Gene Summary

Gene:SOS1; son of sevenless homolog 1 (Drosophila)
Aliases: GF1, HGF, NS4, GGF1, GINGF
Summary:This gene encodes a protein that is a guanine nucleotide exchange factor for RAS proteins, membrane proteins that bind guanine nucleotides and participate in signal transduction pathways. GTP binding activates and GTP hydrolysis inactivates RAS proteins. The product of this gene may regulate RAS proteins by facilitating the exchange of GTP for GDP. Mutations in this gene are associated with gingival fibromatosis 1 and Noonan syndrome type 4. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:son of sevenless homolog 1
Source:NCBIAccessed: 06 August, 2015


What does this gene/protein do?
Show (25)
Pathways:What pathways are this gene/protein implicaed in?
Show (42)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 06 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Intracellular Signaling Peptides and Proteins
  • Messenger RNA
  • MicroRNAs
  • Proto-Oncogene Proteins p21(ras)
  • Epithelial Cells
  • Phosphorylation
  • Noonan Syndrome
  • SOS1 Protein
  • Transcription Factors
  • Neoplasm Proteins
  • Adolescents
  • Signal Transduction
  • Mutation
  • Extracellular Signal-Regulated MAP Kinases
  • p120 GTPase Activating Protein
  • Haematological Malignancies
  • Transduction
  • Neurofibromatosis 1
  • TNF
  • GRB2 Adaptor Protein
  • European Continental Ancestry Group
  • Tumor Markers
  • Uniparental Disomy
  • Mitogen-Activated Protein Kinases
  • Oligonucleotide Array Sequence Analysis
  • DNA Sequence Analysis
  • ras Proteins
  • Cell Proliferation
  • MAP Kinase Signaling System
  • Neoplasm Invasiveness
  • Cancer Gene Expression Regulation
  • Chromosome 2
  • Childhood Cancer
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Gene Expression Profiling
  • Lung Cancer
  • T-Lymphocyte Subsets
  • Cell Movement
  • DNA Mutational Analysis
  • Risk Factors
Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Noonan SyndromeSOS1 mutation in Noonan Syndrome
Noonan Syndrome is an autosamal dominant multi-system disorder, characterised by facial anomalies, short stature, developmental delay, cardiac abnormalities and other symptoms. The syndrome pre-disposes to myeloproliferative disorders ( mainly chronic myeolomonocytic leukemia / juvenile myelomonocytic leukemia and acute lymphoblastic leukemia), with reports of neuroblastoma, rhabdomyosarcoma and a wide range of other tumors.
View Publications12
Haematological MalignanciesSOS1 and Haematological Malignancies View Publications3
Lung CancerSOS1 and Lung Cancer View Publications4
-SOS1 and Noonan Syndrome View Publications12

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: SOS1 (cancer-related)

Skead G, Govender D
Gene of the month: MET.
J Clin Pathol. 2015; 68(6):405-9 [PubMed] Related Publications
The MET receptor tyrosine kinase and its ligand hepatocyte growth factor/scatter factor (HGF/SF) are potential therapeutic targets in many human malignancies, making this pathway an important focus of molecular and cancer research. MET mutations have been detected in various tumours. In addition, many tumour types demonstrate MET and HGF/SF overexpression and amplification. The MET signal transduction cascade is complex, and manifests in a broad spectrum of mitogenic and morphogenic functions, affecting cell proliferation, migration, differentiation, morphology and survival. Cancer cells commandeer the physiological functions of this signalling axis to facilitate invasion and metastasis. Significant progress has been made in the development of agents that inhibit MET-HGF/SF signalling. In this article, we outline the key features of the MET gene, its protein product and the ligand HGF/SF, to provide an overview of this important signalling pathway and offer a summary of the relevant pathological and clinical directions of research.

Finisguerra V, Di Conza G, Di Matteo M, et al.
MET is required for the recruitment of anti-tumoural neutrophils.
Nature. 2015; 522(7556):349-53 [PubMed] Related Publications
Mutations or amplification of the MET proto-oncogene are involved in the pathogenesis of several tumours, which rely on the constitutive engagement of this pathway for their growth and survival. However, MET is expressed not only by cancer cells but also by tumour-associated stromal cells, although its precise role in this compartment is not well characterized. Here we show that MET is required for neutrophil chemoattraction and cytotoxicity in response to its ligand hepatocyte growth factor (HGF). Met deletion in mouse neutrophils enhances tumour growth and metastasis. This phenotype correlates with reduced neutrophil infiltration to both the primary tumour and metastatic sites. Similarly, Met is necessary for neutrophil transudation during colitis, skin rash or peritonitis. Mechanistically, Met is induced by tumour-derived tumour necrosis factor (TNF)-α or other inflammatory stimuli in both mouse and human neutrophils. This induction is instrumental for neutrophil transmigration across an activated endothelium and for inducible nitric oxide synthase production upon HGF stimulation. Consequently, HGF/MET-dependent nitric oxide release by neutrophils promotes cancer cell killing, which abates tumour growth and metastasis. After systemic administration of a MET kinase inhibitor, we prove that the therapeutic benefit of MET targeting in cancer cells is partly countered by the pro-tumoural effect arising from MET blockade in neutrophils. Our work identifies an unprecedented role of MET in neutrophils, suggests a potential 'Achilles' heel' of MET-targeted therapies in cancer, and supports the rationale for evaluating anti-MET drugs in certain inflammatory diseases.

Luo H, Hong H, Slater MR, et al.
PET of c-Met in Cancer with ⁶⁴Cu-Labeled Hepatocyte Growth Factor.
J Nucl Med. 2015; 56(5):758-63 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
UNLABELLED: The hepatocyte growth factor (HGF) and its receptor, c-Met, are actively involved in tumor progression and metastasis and are closely associated with a poor prognostic outcome for cancer patients. Thus, the development of PET agents that can assess c-Met expression would be extremely useful for diagnosing cancer and subsequently monitoring response to c-Met-targeted therapies. Here, we report the characterization of recombinant human HGF (rh-HGF) as a PET tracer for detection of c-Met expression in vivo.
METHODS: rh-HGF was expressed in human embryonic kidney 293 cells and purified by nickel-nitrilotriacetic acid affinity chromatography. The concentrated rh-HGF was conjugated to 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid and labeled with (64)Cu. c-Met binding evaluation by flow cytometry was performed on both U87MG and MDA-MB-231 cell lines, which have a high level and a low level, respectively, of c-Met. PET imaging and biodistribution studies were performed on nude mice bearing U87MG and MDA-MB-231 xenografted tumors.
RESULTS: The rh-HGF expression yield was 150-200 μg of protein per 5 × 10(6) cells after a 48-h transfection, with purity of approximately 85%-90%. Flow cytometry examination confirmed that rh-HGF had a strong and specific capacity to bind to c-Met. After (64)Cu labeling, PET imaging revealed specific and prominent uptake of (64)Cu-NOTA-rh-HGF in c-Met-positive U87MG tumors (percentage injected dose per gram, 6.8 ± 1.8 at 9 h after injection) and significantly lower uptake in c-Met-negative MDA-MB-231 tumors (percentage injected dose per gram, 1.8 ± 0.6 at 9 h after injection). The fact that sonication-denatured rh-HGF had significantly lower uptake in U87MG tumors, along with histology analysis, confirmed the c-Met specificity of (64)Cu-NOTA-rh-HGF.
CONCLUSION: This study provided initial evidence that (64)Cu-NOTA-rh-HGF visualizes c-Met expression in vivo, an application that may prove useful for c-Met-targeted cancer therapy.

