Cancers

19 pages, 3216 KiB

Open AccessArticle

Hypoxia Downregulates LPP3 and Promotes the Spatial Segregation of ATX and LPP1 During Cancer Cell Invasion

by Kelly Harper, Karine Brochu-Gaudreau, Caroline Saucier and Claire M. Dubois

Cancers 2019, 11(9), 1403; https://doi.org/10.3390/cancers11091403 - 19 Sep 2019

Cited by 12 | Viewed by 4241

Hypoxia is a common characteristic of advanced solid tumors and a potent driver of tumor invasion and metastasis. Recent evidence suggests the involvement of autotaxin (ATX) and lysophosphatidic acid receptors (LPARs) in cancer cell invasion promoted by the hypoxic tumor microenvironment; however, the [...] Read more.

Hypoxia is a common characteristic of advanced solid tumors and a potent driver of tumor invasion and metastasis. Recent evidence suggests the involvement of autotaxin (ATX) and lysophosphatidic acid receptors (LPARs) in cancer cell invasion promoted by the hypoxic tumor microenvironment; however, the transcriptional and/or spatiotemporal control of this process remain unexplored. Herein, we investigated whether hypoxia promotes cell invasion by affecting the main enzymes involved in its production (ATX) and degradation (lipid phosphate phosphatases, LPP1 and LPP3). We report that hypoxia not only modulates the expression levels of lysophosphatidic acid (LPA) regulatory enzymes but also induces their significant spatial segregation in a variety of cancers. While LPP3 expression was downregulated by hypoxia, ATX and LPP1 were asymmetrically redistributed to the leading edge and to the trailing edge, respectively. This was associated with the opposing roles of ATX and LPPs in cell invasion. The regulated expression and compartmentalization of these enzymes of opposing function can provide an effective way to control the generation of an LPA gradient that drives cellular invasion and migration in the hypoxic zones of tumors. Full article

(This article belongs to the Special Issue Lysophosphatidic Acid Signalling in Cancer)

► Show Figures

Graphical abstract

23 pages, 1979 KiB

Open AccessEditor’s ChoiceReview

Hyperglycemia Associated Metabolic and Molecular Alterations in Cancer Risk, Progression, Treatment, and Mortality

by Pranay Ramteke, Ankita Deb, Varsha Shepal and Manoj Kumar Bhat

Cancers 2019, 11(9), 1402; https://doi.org/10.3390/cancers11091402 - 19 Sep 2019

Cited by 93 | Viewed by 14501

Abstract

Cancer and diabetes are amongst the leading causes of deaths worldwide. There is an alarming rise in cancer incidences and mortality, with approximately 18.1 million new cases and 9.6 million deaths in 2018. A major contributory but neglected factor for risk of neoplastic [...] Read more.

Cancer and diabetes are amongst the leading causes of deaths worldwide. There is an alarming rise in cancer incidences and mortality, with approximately 18.1 million new cases and 9.6 million deaths in 2018. A major contributory but neglected factor for risk of neoplastic transformation is hyperglycemia. Epidemiologically too, lifestyle patterns resulting in high blood glucose level, with or without the role of insulin, are more often correlated with cancer risk, progression, and mortality. The two conditions recurrently exist in comorbidity, and their interplay has rendered treatment regimens more challenging by restricting the choice of drugs, affecting surgical consequences, and having associated fatal complications. Limited comprehensive literature is available on their correlation, and a lack of clarity in understanding in such comorbid conditions contributes to higher mortality rates. Hence, a critical analysis of the elements responsible for enhanced mortality due to hyperglycemia-cancer concomitance is warranted. Given the lifestyle changes in the human population, increasing metabolic disorders, and glucose addiction of cancer cells, hyperglycemia related complications in cancer underline the necessity for further in-depth investigations. This review, therefore, attempts to shed light upon hyperglycemia associated factors in the risk, progression, mortality, and treatment of cancer to highlight important mechanisms and potential therapeutic targets. Full article

(This article belongs to the Special Issue Metabolic Reprogramming and Vulnerabilities in Cancer)

► Show Figures

Figure 1

18 pages, 252 KiB

Open AccessReview

Prognostic and Predictive Implications of PTEN in Breast Cancer: Unfulfilled Promises but Intriguing Perspectives

by Luisa Carbognin, Federica Miglietta, Ida Paris and Maria Vittoria Dieci

Cancers 2019, 11(9), 1401; https://doi.org/10.3390/cancers11091401 - 19 Sep 2019

Cited by 76 | Viewed by 5721

Abstract

The characterization of tumor biology and consequently the identification of prognostic and predictive biomarkers represent key issues for the translational research in breast cancer (BC). Phosphatase and tensin homolog deleted on chromosome ten (PTEN), the negative regulator of the proto-oncogenic phosphatidylinositol-3-kinase (PI3K)/protein kinase [...] Read more.

