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Special Issue "Alterations to Signalling Pathways in Cancer Cells"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 May 2017)

Special Issue Editor

Guest Editor
Dr. Terrence Piva

School of Health & Biomedical Sciences, RMIT University, PO Box 71 Bundoora, Victoria 3083, Australia
Website | E-Mail
Phone: +61-3-99256503
Fax: +61 3 9925 7063
Interests: cell signalling; skin cancer; photobiology; photoimmunology; enzymology; cell metabolism; oxidative stress; cell death; inflammation; enzyme kinetics; metal oxide nanoparticles; sunscreens

Special Issue Information

Dear Colleagues,

It is well acknowledged that in most transformed and tumour cells, that intracellular signalling pathways are altered to those observed in non-transformed cells.  Considerable interest has been focused on understanding how these signalling pathways have been altered, and how these differences can be used to devise potential therapeutic treatments that may enhance survival rates of these cancer patients.  In the area of melanoma research, a great deal of effort has been directed to understanding how those cells containing the BRAFV600E mutation can overcome treatment with specific inhibitors, such as vemurafenib.  This Special Issue of the International Journal of Molecular Sciences, “Alterations to Signalling Pathways in Cancer Cells”, will focus on how intracellular signalling pathways are altered in tumour cells.  Authors are invited to submit manuscripts that compare how these pathways differ to that seen in untransformed cells, and how they differ to that seen in untransformed cells or in tumour cells undergoing treatment.  The results from these studies may provide useful information in devising treatments that may enhance survival rates of cancer patients.

Dr. Terrence Piva
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • MAPK
  • BRAF
  • Oncogenes
  • Tumour suppressor genes
  • RTK
  • PI3K/Akt
  • Cell survival
  • Metastasis

Published Papers (20 papers)

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Research

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Open AccessArticle Phellinus linteus Grown on Germinated Brown Rice Increases Cetuximab Sensitivity of KRAS-Mutated Colon Cancer
Int. J. Mol. Sci. 2017, 18(8), 1746; https://doi.org/10.3390/ijms18081746
Received: 30 June 2017 / Revised: 1 August 2017 / Accepted: 4 August 2017 / Published: 11 August 2017
PDF Full-text (3831 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Colon cancer is one of the most common types of cancer, and it has recently become a leading cause of death worldwide. Among colon cancers, the v-ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated form is notorious for its non-druggable features. Cetuximab, a
[...] Read more.
Colon cancer is one of the most common types of cancer, and it has recently become a leading cause of death worldwide. Among colon cancers, the v-ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated form is notorious for its non-druggable features. Cetuximab, a monoclonal antibody that binds to the epidermal growth factor receptor, has been introduced as an antitumor therapy; however, secondary resistance and side effects significantly limit its effective use in these cancers. In this study, we prepared Phellinuslinteus on germinated brown rice (PBR) extracts to increase the sensitivity of KRAS-mutated colon cancers to cetuximab. The combined treatment of PBR extract and cetuximab suppressed SW480 cell viability/proliferation, with the cells exhibiting altered cellular morphology and clonogenic potential. AnnexinV–fluorescein isothiocyanate/propidium iodide–stained flow cytometry and Western blotting were performed, and PBR extract combined with cetuximab treatment increased apoptosis of the SW480 cells and suppressed their KRAS protein expression. The potential of PBR as a synergistic anticancer agent was further investigated in a tumor-xenografted mouse model. Tumor growth was significantly suppressed with PBR extract and cetuximab co-treatment. In conclusion, PBR increased the sensitivity of KRAS-mutated colon cancer cells to cetuximab, which indicates the potential use of PBR as a medical food against colon cancer. Full article
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)
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Open AccessArticle Tricetin Induces Apoptosis of Human Leukemic HL-60 Cells through a Reactive Oxygen Species-Mediated c-Jun N-Terminal Kinase Activation Pathway
Int. J. Mol. Sci. 2017, 18(8), 1667; https://doi.org/10.3390/ijms18081667
Received: 24 May 2017 / Revised: 20 July 2017 / Accepted: 25 July 2017 / Published: 31 July 2017
Cited by 3 | PDF Full-text (3131 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Tricetin is a dietary flavonoid with cytostatic properties and antimetastatic activities in various solid tumors. The anticancer effect of tricetin in nonsolid tumors remains unclear. Herein, the molecular mechanisms by which tricetin exerts its anticancer effects on acute myeloid leukemia (AML) cells were
[...] Read more.
Tricetin is a dietary flavonoid with cytostatic properties and antimetastatic activities in various solid tumors. The anticancer effect of tricetin in nonsolid tumors remains unclear. Herein, the molecular mechanisms by which tricetin exerts its anticancer effects on acute myeloid leukemia (AML) cells were investigated. Results showed that tricetin inhibited cell viability in various types of AML cell lines. Tricetin induced morphological features of apoptosis such as chromatin condensation and phosphatidylserine (PS) externalization, and significantly activated proapoptotic signaling including caspase-8, -9, and -3 activation and poly(ADP-ribose) polymerase (PARP) cleavage in HL-60 AML cells. Of note, tricetin-induced cell growth inhibition was dramatically reversed by a pan caspase and caspase-8- and -9-specific inhibitors, suggesting that this compound mainly acts through a caspase-dependent pathway. Moreover, treatment of HL-60 cells with tricetin induced sustained activation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), and inhibition of ERK and JNK by their specific inhibitors respectively promoted and abolished tricetin-induced cell apoptosis. Dichlorofluorescein (DCF) staining showed that intracellular reactive oxygen species (ROS) levels were higher in tricetin-treated HL-60 cells compared to the control group. Moreover, an ROS scavenger, N-acetylcysteine (NAC), reversed tricetin-induced JNK activation and subsequent cell apoptosis. In conclusion, our results indicated that tricetin induced cell death of leukemic HL-60 cells through induction of intracellular oxidative stress following activation of a JNK-mediated apoptosis pathway. A combination of tricetin and an ERK inhibitor may be a better strategy to enhance the anticancer activities of tricetin in AML. Full article
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)
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Open AccessArticle Mollugin Has an Anti-Cancer Therapeutic Effect by Inhibiting TNF-α-Induced NF-κB Activation
Int. J. Mol. Sci. 2017, 18(8), 1619; https://doi.org/10.3390/ijms18081619
Received: 27 May 2017 / Revised: 19 June 2017 / Accepted: 20 July 2017 / Published: 26 July 2017
PDF Full-text (2482 KB) | HTML Full-text | XML Full-text
Abstract
The NF-κB signaling pathway plays a pivotal role in regulating the immune response and inflammation. However, it has been shown that NF-κB also has a major role in oncogenesis. Therefore, NF-κB inhibitors have been considered as potential drugs against cancer. Herein, we searched
[...] Read more.
The NF-κB signaling pathway plays a pivotal role in regulating the immune response and inflammation. However, it has been shown that NF-κB also has a major role in oncogenesis. Therefore, NF-κB inhibitors have been considered as potential drugs against cancer. Herein, we searched for NF-κB inhibitors from natural sources and identified mollugin from the roots of Rubia cordifolia L. as an inhibitor of NF-κB activation. We found that mollugin significantly inhibited the expression of an NF-κB reporter gene induced by tumor necrosis factor (TNF)-α in a dose-dependent manner. Moreover, mollugin inhibited TNF-α-induced phosphorylation and nuclear translocation of p65, phosphorylation and degradation of inhibitor of κB (IκBα), and IκB kinase (IKK) phosphorylation. Furthermore, we discovered that pretreatment of cells with mollugin prevented the TNF-α-induced expression of NF-κB target genes, such as genes related to proliferation (COX-2, Cyclin D1 and c-Myc), anti-apoptosis (Bcl-2, cIAP-1 and survivin), invasion (MMP-9 and ICAM-1), and angiogenesis (VEGF). We also demonstrated that mollugin potentiated TNF-α-induced apoptosis and inhibited proliferation of HeLa cells. We further demonstrated in vivo that mollugin suppressed the growth of tumor xenografts derived from HeLa cells. Taken together, mollugin may be a valuable candidate for cancer treatment by targeting NF-κB. Full article
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)
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Open AccessArticle TGF-β-Dependent Growth Arrest and Cell Migration in Benign and Malignant Breast Epithelial Cells Are Antagonistically Controlled by Rac1 and Rac1b
Int. J. Mol. Sci. 2017, 18(7), 1574; https://doi.org/10.3390/ijms18071574
Received: 21 June 2017 / Revised: 14 July 2017 / Accepted: 16 July 2017 / Published: 20 July 2017
PDF Full-text (2559 KB) | HTML Full-text | XML Full-text
Abstract
Despite improvements in diagnosis and treatment, breast cancer is still the most common cancer type among non-smoking females. TGF-β can inhibit breast cancer development by inducing cell cycle arrest in both, cancer cells and, as part of a senescence program in normal human
[...] Read more.
Despite improvements in diagnosis and treatment, breast cancer is still the most common cancer type among non-smoking females. TGF-β can inhibit breast cancer development by inducing cell cycle arrest in both, cancer cells and, as part of a senescence program in normal human mammary epithelial cells (HMEC). Moreover, TGF-β also drives cell migration and invasion, in part through the small GTPases Rac1 and Rac1b. Depletion of Rac1b or Rac1 and Rac1b in MDA-MB-231 or MDA-MB-435s breast cancer cells by RNA interference enhanced or suppressed, respectively, TGF-β1-induced migration/invasion. Rac1b depletion in MDA-MB-231 cells also increased TGF-β-induced p21WAF1 expression and ERK1/2 phosphorylation. Senescent HMEC (P15/P16), when compared to their non-senescent counterparts (P11/P12), presented with dramatically increased migratory activity. These effects were paralleled by elevated expression of genes associated with TGF-β signaling and metastasis, downregulated Rac1b, and upregulated Rac1. Our data suggest that acquisition of a motile phenotype in HMEC resulted from enhanced autocrine TGF-β signaling, invasion/metastasis-associated gene expression, and a shift in the ratio of antimigratory Rac1b to promigratory Rac1. We conclude that although enhanced TGF-β signaling is considered antioncogenic in HMEC by suppressing oncogene-induced transformation, this occurs at the expense of a higher migration and invasion potential. Full article
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)
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Open AccessArticle Oleic Acid Uptake Reveals the Rescued Enterocyte Phenotype of Colon Cancer Caco-2 by HT29-MTX Cells in Co-Culture Mode
Int. J. Mol. Sci. 2017, 18(7), 1573; https://doi.org/10.3390/ijms18071573
Received: 30 May 2017 / Revised: 7 July 2017 / Accepted: 16 July 2017 / Published: 20 July 2017
PDF Full-text (5528 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Gastrointestinal epithelium is the unique route for nutrients and for many pharmaceuticals to enter the body. The present study aimed to analyze precisely whether co-culture of two colon cancer cell lines, mucus-producing cells HT29-MTX and enterocyte-like Caco-2 cells, ameliorate differentiation into an in
[...] Read more.
Gastrointestinal epithelium is the unique route for nutrients and for many pharmaceuticals to enter the body. The present study aimed to analyze precisely whether co-culture of two colon cancer cell lines, mucus-producing cells HT29-MTX and enterocyte-like Caco-2 cells, ameliorate differentiation into an in vitro intestinal barrier model and the signaling pathways involved. Differentiated Caco-2 cells gene datasets were compared first to intestinal or cancer phenotypes and second to signaling pathway gene datasets. Experimental validations were performed in real-time experiments, immunochemistry, and gene expression analyses on Caco-2 versus co-cultures of Caco-2 and HT29-MTX (10%) cells. Partial maintenance of cancer-cell phenotype in differentiated Caco-2 cells was confirmed and fatty acids merged as potential regulators of cancer signaling pathways. HT29-MTX cells induced morphological changes in Caco-2 cells, slightly increased their proliferation rate and profoundly modified gene transcription of phenotype markers, fatty acid receptors, intracellular transporters, and lipid droplet components as well as functional responses to oleic acid. In vitro, enterocyte phenotype was rescued partially by co-culture of cancer cells with goblet cells and completed through oleic acid interaction with signaling pathways dysregulated in cancer cells. Full article
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)
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Open AccessArticle Significance of Phosphorylated Epidermal Growth Factor Receptor and Its Signal Transducers in Human Soft Tissue Sarcoma
Int. J. Mol. Sci. 2017, 18(6), 1159; https://doi.org/10.3390/ijms18061159
Received: 5 May 2017 / Revised: 22 May 2017 / Accepted: 25 May 2017 / Published: 30 May 2017
Cited by 2 | PDF Full-text (1506 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Previous studies have shown that total epidermal growth factor receptor (EGFR) protein is highly expressed in soft tissue sarcoma (STS). We aimed to investigate the significance of phosphorylated-EGFR (pEGFR) and its activated-downstream signal transducers in STS tissue samples. A tissue microarray comprising 87
[...] Read more.
Previous studies have shown that total epidermal growth factor receptor (EGFR) protein is highly expressed in soft tissue sarcoma (STS). We aimed to investigate the significance of phosphorylated-EGFR (pEGFR) and its activated-downstream signal transducers in STS tissue samples. A tissue microarray comprising 87 STS samples was assessed for total EGFR, pEGFR and its phosphorylated signal transducers and expression was correlated with clinicopathlogical parameters including patient outcome. Although the expression of total EGFR was significantly associated with adverse STS histologic grade (p = 0.004) and clinical stage (p = 0.012) similar to pEGFR, phosphorylated protein kinase B (pAkt) and phosphorylated extracellular signal regulated kinase (pERK), it is not a prognostic factor for survival. By contrast, the expression of pEGFR is an independent factor for cancer specific survival, while pERK is an independent prognostic factor for both overall and cancer specific survival in STS (p < 0.05, Cox proportional hazard model and log-rank test) in addition to the recognised factors of tumour grade and clinical stage. pERK and pEGFR are new independent prognostic factors for overall and/or cancer specific survival in STS. The expression of EGFR/pEGFR, and their associated downstream signal transducers, was associated with STS progression, suggesting that EGFR downstream signalling pathways may jointly support STS cell survival. Full article
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)
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Open AccessArticle Inhibition of Autophagy Promotes Salinomycin-Induced Apoptosis via Reactive Oxygen Species-Mediated PI3K/AKT/mTOR and ERK/p38 MAPK-Dependent Signaling in Human Prostate Cancer Cells
Int. J. Mol. Sci. 2017, 18(5), 1088; https://doi.org/10.3390/ijms18051088
Received: 3 April 2017 / Revised: 15 May 2017 / Accepted: 16 May 2017 / Published: 18 May 2017
Cited by 22 | PDF Full-text (2768 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Recently, the interplay between autophagy and apoptosis has become an important factor in chemotherapy for cancer treatment. Inhibition of autophagy may be an effective strategy to improve the treatment of chemo-resistant cancer by consistent exposure to chemotherapeutic drugs. However, no reports have clearly
[...] Read more.
Recently, the interplay between autophagy and apoptosis has become an important factor in chemotherapy for cancer treatment. Inhibition of autophagy may be an effective strategy to improve the treatment of chemo-resistant cancer by consistent exposure to chemotherapeutic drugs. However, no reports have clearly elucidated the underlying mechanisms. Therefore, in this study, we assessed whether salinomycin, a promising anticancer drug, induces apoptosis and elucidated potential antitumor mechanisms in chemo-resistant prostate cancer cells. Cell viability assay, Western blot, annexin V/propidium iodide assay, acridine orange (AO) staining, caspase-3 activity assay, reactive oxygen species (ROS) production, and mitochondrial membrane potential were assayed. Our data showed that salinomycin alters the sensitivity of prostate cancer cells to autophagy. Pretreatment with 3-methyladenine (3-MA), an autophagy inhibitor, enhanced the salinomycin-induced apoptosis. Notably, salinomycin decreased phosphorylated of AKT and phosphorylated mammalian target of rapamycin (mTOR) in prostate cancer cells. Pretreatment with LY294002, an autophagy and PI3K inhibitor, enhanced the salinomycin-induced apoptosis by decreasing the AKT and mTOR activities and suppressing autophagy. However, pretreatment with PD98059 and SB203580, an extracellular signal-regulated kinases (ERK), and p38 inhibitors, suppressed the salinomycin-induced autophagy by reversing the upregulation of ERK and p38. In addition, pretreatment with N-acetyl-l-cysteine (NAC), an antioxidant, inhibited salinomycin-induced autophagy by suppressing ROS production. Our results suggested that salinomycin induces apoptosis, which was related to ROS-mediated autophagy through regulation of the PI3K/AKT/mTOR and ERK/p38 MAPK signaling pathways. Full article
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)
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Open AccessArticle Redox Regulation of the Tumor Suppressor PTEN by Hydrogen Peroxide and Tert-Butyl Hydroperoxide
Int. J. Mol. Sci. 2017, 18(5), 982; https://doi.org/10.3390/ijms18050982
Received: 2 March 2017 / Revised: 21 April 2017 / Accepted: 25 April 2017 / Published: 10 May 2017
Cited by 1 | PDF Full-text (3393 KB) | HTML Full-text | XML Full-text
Abstract
Organic peroxides and hydroperoxides are skin tumor promoters. Free radical derivatives from these compounds are presumed to be the prominent mediators of tumor promotion. However, the molecular targets of these species are unknown. Phosphatase and tensin homologs deleted on chromosome 10 (PTEN) are
[...] Read more.
Organic peroxides and hydroperoxides are skin tumor promoters. Free radical derivatives from these compounds are presumed to be the prominent mediators of tumor promotion. However, the molecular targets of these species are unknown. Phosphatase and tensin homologs deleted on chromosome 10 (PTEN) are tumor suppressors that play important roles in cell growth, proliferation, and cell survival by negative regulation of phosphoinositol-3-kinase/protein kinase B signaling. PTEN is reversibly oxidized in various cells by exogenous and endogenous hydrogen peroxide. Oxidized PTEN is converted back to the reduced form by cellular reducing agents, predominantly by the thioredoxin (Trx) system. Here, the role of tert-butyl hydroperoxide (t-BHP) in redox regulation of PTEN was analyzed by using cell-based and in vitro assays. Exposure to t-BHP led to oxidation of recombinant PTEN. In contrast to H2O2, PTEN oxidation by t-BHP was irreversible in HeLa cells. However, oxidized PTEN was reduced by exogenous Trx system. Taken together, these results indicate that t-BHP induces PTEN oxidation and inhibits Trx system, which results in irreversible PTEN oxidation in HeLa cells. Collectively, these results suggest a novel mechanism of t-BHP in the promotion of tumorigenesis. Full article
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)
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Open AccessArticle Deguelin Potentiates Apoptotic Activity of an EGFR Tyrosine Kinase Inhibitor (AG1478) in PIK3CA-Mutated Head and Neck Squamous Cell Carcinoma
Int. J. Mol. Sci. 2017, 18(2), 262; https://doi.org/10.3390/ijms18020262
Received: 23 November 2016 / Revised: 21 January 2017 / Accepted: 23 January 2017 / Published: 26 January 2017
Cited by 1 | PDF Full-text (4153 KB) | HTML Full-text | XML Full-text
Abstract
Head and neck squamous cell carcinoma (HNSCC) is known to be intrinsically resistant to inhibitors for epidermal growth factor receptor (EGFR). Until now, clinical outcomes for HNSCC using EGFR inhibitors as single agents have yielded disappointing results. Here, we aimed to study whether
[...] Read more.
Head and neck squamous cell carcinoma (HNSCC) is known to be intrinsically resistant to inhibitors for epidermal growth factor receptor (EGFR). Until now, clinical outcomes for HNSCC using EGFR inhibitors as single agents have yielded disappointing results. Here, we aimed to study whether combinatorial treatment using AG1478 (EGFR tyrosine kinase inhibitor) and deguelin, which is a rotenoid isolated from the African plant Mundulea sericea, could enhance the anti-tumor effects of AG1478 in HNSCC. For Ca9-22 cells with EGFR, KRAS, and PIK3CA wild types, AG1478 alone suppressed both phosphorylated levels of ERK and AKT and induced apoptosis. On the contrary, for HSC-4 cells with EGFR and KRAS wild types, and a PIK3CA mutant, AG1478 alone did not suppress the phosphorylated level of AKT nor induce apoptosis, while it suppressed ERK phosphorylation. Forced expression of constitutively active PIK3CA (G1633A mutation) significantly reduced the apoptotic effect of AG1478 on the PIK3CA wild-type Ca9-22 cells. When HSC-4 cells with the PIK3CA G1633A mutation were treated with a combination of AG1478 and deguelin, combination effects on apoptosis induction were observed through the inhibition of the AKT pathway. These results suggest that the combination of EGFR tyrosine kinase inhibitor with deguelin is a potential therapeutic approach to treat PIK3CA-mutated HNSCC. Full article
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)
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Open AccessArticle Somatic Genetic Variation in Solid Pseudopapillary Tumor of the Pancreas by Whole Exome Sequencing
Int. J. Mol. Sci. 2017, 18(1), 81; https://doi.org/10.3390/ijms18010081
Received: 16 November 2016 / Revised: 21 December 2016 / Accepted: 28 December 2016 / Published: 3 January 2017
Cited by 3 | PDF Full-text (1091 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Solid pseudopapillary tumor of the pancreas (SPT) is a rare pancreatic disease with a unique clinical manifestation. Although CTNNB1 gene mutations had been universally reported, genetic variation profiles of SPT are largely unidentified. We conducted whole exome sequencing in nine SPT patients to
[...] Read more.
Solid pseudopapillary tumor of the pancreas (SPT) is a rare pancreatic disease with a unique clinical manifestation. Although CTNNB1 gene mutations had been universally reported, genetic variation profiles of SPT are largely unidentified. We conducted whole exome sequencing in nine SPT patients to probe the SPT-specific insertions and deletions (indels) and single nucleotide polymorphisms (SNPs). In total, 54 SNPs and 41 indels of prominent variations were demonstrated through parallel exome sequencing. We detected that CTNNB1 mutations presented throughout all patients studied (100%), and a higher count of SNPs was particularly detected in patients with older age, larger tumor, and metastatic disease. By aggregating 95 detected variation events and viewing the interconnections among each of the genes with variations, CTNNB1 was identified as the core portion in the network, which might collaborate with other events such as variations of USP9X, EP400, HTT, MED12, and PKD1 to regulate tumorigenesis. Pathway analysis showed that the events involved in other cancers had the potential to influence the progression of the SNPs count. Our study revealed an insight into the variation of the gene encoding region underlying solid-pseudopapillary neoplasm tumorigenesis. The detection of these variations might partly reflect the potential molecular mechanism. Full article
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)
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Open AccessArticle The Epidermal Growth Factor Receptor (EGFR) Inhibitor Gefitinib Reduces but Does Not Prevent Tumorigenesis in Chemical and Hormonal Induced Hepatocarcinogenesis Rat Models
Int. J. Mol. Sci. 2016, 17(10), 1618; https://doi.org/10.3390/ijms17101618
Received: 24 July 2016 / Revised: 27 August 2016 / Accepted: 14 September 2016 / Published: 23 September 2016
Cited by 2 | PDF Full-text (11092 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Activation of the epidermal growth factor receptor (EGFR) signaling pathway promotes the development of hepatocellular adenoma (HCA) and carcinoma (HCC). The selective EGFR inhibitor Gefitinib was found to prevent hepatocarcinogenesis in rat cirrhotic livers. Thus, Gefitinib might reduce progression of pre-neoplastic liver lesions
[...] Read more.
Activation of the epidermal growth factor receptor (EGFR) signaling pathway promotes the development of hepatocellular adenoma (HCA) and carcinoma (HCC). The selective EGFR inhibitor Gefitinib was found to prevent hepatocarcinogenesis in rat cirrhotic livers. Thus, Gefitinib might reduce progression of pre-neoplastic liver lesions to HCC. In short- and long-term experiments, administration of N-Nitrosomorpholine (NNM) or intrahepatic transplantation of pancreatic islets in diabetic (PTx), thyroid follicles in thyroidectomized (TTx) and ovarian fragments in ovariectomized (OTx) rats was conducted for the induction of foci of altered hepatocytes (FAH). Gefitinib was administered for two weeks (20 mg/kg) or three and nine months (10 mg/kg). In NNM-treated rats, Gefitinib administration decreased the amount of FAH when compared to controls. The amount of HCA and HCC was decreased, but development was not prevented. Upon all transplantation models, proliferative activity of FAH was lower after administration of Gefitinib in short-term experiments. Nevertheless, the burden of HCA and HCC was not changed in later stages. Thus, EGFR inhibition by Gefitinib diminishes chemical and hormonal also induced hepatocarcinogenesis in the initiation stage in the non-cirrhotic liver. However, progression to malignant hepatocellular tumors was not prevented, indicating only a limited relevance of the EGFR signaling cascade in later stages of hepatocarcinogenesis. Full article
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)
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Review

Jump to: Research, Other

Open AccessReview Recent Advances in Comprehending the Signaling Pathways Involved in the Progression of Breast Cancer
Int. J. Mol. Sci. 2017, 18(11), 2321; https://doi.org/10.3390/ijms18112321
Received: 26 August 2017 / Revised: 30 October 2017 / Accepted: 31 October 2017 / Published: 3 November 2017
Cited by 1 | PDF Full-text (1213 KB) | HTML Full-text | XML Full-text
Abstract
This review describes recent advances in the comprehension of signaling pathways involved in breast cancer progression. Calcium sensing receptor (CaSR), caveolae signaling, signaling referred to hypoxia-inducing factors and disturbances in the apoptotic machinery are related to more general biological mechanisms and are considered
[...] Read more.
This review describes recent advances in the comprehension of signaling pathways involved in breast cancer progression. Calcium sensing receptor (CaSR), caveolae signaling, signaling referred to hypoxia-inducing factors and disturbances in the apoptotic machinery are related to more general biological mechanisms and are considered first. The others refer to signaling pathways of more specific biological mechanisms, namely the heparin/heparin-sulfate interactome, over-expression of miRNA-378a-5p, restriction of luminal and basal epithelial cells, fatty-acid synthesis, molecular pathways related to epithelial to mesenchimal transition (EMT), HER-2/neu gene amplification and protein expression, and the expression of other members of the epithelial growth factor receptor family. This progress in basic research is fundamental to foster the ongoing efforts that use the new genotyping technologies, and aim at defining new prognostic and predictive biomarkers for a better personalized management of breast cancer disease. Full article
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)
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Open AccessReview Aberrant Signaling Pathways in T-Cell Acute Lymphoblastic Leukemia
Int. J. Mol. Sci. 2017, 18(9), 1904; https://doi.org/10.3390/ijms18091904
Received: 8 August 2017 / Revised: 30 August 2017 / Accepted: 1 September 2017 / Published: 5 September 2017
Cited by 2 | PDF Full-text (909 KB) | HTML Full-text | XML Full-text
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease caused by the malignant transformation of immature progenitors primed towards T-cell development. Clinically, T-ALL patients present with diffuse infiltration of the bone marrow by immature T-cell blasts high blood cell counts, mediastinal involvement, and
[...] Read more.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease caused by the malignant transformation of immature progenitors primed towards T-cell development. Clinically, T-ALL patients present with diffuse infiltration of the bone marrow by immature T-cell blasts high blood cell counts, mediastinal involvement, and diffusion to the central nervous system. In the past decade, the genomic landscape of T-ALL has been the target of intense research. The identification of specific genomic alterations has contributed to identify strong oncogenic drivers and signaling pathways regulating leukemia growth. Notwithstanding, T-ALL patients are still treated with high-dose multiagent chemotherapy, potentially exposing these patients to considerable acute and long-term side effects. This review summarizes recent advances in our understanding of the signaling pathways relevant for the pathogenesis of T-ALL and the opportunities offered for targeted therapy. Full article
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)
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Open AccessReview Role Played by Signalling Pathways in Overcoming BRAF Inhibitor Resistance in Melanoma
Int. J. Mol. Sci. 2017, 18(7), 1527; https://doi.org/10.3390/ijms18071527
Received: 19 June 2017 / Revised: 6 July 2017 / Accepted: 12 July 2017 / Published: 14 July 2017
Cited by 2 | PDF Full-text (728 KB) | HTML Full-text | XML Full-text
Abstract
The discovery of the BRAFV600E mutation led to the development of vemurafenib (PLX4032), a selective BRAF inhibitor specific to the kinase, for the treatment of metastatic melanomas. However, initial success of the drug was dampened by the development of acquired resistance. Melanoma
[...] Read more.
The discovery of the BRAFV600E mutation led to the development of vemurafenib (PLX4032), a selective BRAF inhibitor specific to the kinase, for the treatment of metastatic melanomas. However, initial success of the drug was dampened by the development of acquired resistance. Melanoma was shown to relapse in patients following treatment with vemurafenib which eventually led to patients’ deaths. It has been proposed that mechanisms of resistance can be due to (1) reactivation of the mitogen-activated protein kinase (MAPK) signalling pathway via secondary mutations, amplification or activation of target kinase(s), (2) the bypass of oncogenic pathway via activation of alternative signalling pathways, (3) other uncharacterized mechanisms. Studies showed that receptor tyrosine kinases (RTK) such as PDGFRβ, IGF1R, EGFR and c-Met were overexpressed in melanoma cells. Along with increased secretion of growth factors such as HGF and TGF-α, this will trigger intracellular signalling cascades. This review discusses the role MAPK and Phosphatidylinositol-3-kinase-protein kinase B-mammalian target of rapamycin (PI3K-AKT-mTOR) pathways play in the mechanism of resistance of melanomas. Full article
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)
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Open AccessReview Alteration of SHP-1/p-STAT3 Signaling: A Potential Target for Anticancer Therapy
Int. J. Mol. Sci. 2017, 18(6), 1234; https://doi.org/10.3390/ijms18061234
Received: 2 May 2017 / Revised: 1 June 2017 / Accepted: 5 June 2017 / Published: 8 June 2017
Cited by 5 | PDF Full-text (943 KB) | HTML Full-text | XML Full-text
Abstract
The Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 1 (SHP-1), a non-receptor protein tyrosine phosphatase, has been reported as a negative regulator of phosphorylated signal transducer and activator of transcription 3 (STAT3) and linked to tumor development. In this present review, we
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The Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 1 (SHP-1), a non-receptor protein tyrosine phosphatase, has been reported as a negative regulator of phosphorylated signal transducer and activator of transcription 3 (STAT3) and linked to tumor development. In this present review, we will discuss the importance and function of SHP-1/p-STAT3 signaling in nonmalignant conditions as well as malignancies, its cross-talk with other pathways, the current clinical development and the potential role of inhibitors of this pathway in anticancer therapy and clinical relevance of SHP-1/p-STAT3 in cancers. Lastly, we will summarize and highlight work involving novel drugs/compounds targeting SHP-1/p-STAT3 signaling and combined strategies that were/are discovered in our and our colleagues’ laboratories. Full article
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)
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Open AccessReview Oleanolic Acid Alters Multiple Cell Signaling Pathways: Implication in Cancer Prevention and Therapy
Int. J. Mol. Sci. 2017, 18(3), 643; https://doi.org/10.3390/ijms18030643
Received: 24 December 2016 / Revised: 6 March 2017 / Accepted: 9 March 2017 / Published: 16 March 2017
Cited by 11 | PDF Full-text (471 KB) | HTML Full-text | XML Full-text
Abstract
Nowadays, much attention has been paid to diet and dietary supplements as a cost-effective therapeutic strategy for prevention and treatment of a myriad of chronic and degenerative diseases. Rapidly accumulating scientific evidence achieved through high-throughput technologies has greatly expanded the understanding about the
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Nowadays, much attention has been paid to diet and dietary supplements as a cost-effective therapeutic strategy for prevention and treatment of a myriad of chronic and degenerative diseases. Rapidly accumulating scientific evidence achieved through high-throughput technologies has greatly expanded the understanding about the multifaceted nature of cancer. Increasingly, it is being realized that deregulation of spatio-temporally controlled intracellular signaling cascades plays a contributory role in the onset and progression of cancer. Therefore, targeting regulators of oncogenic signaling cascades is essential to prevent and treat cancer. A plethora of preclinical and epidemiological evidences showed promising role of phytochemicals against several types of cancer. Oleanolic acid, a common pentacyclic triterpenoid, is mainly found in olive oil, as well as several plant species. It is a potent inhibitor of cellular inflammatory process and a well-known inducer of phase 2 xenobiotic biotransformation enzymes. Main molecular mechanisms underlying anticancer effects of oleanolic acid are mediated by caspases, 5′ adenosine monophosphate-activated protein kinase, extracellular signal–regulated kinase 1/2, matrix metalloproteinases, pro-apoptotic Bax and bid, phosphatidylinositide 3-kinase/Akt1/mechanistic target of rapamycin, reactive oxygen species/apoptosis signal-regulating kinase 1/p38 mitogen-activated protein kinase, nuclear factor-κB, cluster of differentiation 1, CKD4, s6k, signal transducer and activator of transcription 3, as well as aforementioned signaling pathways . In this work, we critically review the scientific literature on the molecular targets of oleanolic acid implicated in the prevention and treatment of several types of cancer. We also discuss chemical aspects, natural sources, bioavailability, and safety of this bioactive phytochemical. Full article
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)
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Open AccessReview Strategies for Overcoming Resistance in Tumours Harboring BRAF Mutations
Int. J. Mol. Sci. 2017, 18(3), 585; https://doi.org/10.3390/ijms18030585
Received: 10 January 2017 / Revised: 7 February 2017 / Accepted: 23 February 2017 / Published: 8 March 2017
Cited by 9 | PDF Full-text (442 KB) | HTML Full-text | XML Full-text
Abstract
The development of resistance to previously effective treatments has been a challenge for health care providers and a fear for patients undergoing cancer therapy. This is an unfortunately frequent occurrence for patients undergoing targeted therapy for tumours harboring the activating V600E mutation of
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The development of resistance to previously effective treatments has been a challenge for health care providers and a fear for patients undergoing cancer therapy. This is an unfortunately frequent occurrence for patients undergoing targeted therapy for tumours harboring the activating V600E mutation of the BRAF gene. Since the initial identification of the BRAF mutation in 2002, a series of small molecular inhibitors that target the BRAFV600E have been developed, but intrinsic and acquired resistance to these drugs has presented an ongoing challenge. More recently, improvements in therapy have been achieved by combining the use of BRAF inhibitors with other drugs, such as inhibitors of the downstream effector mitogen activated protein kinase (MAPK)/extracellular-signal regulated kinase (ERK) kinase (MEK). Despite improved success in response rates and in delaying resistance using combination therapy, ultimately, the acquisition of resistance remains a concern. Recent research articles have shed light on some of the underlying mechanisms of this resistance and have proposed numerous strategies that might be employed to overcome or avoid resistance to targeted therapies. This review will explore some of the resistance mechanisms, compare what is known in melanoma cancer to colorectal cancer, and discuss strategies under development to manage the development of resistance. Full article
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)
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Open AccessReview Molecular Biomarkers for Prediction of Targeted Therapy Response in Metastatic Breast Cancer: Trick or Treat?
Int. J. Mol. Sci. 2017, 18(1), 85; https://doi.org/10.3390/ijms18010085
Received: 29 November 2016 / Revised: 23 December 2016 / Accepted: 26 December 2016 / Published: 4 January 2017
Cited by 9 | PDF Full-text (1615 KB) | HTML Full-text | XML Full-text
Abstract
In recent years, the study of genomic alterations and protein expression involved in the pathways of breast cancer carcinogenesis has provided an increasing number of targets for drugs development in the setting of metastatic breast cancer (i.e., trastuzumab, everolimus, palbociclib, etc.) significantly improving
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In recent years, the study of genomic alterations and protein expression involved in the pathways of breast cancer carcinogenesis has provided an increasing number of targets for drugs development in the setting of metastatic breast cancer (i.e., trastuzumab, everolimus, palbociclib, etc.) significantly improving the prognosis of this disease. These drugs target specific molecular abnormalities that confer a survival advantage to cancer cells. On these bases, emerging evidence from clinical trials provided increasing proof that the genetic landscape of any tumor may dictate its sensitivity or resistance profile to specific agents and some studies have already showed that tumors treated with therapies matched with their molecular alterations obtain higher objective response rates and longer survival. Predictive molecular biomarkers may optimize the selection of effective therapies, thus reducing treatment costs and side effects. This review offers an overview of the main molecular pathways involved in breast carcinogenesis, the targeted therapies developed to inhibit these pathways, the principal mechanisms of resistance and, finally, the molecular biomarkers that, to date, are demonstrated in clinical trials to predict response/resistance to targeted treatments in metastatic breast cancer. Full article
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)
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Open AccessPerspective Deconstructing Signaling Pathways in Cancer for Optimizing Cancer Combination Therapies
Int. J. Mol. Sci. 2017, 18(6), 1258; https://doi.org/10.3390/ijms18061258
Received: 27 April 2017 / Revised: 27 May 2017 / Accepted: 5 June 2017 / Published: 12 June 2017
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Abstract
A single cancer cell left behind after surgery and/or chemotherapy could cause a recurrence of cancer. It is our belief that the failure of chemotherapies is the failure to induce apoptosis in all cancer cells. Given the extraordinary heterogeneity of cancer, it is
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A single cancer cell left behind after surgery and/or chemotherapy could cause a recurrence of cancer. It is our belief that the failure of chemotherapies is the failure to induce apoptosis in all cancer cells. Given the extraordinary heterogeneity of cancer, it is very difficult to eliminate all cancer cells with a single agent targeting a particular gene product. Furthermore, combinations of any two or three agents exhibiting some proven efficacy on a particular cancer type have not fared better, often compounding adverse effects without evidence of expected synergistic effects. Thus, it is imperative that a way be found to select candidates that when combined, will (1) synergize, making the combination therapy greater than the sum of its parts, and (2) target all the cancer cells in a patient. In this article, we discuss our experience and relation to current evidence in the cancer treatment literature in which, by deconstructing signaling networks, we have identified a lynchpin that connects the growth signals present in cancer with mitochondria-dependent apoptotic pathways. By targeting this lynchpin, we have added a key component to a combination therapy that sensitizes cancer cells for apoptosis. Full article
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)
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Open AccessCase Report Down’s Syndrome and Triple Negative Breast Cancer: A Rare Occurrence of Distinctive Clinical Relationship
Int. J. Mol. Sci. 2017, 18(6), 1218; https://doi.org/10.3390/ijms18061218
Received: 17 April 2017 / Revised: 31 May 2017 / Accepted: 5 June 2017 / Published: 7 June 2017
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Abstract
Down’s syndrome (DS), the most common genetic cause of significant intellectual disability in children and adults is caused by the trisomy of either all or a part of human chromosome 21 (HSA21). Patients with DS mostly suffer from characteristic tumor types. Although individual
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Down’s syndrome (DS), the most common genetic cause of significant intellectual disability in children and adults is caused by the trisomy of either all or a part of human chromosome 21 (HSA21). Patients with DS mostly suffer from characteristic tumor types. Although individual patients of DS are at a higher risk for acute leukemia and testicular cancers, other types of solid tumors including breast cancers are mostly uncommon and have significantly lower-than-expected age-adjusted incidence rates. Except for an increased risk of retinoblastomas, and lymphomas, the risk of developing solid tumors has been found to be lower in both children and adults, and breast cancer was found to be almost absent (Hasle H., The Lancet Oncology, 2001). A study conducted in the United States found only one death when 11.65 were expected (Scholl T et al., Dev Med Child Neurol. 1982). A recent study examined mammogram reports of women with DS treated in the largest medical facility specifically serving adults with DS in the United States. It was found that only 0.7% women with DS had been diagnosed with breast cancers (Chicoine B et al., Intellect Dev Disabil. 2015). Here we describe a case of breast cancer in a 25-year-old patient with DS. The disease was presented as lymph node positive carcinoma with alterations of tumor suppressor genes characteristic to the triple negative breast cancer subtype. Comprehensive Genomic Profiling (CGP) revealed a wild-type status for BRCA1. The CGP report showed a frameshift mutation, A359fs*10 of the tumor suppressor gene INPP4B and another frameshift mutation, R282fs*63 of tumor suppressor gene TP53 in the tumor biopsy as characteristically found in triple-negative breast cancers. The VUS (Variance of Unknown Significance) alteration(s) were identified in ASXL1 (L1395V), NTRK1 (G18E), DDR2 (I159T), RUNX1 (amplification), ERG (amplification), SOX2 (T26A), FAM123B (G1031D), and HNF1A (A301T). Bonafide cancer-related genes of chromosome 21 amplified in the patient’s tumor are RUNX1 and ERG genes. After the completion of the radiation, the patient was placed on everolimus which was based on the result of her CGP report. Thus, post-mastectomy radiation therapy was completed with a recommendation for everolimus for one year. During the time of writing of this report, no metastatic lesions were identified. The patient currently has no evidence of disease. Full article
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells)
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