Hao NB, Tang B, Wang GZ, et al.
Hepatocyte growth factor (HGF) upregulates heparanase expression via the PI3K/Akt/NF-κB signaling pathway for gastric cancer metastasis.
Cancer Lett. 2015; 361(1):57-66 [PubMed] Related Publications
Heparanase (HPA) is an endoglucuronidase that can promote the shedding of associated cytokines in several types of tumors. However, little is known about what controls the expression of HPA or its role in gastric cancer. In this study, we report for the first time that HGF regulates HPA expression to promote gastric cancer metastasis. In this study, HGF and HPA were found to be significantly expressed in 58 gastric cancer patients. High expression of both HGF and HPA was positively associated with TNM stage, invasion depth and poor prognosis. In MKN74 cells, exogenous HGF significantly increased HPA expression at both the mRNA and protein levels. Further study revealed that HGF first activated PI3K/Akt signaling. NF-κB signaling was activated downstream of PI3K/Akt and promoted HPA expression. However, when c-met, PI3K/Akt or NF-κB signal inhibitors were used, HPA expression was significantly decreased. All of these results indicate that HGF regulates HPA expression by PI3K/Akt and downstream NF-κB signaling. Using bioinformatics and the ChIP assay, p65 was observed to bind to the HPA promoter. Furthermore, HGF significantly induced tumor cell migration, whereas treatment with an NF-κB inhibitor decreased migration. Moreover, when HPA was overexpressed in MKN74 cells, migration was significantly enhanced, and the HGF concentration was increased. However, when HPA was down-regulated in MKN45 cells, migration and HGF levels decreased. Together, these results demonstrate that HGF/c-met can activate PI3K/Akt and downstream NF-κB signaling to promote HPA expression and subsequent tumor metastasis.

Thiel A, Ristimäki A
Targeted therapy in gastric cancer.
APMIS. 2015; 123(5):365-72 [PubMed] Related Publications
Gastric cancer is often diagnosed at an advanced stage. Although chemotherapy prolongs survival and improves quality of life, the survival of gastric cancer patients with advanced disease is short. Thanks to recent insights into the molecular pathways involved in gastric carcinogenesis, new targeted treatment options have become available for gastric cancer patients. Trastuzumab, an antibody targeted to HER-2, was shown to improve survival of advanced gastric cancer patients harboring HER-2 overexpression due to gene amplification in their tumor cells, and is currently also explored in adjuvant and neoadjuvant settings. Another agent with promising results in clinical trials is ramucirumab, an antibody targeting VEGFR-2. No clear survival benefit, however, were experienced with agents targeting EGFR (cetuximab, panitumumab), VEGF-A (bevacizumab), or mTOR (everolimus). Drugs targeting c-MET/HGF are currently under investigation in biomarker-selected cohorts, with promising results in early clinical trials. This review will summarize the current status of targeted treatment options in gastric cancer.

Peterson EA, Teffera Y, Albrecht BK, et al.
Discovery of potent and selective 8-fluorotriazolopyridine c-Met inhibitors.
J Med Chem. 2015; 58(5):2417-30 [PubMed] Related Publications
The overexpression of c-Met and/or hepatocyte growth factor (HGF), the amplification of the MET gene, and mutations in the c-Met kinase domain can activate signaling pathways that contribute to cancer progression by enabling tumor cell proliferation, survival, invasion, and metastasis. Herein, we report the discovery of 8-fluorotriazolopyridines as inhibitors of c-Met activity. Optimization of the 8-fluorotriazolopyridine scaffold through the combination of structure-based drug design, SAR studies, and metabolite identification provided potent (cellular IC50 < 10 nM), selective inhibitors of c-Met with desirable pharmacokinetic properties that demonstrate potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver pharmacodynamic model.

Balan M, Mier y Teran E, Waaga-Gasser AM, et al.
Novel roles of c-Met in the survival of renal cancer cells through the regulation of HO-1 and PD-L1 expression.
J Biol Chem. 2015; 290(13):8110-20 [PubMed] Article available free on PMC after 27/03/2016 Related Publications
The receptor tyrosine kinase c-Met is overexpressed in renal cancer cells and can play major role in the growth and survival of tumor. We investigated how the c-Met-mediated signaling through binding to its ligand hepatocyte growth factor (HGF) can modulate the apoptosis and immune escape mechanism(s) of renal cancer cells by the regulations of novel molecules heme oxygenase-1 (HO-1) and programmed death-1 ligand 1 (PD-L1). We found that HGF/c-Met-mediated signaling activated the Ras/Raf pathway and down-regulated cancer cell apoptosis; and it was associated with the overexpression of cytoprotective HO-1 and anti-apoptotic Bcl-2/Bcl-xL. c-Met-induced HO-1 overexpression was regulated at the transcriptional level. Next, we observed that c-Met induction markedly up-regulated the expression of the negative co-stimulatory molecule PD-L1, and this can be prevented following treatment of the cells with pharmacological inhibitors of c-Met. Interestingly, HGF/c-Met-mediated signaling could not induce PD-L1 at the optimum level when either Ras or HO-1 was knocked down. To study the functional significance of c-Met-induced PD-L1 expression, we performed a co-culture assay using mouse splenocytes (expressing PD-L1 receptor PD-1) and murine renal cancer cells (RENCA, expressing high PD-L1). We observed that the splenocyte-mediated apoptosis of cancer cells during co-culture was markedly increased in the presence of either c-Met inhibitor or PD-L1 neutralizing antibody. Finally, we found that both c-Met and PD-L1 are significantly up-regulated and co-localized in human renal cancer tissues. Together, our study suggests a novel mechanism(s) by which c-Met can promote increased survival of renal cancer cells through the regulation of HO-1 and PD-L1.

Deng XB, Xiao L, Wu Y, et al.
Inhibition of mesothelioma cancer stem-like cells with adenovirus-mediated NK4 gene therapy.
Int J Cancer. 2015; 137(2):481-90 [PubMed] Article available free on PMC after 15/07/2016 Related Publications
Malignant mesothelioma (MM) is a highly invasive and chemoresistant malignancy induced by asbestos fibers. NK4, a hepatocyte growth factor antagonist and angiogenesis inhibitor, consists of the N-terminal hairpin domain and four kringle domains of the α-chain of hepatocyte growth factor. The therapeutic potential of NK4 has been demonstrated in a variety of tumor types. However, the mechanisms by which NK4 inhibits tumor growth have not been well delineated. In this study, it is shown that the NK4 adenovirus (Ad-NK4) potently inhibits cell viability, invasiveness and tumorigenicity of human MM cells. Significantly, this study demonstrates for the first time that Ad-NK4 inhibits cancer stem-like cell (CSC) properties as assessed by spheroid formation assay, side population analysis and flow cytometric sorting of CD24 cells. In addition to inhibiting phosphorylation of Met and AKT, Ad-NK4 markedly suppressed the active form of β-catenin, a key mediator of both Wnt and AKT pathways. It is further demonstrated that expression of NK4 suppresses β-catenin nuclear localization and transcriptional activity. Intriguingly, the expression levels of Oct4 and Myc, two critical stem cell factors and downstream targets of β-catenin, were also diminished by Ad-NK4. Furthermore, the strong antitumor effect of NK4 was found to be linked to its ability to inhibit CSCs as revealed by immunohistochemical examination of tumor specimens from a mouse xenograft model of human MM. These findings suggest that NK4 acts as a CSC inhibitor by impeding Met/AKT/β-catenin signaling and holds promise for achieving durable therapeutic responses in MM by constraining the CSC component of these aggressive tumors.

Gao Y, Zeng F, Wu JY, et al.
MiR-335 inhibits migration of breast cancer cells through targeting oncoprotein c-Met.
Tumour Biol. 2015; 36(4):2875-83 [PubMed] Related Publications
Metastasis is the leading cause of death in patients with breast cancer and aberrantly expressed microRNAs (miRNAs) are highly associated with this process. A previous study has shown that miR-335 is downregulated in breast cancer and can suppress tumor invasion and metastasis. Emerging evidences indicate that c-Met is implicated in cell scattering, migration, and invasion. However, little is known about the relationship between miR-335 expression and c-Met alteration in breast cancer. In the present study, we found that miR-335 expression was downregulated and c-Met protein expression was upregulated in two human breast cell lines. MiR-335 was found to negatively regulate c-Met protein level by directly targeting its 3' untranslated region (UTR). Forced expression of miR-335 decreased c-Met expression at protein levels and consequently diminished hepatocyte growth factor (HGF)-induced phosphorylation of c-Met and subsequently inhibited HGF promotion of breast cancer cell migration in a c-Met-dependent manner. MiR-335 expression was increased after 5-aza-2'-deoxycytidine (5-AZA-CdR) treatment, and 5-AZA-CdR treatment resulted in the same phenotype as the effect of miR-335 overexpression. Taken together, these results demonstrate that miR-335 suppresses breast cancer cell migration by negatively regulating the HGF/c-Met pathway.

Hao C, Wang L, Peng S, et al.
Gene mutations in primary tumors and corresponding patient-derived xenografts derived from non-small cell lung cancer.
Cancer Lett. 2015; 357(1):179-85 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Molecular annotated patient-derived xenograft (PDX) models are useful for the preclinical investigation of anticancer drugs and individualized anticancer therapy. We established 23 PDXs from 88 surgical specimens of lung cancer patients and determined gene mutations in these PDXs and their paired primary tumors by ultradeep exome sequencing on 202 cancer-related genes. The numbers of primary tumors with deleterious mutations in TP53, KRAS, PI3KCA, ALK, STK11, and EGFR were 43.5%, 21.7%, 17.4%, 17.4%, 13.0%, and 8.7%, respectively. Other genes with deleterious mutations in ≥3 (13.0%) primary tumors were MLL3, SETD2, ATM, ARID1A, CRIPAK, HGF, BAI3, EP300, KDR, PDGRRA and RUNX1. Of 315 mutations detected in the primary tumors, 293 (93%) were also detected in their corresponding PDXs, indicating that PDXs have the capacity to recapitulate the mutations in primary tumors. Nevertheless, a substantial number of mutations had higher allele frequencies in the PDXs than in the primary tumors, or were not detectable in the primary tumor, suggesting the possibility of tumor cell enrichment in PDXs or heterogeneity in the primary tumors. The molecularly annotated PDXs generated from this study could be useful for future translational studies.

Stewart MD, Ramani VC, Sanderson RD
Shed syndecan-1 translocates to the nucleus of cells delivering growth factors and inhibiting histone acetylation: a novel mechanism of tumor-host cross-talk.
J Biol Chem. 2015; 290(2):941-9 [PubMed] Article available free on PMC after 09/01/2016 Related Publications
The heparan sulfate proteoglycan syndecan-1 is proteolytically shed from the surface of multiple myeloma cells and is abundant in the bone marrow microenvironment where it promotes tumor growth, angiogenesis, and metastasis. In this study, we demonstrate for the first time that shed syndecan-1 present in the medium conditioned by tumor cells is taken up by bone marrow-derived stromal cells and transported to the nucleus. Translocation of shed syndecan-1 (sSDC1) to the nucleus was blocked by addition of exogenous heparin or heparan sulfate, pretreatment of conditioned medium with heparinase III, or growth of cells in sodium chlorate, indicating that sulfated heparan sulfate chains are required for nuclear translocation. Interestingly, cargo bound to sSDC1 heparan sulfate chains (i.e. hepatocyte growth factor) was transported to the nucleus along with sSDC1, and removal of heparan sulfate-bound cargo from sSDC1 abolished its translocation to the nucleus. Once in the nucleus, sSDC1 binds to the histone acetyltransferase enzyme p300, and histone acetyltransferase activity and histone acetylation are diminished. These findings reveal a novel function for shed syndecan-1 in mediating tumor-host cross-talk by shuttling growth factors to the nucleus and by altering histone acetylation in host cells. In addition, this work has broad implications beyond myeloma because shed syndecan-1 is present in high levels in many tumor types as well as in other disease states.

Durgan J, Tao G, Walters MS, et al.
SOS1 and Ras regulate epithelial tight junction formation in the human airway through EMP1.
EMBO Rep. 2015; 16(1):87-96 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
The human airway is lined with respiratory epithelial cells, which create a critical barrier through the formation of apical tight junctions. To investigate the molecular mechanisms underlying this process, an RNAi screen for guanine nucleotide exchange factors (GEFs) was performed in human bronchial epithelial cells (16HBE). We report that SOS1, acting through the Ras/MEK/ERK pathway, is essential for tight junction formation. Global microarray analysis identifies epithelial membrane protein 1 (EMP1), an integral tetraspan membrane protein, as a major transcriptional target. EMP1 is indispensable for tight junction formation and function in 16HBE cells and in a human airway basal progenitor-like cell line (BCi-NS1.1). Furthermore, EMP1 is significantly downregulated in human lung cancers. Together, these data identify important roles for SOS1/Ras and EMP1 in tight junction assembly during airway morphogenesis.

Goździk-Spychalska J, Szyszka-Barth K, Spychalski L, et al.
C-MET inhibitors in the treatment of lung cancer.
Curr Treat Options Oncol. 2014; 15(4):670-82 [PubMed] Related Publications
OPINION STATEMENT: Lung cancer is the most common malignant neoplasm and constitutes the most common neoplastic cause of death globally. The results of therapies employing standard chemotherapy are unsatisfactory. Currently, efforts are being made to personalize the therapy; numerous clinical studies are being conducted around the world to assess the efficacy and safety of agents directed at molecular targets. One of these molecular targets is the c-MET proto-oncogene, whose primary ligand is hepatocyte growth factor (HGF). C-MET hyperactivity has been observed in numerous neoplasms, including non-small-cell lung carcinoma. Prolonged or continuous activity of the receptor leads to excessive cell proliferation and is related to the development or progression of neoplastic disease. C-MET inhibitors can be classified into three groups: small-molecule tyrosine kinase inhibitors of the c-MET receptor (crizotinib, tivantinib, cabozantinib, foretinib), as well as monoclonal antibodies against c-MET (onartuzumab) and against the HGF ligand (ficlatuzumab, rilotumumab). The efficacy and safety of these agents is assessed both in monotherapy and in combination with other molecularly targeted agents. Furthermore, the toxicity profile of c-MET inhibitors is completely different from that of standard chemotherapy. The best understood c-MET inhibitor used in the treatment of non-small-cell lung carcinoma patients is crizotinib. It is registered for patients with the presence of ALK gene rearrangements after the failure of the first line of treatment based on platinum derivatives. The purpose of this present paper is to present clinical studies that assessed the efficacy and safety of c-MET inhibitors for the treatment of non-small-cell lung carcinoma, as well as current indications for the use of these molecules.

Matsumoto Y, Maemondo M, Ishii Y, et al.
A phase II study of erlotinib monotherapy in pre-treated non-small cell lung cancer without EGFR gene mutation who have never/light smoking history: re-evaluation of EGFR gene status (NEJ006/TCOG0903).
Lung Cancer. 2014; 86(2):195-200 [PubMed] Related Publications
OBJECTIVES: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are particularly effective in non-small cell lung cancer (NSCLC) patients harboring active EGFR mutations. However, some studies have reported survival benefits in NSCLC patients with wild-type EGFR upon erlotinib treatment. This trial was conducted to evaluate the efficacy of erlotinib monotherapy and investigate the predictive values of several biomarkers.
PATIENTS AND METHODS: Patients with previously treated NSCLC but without EGFR gene mutations that had never or light smoked were eligible for this study. Gene status screening was performed using the PNA-LNA PCR clamp method. Erlotinib was administered until disease progression or unacceptable toxicities occurred. EGFR gene status was re-evaluated using the fragment method to detect exon 19 deletions and the Cycleave-PCR method to detect point mutations. Expression of hepatocyte growth factor (HGF), Met, and thymidylate synthase (TS) were evaluated using immunohistochemistry.
RESULTS: Forty-seven patients were enrolled in the study between March 2010 and November 2011. Objective response rate (ORR) and disease control rate (DCR) were 15.2% and 41.3%. Re-evaluations for EGFR gene were performed in 32 tumor samples. EGFR gene mutations were found in eight samples (5:exon 19 deletion, 2:G719X, 1:L858R). Six patients had PR and two had SD among these eight patients. A total of 24 patients were confirmed as wild-type EGFR using different methods. ORR and DCR were 4.2% and 41.7%. The median progression free survival (PFS) and median survival times were 2.0 and 6.0 months, respectively. Patients with tumors expressing HGF showed shorter PFS but not MET or TS.
CONCLUSIONS: Re-examination of EGFR gene status using different detecting method or different sample should be considered to grasp a chance of erlotinib treatment after first line treatment. In confirmed EGFR wild NSCLC, negative HGF staining could be a biomarker for longer PFS by erlotonib treatment.

Seneviratne D, Ma J, Tan X, et al.
Genomic instability causes HGF gene activation in colon cancer cells, promoting their resistance to necroptosis.
Gastroenterology. 2015; 148(1):181-191.e17 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
BACKGROUND & AIMS: Genomic instability promotes colon carcinogenesis by inducing genetic mutations, but not all genes affected by this process have been identified. We investigated whether genomic instability in human colorectal cancer (CRC) cells produces mutations in the hepatocyte growth factor (HGF) gene.
METHODS: We genotyped human colon tumor tissues and adjacent nontumor tissues collected from 78 patients University of Pittsburgh Health Sciences and Veterans Hospital, along with 40 human CRC and adjacent nontumor tissues in a commercial microarray. We used cellular, biochemical, and molecular biological techniques to investigate the factors that alter HGF signaling in colon cancer cells and its effects on cell proliferation and survival.
RESULTS: All tested human CRC tissues and cell lines that had microsatellite instability contained truncations in the regulatory deoxyadenosine tract element (DATE) of the HGF gene promoter. The DATE was unstable in 14% (11 of 78) of CRC samples; DATE truncation was also polymorphic and detected in 18% (13 of 78) of CRC tissues without microsatellite instability. In CRC cell lines, truncation of DATE activated expression of HGF, resulting in its autocrine signaling via MET. This promoted cell proliferation and resistance to necroptosis. HGF signaling via MET reduced levels of the receptor-interacting serine-threonine kinase 1, a mediator of necroptosis, in CRC cells. High levels of HGF protein in tumor tissues correlated with lower levels of receptor-interacting serine-threonine kinase 1 and shorter survival times of patients.
CONCLUSIONS: Thirty-one percent of CRC samples contain alterations in the DATE of the HGF promoter. Disruption of the DATE increased HGF signaling via MET and reduced levels of receptor-interacting serine-threonine kinase 1 and CRC cell necroptosis. DATE alteration might be used as a prognostic factor or to select patients for therapies that target HGF-MET signaling.

Liu L, Zeng W, Wortinger MA, et al.
LY2875358, a neutralizing and internalizing anti-MET bivalent antibody, inhibits HGF-dependent and HGF-independent MET activation and tumor growth.
Clin Cancer Res. 2014; 20(23):6059-70 [PubMed] Related Publications
PURPOSE: MET, the receptor for hepatocyte growth factor (HGF), has been implicated in driving tumor proliferation and metastasis. High MET expression is correlated with poor prognosis in multiple cancers. Activation of MET can be induced either by HGF-independent mechanisms such as gene amplification, specific genetic mutations, and transcriptional upregulation or by HGF-dependent autocrine or paracrine mechanisms.
EXPERIMENTAL DESIGN/RESULTS: Here, we report on LY2875358, a novel humanized bivalent anti-MET antibody that has high neutralization and internalization activities, resulting in inhibition of both HGF-dependent and HGF-independent MET pathway activation and tumor growth. In contrast to other bivalent MET antibodies, LY2875358 exhibits no functional agonist activity and does not stimulate biologic activities such as cell proliferation, scattering, invasion, tubulogenesis, or apoptosis protection in various HGF-responsive cells and no evidence of inducing proliferation in vivo in a monkey toxicity study. LY2875358 blocks HGF binding to MET and HGF-induced MET phosphorylation and cell proliferation. In contrast to the humanized one-armed 5D5 anti-MET antibody, LY2875358 induces internalization and degradation of MET that inhibits cell proliferation and tumor growth in models where MET is constitutively activated. Moreover, LY2875358 has potent antitumor activity in both HGF-dependent and HGF-independent (MET-amplified) xenograft tumor models. Together, these findings indicate that the mechanism of action of LY2875358 is different from that of the one-armed MET antibody.
CONCLUSIONS: LY2875358 may provide a promising therapeutic strategy for patients whose tumors are driven by both HGF-dependent and HGF-independent MET activation. LY2875358 is currently being investigated in multiple clinical studies.

Ferrucci A, Moschetta M, Frassanito MA, et al.
A HGF/cMET autocrine loop is operative in multiple myeloma bone marrow endothelial cells and may represent a novel therapeutic target.
Clin Cancer Res. 2014; 20(22):5796-807 [PubMed] Related Publications
PURPOSE: The aim of this study was to investigate the angiogenic role of the hepatocyte growth factor (HGF)/cMET pathway and its inhibition in bone marrow endothelial cells (EC) from patients with multiple myeloma versus from patients with monoclonal gammopathy of undetermined significance (MGUS) or benign anemia (control group).
EXPERIMENTAL DESIGN: The HGF/cMET pathway was evaluated in ECs from patients with multiple myeloma (multiple myeloma ECs) at diagnosis, at relapse after bortezomib- or lenalidomide-based therapies, or on refractory phase to these drugs; in ECs from patients with MGUS (MGECs); and in those patients from the control group. The effects of a selective cMET tyrosine kinase inhibitor (SU11274) on multiple myeloma ECs' angiogenic activities were studied in vitro and in vivo.
RESULTS: Multiple myeloma ECs express more HGF, cMET, and activated cMET (phospho (p)-cMET) at both RNA and protein levels versus MGECs and control ECs. Multiple myeloma ECs are able to maintain the HGF/cMET pathway activation in absence of external stimulation, whereas treatment with anti-HGF and anti-cMET neutralizing antibodies (Ab) is able to inhibit cMET activation. The cMET pathway regulates several multiple myeloma EC activities, including chemotaxis, motility, adhesion, spreading, and whole angiogenesis. Its inhibition by SU11274 impairs these activities in a statistically significant fashion when combined with bortezomib or lenalidomide, both in vitro and in vivo.
CONCLUSIONS: An autocrine HGF/cMET loop sustains multiple myeloma angiogenesis and represents an appealing new target to potentiate the antiangiogenic management of patients with multiple myeloma.

Sasi W, Ye L, Jiang WG, et al.
In vitro and in vivo effects of suppressor of cytokine signalling 7 knockdown in breast cancer: the influence on cellular response to hepatocyte growth factor.
Biomed Res Int. 2014; 2014:648040 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
PURPOSE: Suppressor of cytokine signaling 7 (SOCS7) is a member of the SOCS family and is known to interact with phospholipase Cγ-1 (PLCγ-1), a key downstream mediator of the hepatocyte growth factor (HGF)/C-MET axis. Here, we report our observations of the effect of knocking down SOCS7 gene on the behaviour of breast cancer cells both in vitro and in vivo and to elucidate whether this involves HGF/C-MET pathway using the PLCγ-1 blocker U73122.
METHODS: MCF7 and MDA-MB-231 breast cancer cells were transfected with anti-SOCS7 ribozymal transgene, to create sublines with SOCS7 knockdown. The in vitro growth and migration of the cells were evaluated in basic conditions and with HGF and U73122 treatment using growth assays, scratch-wound, and electrical cell impedance sensing (ECIS) migration assays. MCF7 and MDA-MB-231 in vivo tumour xenograft growth were also studied.
RESULTS: Basal in vitro growth and migration of both cellular lines and the in vivo MCF7 xenograft growth were significantly enhanced with SOCS7 knockdown. In vitro HGF treatment has further influenced the growth and migration when SOCS7 gene was knocked-down in both cellular lines (P < 0.05). PLCγ-1 pharmacological inhibition of the HGF/C-MET cascade during their in vitro growth and migration seemed to only occur when SOCS7 gene was knocked down.
CONCLUSIONS: We report a unique regulatory role for SOCS7 in controlling the malignant behaviour of breast cancer lines MCF7 and MDA-MB-231 in vitro and the MCF7 tumour xenografts in vivo. We also report a regulatory role for SOCS7 during the in vitro HGF-induced growth and migration in these cells as HGF treatment and SOCS7 loss have synergistically enhanced these functions. This SOCS7 knockdown-attributed effect could be due to a precise anti-PLCγ-1 role.

Korhan P, Erdal E, Kandemiş E, et al.
Reciprocal activating crosstalk between c-Met and caveolin 1 promotes invasive phenotype in hepatocellular carcinoma.
PLoS One. 2014; 9(8):e105278 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
c-Met, the receptor for Hepatocyte Growth Factor (HGF), overexpressed and deregulated in Hepatocellular Carcinoma (HCC). Caveolin 1 (CAV1), a plasma membrane protein that modulates signal transduction molecules, is also overexpressed in HCC. The aim of this study was to investigate biological and clinical significance of co-expression and activation of c-Met and CAV1 in HCC. We showed that c-Met and CAV1 were co-localized in HCC cells and HGF treatment increased this association. HGF-triggered c-Met activation caused a concurrent rise in both phosphorylation and expression of CAV1. Ectopic expression of CAV1 accelerated c-Met signaling, resulted in enhanced migration, invasion, and branching-morphogenesis. Silencing of CAV1 downregulated c-Met signaling, and decreased migratory/invasive capability of cells and attenuated branching morphogenesis. In addition, activation and co-localization of c-Met and CAV1 were elevated during hepatocarcinogenesis. In conclusion reciprocal activating crosstalk between c-Met and CAV1 promoted oncogenic signaling of c-Met contributed to the initiation and progression of HCC.

Gangemi R, Amaro A, Gino A, et al.
ADAM10 correlates with uveal melanoma metastasis and promotes in vitro invasion.
Pigment Cell Melanoma Res. 2014; 27(6):1138-48 [PubMed] Related Publications
Uveal melanoma (UM) is a rare ocular tumor that may lead to deadly metastases in 50% of patients. A disintegrin and metalloproteinase (ADAM)10, ADAM17, and the HGF-receptor c-Met support invasiveness in different tumors. Here, we report that high ADAM10, MET, and, to a lesser extent, ADAM17 gene expression correlates with poor progression-free survival in UM patients (hazard ratio 2.7, 2.6, and 1.9, respectively). About 60% of primary UM expresses c-Met and/or ADAM10 proteins. Four UM cell lines display high levels of ADAM10 and ADAM17, which constitutively cleave c-Met, inducing the release of soluble c-Met. ADAM10/17 pharmacological inhibition or gene silencing reduces c-Met shedding, but has limited impact on surface c-Met, which is overexpressed. Importantly, ADAM10 silencing inhibits UM cell invasion driven by FCS or HGF, while ADAM17 silencing has a limited effect. Altogether our data indicate that ADAM10 has a pro-invasive role and may contribute to UM progression.

Kirzin S, Marisa L, Guimbaud R, et al.
Sporadic early-onset colorectal cancer is a specific sub-type of cancer: a morphological, molecular and genetics study.
PLoS One. 2014; 9(8):e103159 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
Sporadic early onset colorectal carcinoma (EOCRC) which has by definition no identified hereditary predisposition is a growing problem that remains poorly understood. Molecular analysis could improve identification of distinct sub-types of colorectal cancers (CRC) with therapeutic implications and thus can help establish that sporadic EOCRC is a distinct entity. From 954 patients resected for CRC at our institution, 98 patients were selected. Patients aged 45-60 years were excluded to help define "young" and "old" groups. Thirty-nine cases of sporadic EOCRC (patients ≤ 45 years with microsatellite stable tumors) were compared to both microsatellite stable tumors from older patients (36 cases, patients>60 years) and to groups of patients with microsatellite instability. Each group was tested for TP53, KRAS, BRAF, PIK3CA mutations and the presence of a methylator phenotype. Gene expression profiles were also used for pathway analysis. Compared to microsatellite stable CRC from old patients, sporadic EOCRC were characterized by distal location, frequent synchronous metastases and infrequent synchronous adenomas but did not have specific morphological characteristics. A familial history of CRC was more common in sporadic EOCRC patients despite a lack of identified hereditary conditions (p = 0.013). Genetic studies also showed the absence of BRAF mutations (p = 0.022) and the methylator phenotype (p = 0.005) in sporadic EOCRC compared to older patients. Gene expression analysis implicated key pathways such as Wnt/beta catenin, MAP Kinase, growth factor signaling (EGFR, HGF, PDGF) and the TNFR1 pathway in sporadic EOCRC. Wnt/beta catenin signaling activation was confirmed by aberrant nuclear beta catenin immunostaining (p = 0.01). This study strongly suggests that sporadic EOCRC is a distinct clinico-molecular entity presenting as a distal and aggressive disease associated with chromosome instability. Furthermore, several signaling pathways including the TNFR1 pathway have been identified as potential biomarkers for both the diagnosis and treatment of this disease.

De S, Dermawan JK, Stark GR
EGF receptor uses SOS1 to drive constitutive activation of NFκB in cancer cells.
Proc Natl Acad Sci U S A. 2014; 111(32):11721-6 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
Activation of nuclear factor κB (NFκB) is a central event in the responses of normal cells to inflammatory signals, and the abnormal constitutive activation of NFκB is important for the survival of most cancer cells. In nonmalignant human cells, EGF stimulates robust activation of NFκB. The kinase activity of the EGF receptor (EGFR) is required, because the potent and specific inhibitor erlotinib blocks the response. Down-regulating EGFR expression or inhibiting EGFR with erlotinib impairs constitutive NFκB activation in several different types of cancer cells and, conversely, increased activation of NFκB leads to erlotinib resistance in these cells. We conclude that EGF is an important mediator of NFκB activation in cancer cells. To explore the mechanism, we selected an erlotinib-resistant cell line in which the guanine nucleotide exchange factor Son of Sevenless 1 (SOS1), well known to be important for EGF-dependent signaling to MAP kinases, is overexpressed. Increased expression of SOS1 increases NFκB activation in several different types of cancer cells, and ablation of SOS1 inhibits EGF-induced NFκB activation in these cells, indicating that SOS1 is a functional component of the pathway connecting EGFR to NFκB activation. Importantly, the guanine nucleotide exchange activity of SOS1 is not required for NFκB activation.