The characterization of tumor biology and consequently the identification of prognostic and predictive biomarkers represent key issues for the translational research in breast cancer (BC). Phosphatase and tensin homolog deleted on chromosome ten (PTEN), the negative regulator of the proto-oncogenic phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway, constitutes one of the most intriguing tumor suppressor genes involved in a series of biological processes, such as cell growth and survival, cellular migration and genomic stability. Loss of PTEN activity, due to protein, genetic or epigenetic alterations, was reported in up to almost half of BC cases. Recently, besides the role of PTEN in the pathogenesis of BC, investigated for over 20 years after the PTEN discovery, several retrospective and prospective translational studies, in the early and advanced setting, reported controversial results regarding the association between PTEN functional status and both clinical outcome and response to various BC treatments. This review explores the pre-clinical and clinical role of PTEN in BC with regard to the potential association of PTEN with prognosis and treatment response or resistance, underlying the complexity of the interpretation of available results and suggesting potential future perspectives. Full article

(This article belongs to the Special Issue PTEN: A Multifaceted Tumor Suppressor)

18 pages, 2852 KiB

Open AccessArticle

Blockade of PD-L1 Enhances Cancer Immunotherapy by Regulating Dendritic Cell Maturation and Macrophage Polarization

by Nai-Yun Sun, Yu-Li Chen, Wen-Yih Wu, Han-Wei Lin, Ying-Cheng Chiang, Chi-Fang Chang, Yi-Jou Tai, Heng-Cheng Hsu, Chi-An Chen, Wei-Zen Sun and Wen-Fang Cheng

Cancers 2019, 11(9), 1400; https://doi.org/10.3390/cancers11091400 - 19 Sep 2019

Cited by 48 | Viewed by 6734

Abstract

The immuno-inhibitory checkpoint PD-L1, regulated by tumor cells and antigen-presenting cells (APCs), dampened the activation of T cells from the PD-1/PD-L1 axis. PD-L1-expressing APCs rather than tumor cells demonstrated the essential anti-tumor effects of anti-PD-L1 monotherapy in preclinical tumor models. Using the murine [...] Read more.

The immuno-inhibitory checkpoint PD-L1, regulated by tumor cells and antigen-presenting cells (APCs), dampened the activation of T cells from the PD-1/PD-L1 axis. PD-L1-expressing APCs rather than tumor cells demonstrated the essential anti-tumor effects of anti-PD-L1 monotherapy in preclinical tumor models. Using the murine tumor model, we investigated whether anti-PD-L1 antibody increased the antigen-specific immune response and anti-tumor effects induced by the antigen-specific protein vaccine, as well as the possible mechanisms regarding activation of APCs. Anti-PD-L1 antibody combined with the PEK protein vaccine generated more potent E7-specific immunity (including the number and cytotoxic activity of E7-specific cytotoxic CD8⁺ T lymphocytes) and anti-tumor effects than protein vaccine alone. Anti-PD-L1 antibody enhanced the maturation of dendritic cells and the proportion of M1-like macrophages in tumor-draining lymph nodes and tumors in tumor-bearing mice treated with combinatorial therapy. PD-L1 blockade overturned the immunosuppressive status of the tumor microenvironment and then enhanced the E7 tumor-specific antigen-specific immunity and anti-tumor effects generated by an E7-specific protein vaccine through modulation of APCs in an E7-expressing small tumor model. Tumor-specific antigen (like HPV E7 antigen)-specific immunotherapy combined with APC-targeting modality by PD-L1 blockade has a high translational potential in E7-specific cancer therapy. Full article

► Show Figures

Figure 1

16 pages, 1002 KiB

Open AccessArticle

Matched Whole-Genome Sequencing (WGS) and Whole-Exome Sequencing (WES) of Tumor Tissue with Circulating Tumor DNA (ctDNA) Analysis: Complementary Modalities in Clinical Practice

by Robin Imperial, Marjan Nazer, Zaheer Ahmed, Audrey E. Kam, Timothy J. Pluard, Waled Bahaj, Mia Levy, Timothy M. Kuzel, Dana M. Hayden, Sam G. Pappas, Janakiraman Subramanian and Ashiq Masood

Cancers 2019, 11(9), 1399; https://doi.org/10.3390/cancers11091399 - 19 Sep 2019

Cited by 33 | Viewed by 6394

Abstract

Tumor heterogeneity, especially intratumoral heterogeneity, is a primary reason for treatment failure. A single biopsy may not reflect the complete genomic architecture of the tumor needed to make therapeutic decisions. Circulating tumor DNA (ctDNA) is believed to overcome these limitations. We analyzed concordance [...] