. 23:879–894. 2005. View Article : Google Scholar : PubMed/NCBI

108 

Phillips TM, McBride WH and Pajonk F: The response of CD24−/low/CD44+ breast cancer-initiating cells to radiation. J Natl Cancer Inst. 98:1777–1785. 2006. View Article : Google Scholar : PubMed/NCBI

109 

Martin TA and Jiang WG: Evaluation of the expression of stem cell markers in human breast cancer reveals a correlation with clinical progression and metastatic disease in ductal carcinoma. Oncol Rep. 31:262–272. 2014.PubMed/NCBI

110 

Bardelli A, Corso S, Bertotti A, Hobor S, Valtorta E, Siravegna G, Sartore-Bianchi A, Scala E, Cassingena A, Zecchin D, et al: Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer Discov. 3:658–673. 2013. View Article : Google Scholar : PubMed/NCBI

111 

Turke AB, Zejnullahu K, Wu YL, Song Y, Dias-Santagata D, Lifshits E, Toschi L, Rogers A, Mok T, Sequist L, et al: Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell. 17:77–88. 2010. View Article : Google Scholar : PubMed/NCBI

112 

Yano S, Wang W, Li Q, Matsumoto K, Sakurama H, Nakamura T, Ogino H, Kakiuchi S, Hanibuchi M, Nishioka Y, et al: Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations. Cancer Res. 68:9479–9487. 2008. View Article : Google Scholar : PubMed/NCBI

113 

Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, Peng J, Lin E, Wang Y, Sosman J, et al: Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature. 487:505–509. 2012. View Article : Google Scholar : PubMed/NCBI

114 

Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, Davis A, Mongare MM, Gould J, Frederick DT, et al: Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 487:500–504. 2012. View Article : Google Scholar : PubMed/NCBI

115 

Luraghi P, Reato G, Cipriano E, Sassi F, Orzan F, Bigatto V, De Bacco F, Menietti E, Han M, Rideout WM III, et al: MET signaling in colon cancer stem-like cells blunts the therapeutic response to EGFR inhibitors. Cancer Res. 74:1857–1869. 2014. View Article : Google Scholar : PubMed/NCBI

116 

Vermeulen L, De Sousa E, Melo F, van der Heijden M, Cameron K, de Jong JH, Borovski T, Tuynman JB, Todaro M, Merz C, Rodermond H, et al: Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol. 12:468–476. 2010. View Article : Google Scholar : PubMed/NCBI

117 

Kim KH, Seol HJ, Kim EH, Rheey J, Jin HJ, Lee Y, Joo KM, Lee J and Nam DH: Wnt/β-catenin signaling is a key downstream mediator of MET signaling in glioblastoma stem cells. Neuro Oncol. 15:161–171. 2013. View Article : Google Scholar : PubMed/NCBI

118 

Hashida S, Yamamoto H, Shien K, Miyoshi Y, Ohtsuka T, Suzawa K, Watanabe M, Maki Y, Soh J, Asano H, et al: Acquisition of cancer stem cell-like properties in non-small cell lung cancer with acquired resistance to afatinib. Cancer Sci. 106:1377–1384. 2015. View Article : Google Scholar : PubMed/NCBI

119 

Sugano T, Seike M, Noro R, Soeno C, Chiba M, Zou F, Nakamichi S, Nishijima N, Matsumoto M, Miyanaga A, et al: Inhibition of ABCB1 overcomes cancer stem cell-like properties and acquired resistance to MET inhibitors in non-small cell lung cancer. Mol Cancer Ther. 14:2433–2440. 2015. View Article : Google Scholar : PubMed/NCBI

120 

Figlin RA, Kaufmann I and Brechbiel J: Targeting PI3K and mTORC2 in metastatic renal cell carcinoma: New strategies for overcoming resistance to VEGFR and mTORC1 inhibitors. Int J Cancer. 133:788–796. 2013. View Article : Google Scholar : PubMed/NCBI

121 

Weinstein IB: Cancer. Addiction to oncogenes - the Achilles heal of cancer. Science. 297:63–64. 2002. View Article : Google Scholar : PubMed/NCBI

122 

Sharma SV and Settleman J: Oncogene addiction: Setting the stage for molecularly targeted cancer therapy. Genes Dev. 21:3214–3231. 2007. View Article : Google Scholar : PubMed/NCBI

123 

Viedma-Rodríguez R, Baiza-Gutman L, Salamanca-Gómez F, Diaz-Zaragoza M, Martínez-Hernández G, Esparza-Garrido R Ruiz, Velázquez-Flores MA and Arenas-Aranda D: Mechanisms associated with resistance to tamoxifen in estrogen receptor-positive breast cancer (Review). Oncol Rep. 32:3–15. 2014.PubMed/NCBI

Related Articles

Journal Cover

February-2017
Volume 37 Issue 2

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Miekus K: The Met tyrosine kinase receptor as a therapeutic target and a potential cancer stem cell factor responsible for therapy resistance (Review). Oncol Rep 37: 647-656, 2017.
APA
Miekus, K. (2017). The Met tyrosine kinase receptor as a therapeutic target and a potential cancer stem cell factor responsible for therapy resistance (Review). Oncology Reports, 37, 647-656. https://doi.org/10.3892/or.2016.5297
MLA
Miekus, K."The Met tyrosine kinase receptor as a therapeutic target and a potential cancer stem cell factor responsible for therapy resistance (Review)". Oncology Reports 37.2 (2017): 647-656.
Chicago
Miekus, K."The Met tyrosine kinase receptor as a therapeutic target and a potential cancer stem cell factor responsible for therapy resistance (Review)". Oncology Reports 37, no. 2 (2017): 647-656. https://doi.org/10.3892/or.2016.5297