Korhan P, Erdal E, Atabey N
MiR-181a-5p is downregulated in hepatocellular carcinoma and suppresses motility, invasion and branching-morphogenesis by directly targeting c-Met.
Biochem Biophys Res Commun. 2014; 450(4):1304-12 [PubMed] Related Publications
c-Met receptor tyrosine kinase has been regarded as a promising therapeutic target for hepatocellular carcinoma (HCC). Recently, microRNAs (miRNAs) have been shown as a novel mechanism to control c-Met expression in cancer. In this study, we investigate the potential contribution of miR-181a-5p dysregulation to the biology of c-Met overexpression in HCC. Herein, we found an inverse expression pattern between miR-181a-5p and c-Met expression in normal, cirrhotic and HCC liver tissues. Luciferase assay confirmed that miR-181a-5p binding to the 3'-UTR of c-Met downregulated the expression of c-Met in HCC cells. Overexpression of miR-181a-5p suppressed both HGF-independent and -dependent activation of c-Met and consequently diminished branching-morphogenesis and invasion. Combined treatment with miR-181a-5p and c-Met inhibitor led to a further inhibition of c-Met-driven cellular activities. Knockdown of miR-181a-5p promoted HGF-independent/-dependent signaling of c-Met and accelerated migration, invasion and branching-morphogenesis. In conclusion, our results demonstrated for the first time that c-Met is a functional target gene of miR-181a-5p and the loss of miR-181a-5p expression led to the activation of c-Met-mediated oncogenic signaling in hepatocarcinogenesis. These findings display a novel molecular mechanism of c-Met regulation in HCC and strategies to increase miR-181a5p level might be an alternative approach for the enhancement of the inhibitory effects of c-Met inhibitors.

Stabile LP, Rothstein ME, Gubish CT, et al.
Co-targeting c-Met and COX-2 leads to enhanced inhibition of lung tumorigenesis in a murine model with heightened airway HGF.
J Thorac Oncol. 2014; 9(9):1285-93 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: The hepatocyte growth factor (HGF)/c-Met pathway is often dysregulated in non-small-cell lung cancer (NSCLC). HGF activation of c-Met induces cyclooxygenase-2 (COX-2), resulting in downstream stimulation by prostaglandin E2 of additional pathways. Targeting both c-Met and COX-2 might lead to enhanced antitumor effects by blocking signaling upstream and downstream of c-Met.
METHODS: Effects of crizotinib or celecoxib alone or in combination were tested in NSCLC cells in vitro and in mice transgenic for airway expression of human HGF.
RESULTS: Proliferation and invasion of NSCLC cells treated with a combination of crizotinib and celecoxib were significantly lower compared with single treatments. Transgenic mice showed enhanced COX-2 expression localized to preneoplastic areas following exposure to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, which was not present without carcinogen exposure. This shows that COX-2 activity is present during lung tumor development in a high HGF environment. After 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone treatment, a significant decrease in the number of lung tumors per animal was observed after 13-week treatments of crizotinib, celecoxib, or the combination compared with placebo (p < 0.001). With combination treatment, the number of tumors was also significantly lower than single agent treatment (p < 0.001). In the resulting lung tumors, P-c-Met, COX-2, prostaglandin E2, and P-MAPK were significantly downmodulated by combination treatment compared with single treatment. Expression of the epithelial-mesenchymal transition markers E-cadherin and snail was also modulated by combination treatment.
CONCLUSIONS: In the presence of high HGF, dual inhibition of c-Met and COX-2 may enhance antitumor effects. This combination may have clinical potential in NSCLCs with high HGF/c-Met expression or epithelial-mesenchymal transition phenotype.

Frittoli E, Palamidessi A, Marighetti P, et al.
A RAB5/RAB4 recycling circuitry induces a proteolytic invasive program and promotes tumor dissemination.
J Cell Biol. 2014; 206(2):307-28 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
The mechanisms by which tumor cells metastasize and the role of endocytic proteins in this process are not well understood. We report that overexpression of the GTPase RAB5A, a master regulator of endocytosis, is predictive of aggressive behavior and metastatic ability in human breast cancers. RAB5A is necessary and sufficient to promote local invasion and distant dissemination of various mammary and nonmammary tumor cell lines, and this prometastatic behavior is associated with increased intratumoral cell motility. Specifically, RAB5A is necessary for the formation of invadosomes, membrane protrusions specialized in extracellular matrix (ECM) degradation. RAB5A promotes RAB4- and RABENOSYN-5-dependent endo/exocytic cycles (EECs) of critical cargos (membrane-type 1 matrix metalloprotease [MT1-MMP] and β3 integrin) required for invadosome formation in response to motogenic stimuli. This trafficking circuitry is necessary for spatially localized hepatocyte growth factor (HGF)/MET signaling that drives invasive, proteolysis-dependent chemotaxis in vitro and for conversion of ductal carcinoma in situ to invasive ductal carcinoma in vivo. Thus, RAB5A/RAB4 EECs promote tumor dissemination by controlling a proteolytic, mesenchymal invasive program.

Koyama N, Saito K, Nishioka Y, et al.
Pharmacodynamic change in plasma angiogenic proteins: a dose-escalation phase 1 study of the multi-kinase inhibitor lenvatinib.
BMC Cancer. 2014; 14:530 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: Lenvatinib (E7080), an oral multi-kinase inhibitor, has inhibitory action on tumor cell proliferation and tumor angiogenesis in preclinical models. We evaluated correlations between pharmacodynamic (PD) biomarkers with patient clinical outcomes in a lenvatinib phase 1 dose-escalation study.
METHODS: Plasma angiogenic proteins were evaluated as potential PD biomarkers of response to lenvatinib in a dose-escalation phase 1 study. Lenvatinib was administered to 27 patients by twice-daily dosing in 3-week cycles; 2 weeks of treatment followed by 1 week of rest until discontinuation. Blood samples for plasma proteins were collected on days 1 (baseline), 8, and 15 of cycle 1, and days 1, 8, and 15 of cycle 2. Selected clinical outcomes, including tumor shrinkage and adverse events (AEs), were used for correlative analyses of pharmacokinetic parameters and PD biomarkers.
RESULTS: Tumor shrinkage and changes in PD biomarkers (increased vascular endothelial growth factor [VEGF] and stromal cell-derived factor 1 alpha [SDF1α] levels and decreased soluble VEGF receptor 2 [sVEGFR2] levels) significantly correlated with increasing lenvatinib exposure. Observed changes in levels of VEGF, SDF1α, and sVEGFR2 were maintained on day 15 of cycle 1, but returned to baseline during the 1-week rest period, and similar changes were induced by reinstitution of treatment in cycle 2. The worst grades of hypertension, proteinuria, and fatigue were associated with changes in VEGF and HGF at day 8 of cycle 1. Maximum tumor shrinkage was correlated with increased SDF1α levels. Decreased sVEGFR2 level was also correlated with tumor shrinkage and frequency of hypertension, proteinuria, and fatigue. Tumor shrinkage significantly correlated with the worst grade of proteinuria, but not with hypertension or fatigue.
CONCLUSION: PD biomarker changes observed in plasma angiogenic proteins are correlated with lenvatinib-induced tumor shrinkage and AEs. Our findings warrant further assessment of plasma proteins associated with angiogenesis as potential biomarkers of lenvatinib activity.
TRIAL REGISTRATION: NCT00280397 (January 20, 2006).

Zhou JY, Chen X, Zhao J, et al.
MicroRNA-34a overcomes HGF-mediated gefitinib resistance in EGFR mutant lung cancer cells partly by targeting MET.
Cancer Lett. 2014; 351(2):265-71 [PubMed] Related Publications
In non-small-cell lung cancer (NSCLC) that harbours an activating epidermal growth factor receptor (EGFR) mutation, over-expression of hepatocyte growth factor (HGF) is an important mechanism involved in the acquired resistance to EGFR-tyrosine kinase inhibitors (TKIs) by restoring activity of the PI3K/Akt pathway via phosphorylation of MET. In our study, we found that the forced expression of miR-34a inhibited cell growth and induced apoptosis partly by targeting MET in HGF-induced gefitinib-resistant HCC827 and PC-9 cells. Furthermore, dramatic tumour regression was observed in the miR-34a plus gefitinib group in HGF-induced gefitinib resistant mouse xenograft models. This study demonstrates for the first time that miR-34a rescues HGF-induced gefitinib resistance in EGFR mutant NSCLC cells.

Sanders AJ, Ye L, Li J, et al.
Tumour angiogenesis and repulsive guidance molecule b: a role in HGF- and BMP-7-mediated angiogenesis.
Int J Oncol. 2014; 45(3):1304-12 [PubMed] Related Publications
Hepatocyte growth factor (HGF) is a key growth factor linked to promoting cancer progression and angiogenesis. The present study identifies repulsive guidance molecule b (RGMb), a bone morphogenetic protein (BMP) co-receptor, as a gene whose expression is regulated by HGF and explores the potential of RGMb to contribute to the process of angiogenesis. Microarray analysis was used to identify HGF responsive genes in HECV endothelial cells, identifying RGMb. RGMb was subsequently targeted using a ribozyme transgene system and its role in angiogenesis assessed using in vitro and in vivo assays. The importance of RGMb in pro-angiogenic responses to HGF and BMP-7 was also assessed. Microarray analysis identified RGMb as a gene upregulated as a result of HGF treatment. Knockdown of RGMb, in HECV cells, had minimal effects on tubule formation, brought about a general, although non-significant increase in cell growth and enhanced cell migration. Similarly, no significant effect of RGMb knockdown was found in vivo using a co-inoculation angiogenesis model. Knockdown of RGMb was, however, found to reduce the responsiveness of HECV cells to HGF treatment and particularly to BMP-7 treatment in regard to the enhanced migratory and tubule formation brought about by these treatments in vitro. Our results indicate that RGMb expression can be influenced by HGF treatment. Whilst this molecule appears to have minimal impact on angiogenic traits individually, it demonstrates an involvement in propagating pro-angiogenic effects of HGF and particularly BMP-7 and thus, may play a role in regulating angiogenic responses to HGF and BMP-7.

Mariani M, McHugh M, Petrillo M, et al.
HGF/c-Met axis drives cancer aggressiveness in the neo-adjuvant setting of ovarian cancer.
Oncotarget. 2014; 5(13):4855-67 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Ovarian cancer is the most lethal gynecologic malignancy. Recently, NACT (Neo Adjuvant Chemotherapy) has been tested as alternative approach for the management of ovarian cancer patients. A biological predictor helpful in selecting patients for NACT would be desirable. This study was aimed at identifying actionable mechanisms of resistance to NACT. Expression of a panel of microRNAs was screened in a discovery set of 85 patients. Analysis of the potential targets was conducted in the same RNAs by calculating significant correlations between microRNAs and genes. Quantitative fluorescent immunohistochemistry was employed in a validation set of 109 patients. MiR-193a-5p was significantly overexpressed in the NACT setting. Analysis of its potential targets demonstrated that this microRNA is also significantly correlated with HGF and MET genes. Analysis of protein expression in samples taken before and after NACT demonstrated that both HGF and c-Met are increased after NACT. Patients who relapse shortly after NACT exhibited the highest relative basal expression of both HGF and c-Met, while the opposite phenomenon was observed in the best responders. Mir-193a-5p, HGF and c-Met expression may help select eligible patients for this modality of treatment. Moreover, inhibitors of this pathway may improve the efficacy of NACT.

Outani H, Tanaka T, Wakamatsu T, et al.
Establishment of a novel clear cell sarcoma cell line (Hewga-CCS), and investigation of the antitumor effects of pazopanib on Hewga-CCS.
BMC Cancer. 2014; 14:455 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: Clear cell sarcoma (CCS) is a therapeutically unresolved, aggressive, soft tissue sarcoma (STS) that predominantly affects young adults. This sarcoma is defined by t(12;22)(q13;q12) translocation, which leads to the fusion of Ewing sarcoma gene (EWS) to activating transcription factor 1 (ATF1) gene, producing a chimeric EWS-ATF1 fusion gene. We established a novel CCS cell line called Hewga-CCS and developed an orthotopic tumor xenograft model to enable comprehensive bench-side investigation for intensive basic and preclinical research in CCS with a paucity of experimental cell lines.
METHODS: Hewga-CCS was derived from skin metastatic lesions of a CCS developed in a 34-year-old female. The karyotype and chimeric transcript were analyzed. Xenografts were established and characterized by morphology and immunohistochemical reactivity. Subsequently, the antitumor effects of pazopanib, a recently approved, novel, multitargeted, tyrosine kinase inhibitor (TKI) used for the treatment of advanced soft tissue sarcoma, on Hewga-CCS were assessed in vitro and in vivo.
RESULTS: Hewga-CCS harbored the type 2 EWS-ATF1 transcript. Xenografts morphologically mimicked the primary tumor and expressed S-100 protein and antigens associated with melanin synthesis (Melan-A, HMB45). Pazopanib suppressed the growth of Hewga-CCS both in vivo and in vitro. A phospho-receptor tyrosine kinase array revealed phosphorylation of c-MET, but not of VEGFR, in Hewga-CCS. Subsequent experiments showed that pazopanib exerted antitumor effects through the inhibition of HGF/c-MET signaling.
CONCLUSIONS: CCS is a rare, devastating disease, and our established CCS cell line and xenograft model may be a useful tool for further in-depth investigation and understanding of the drug-sensitivity mechanism.

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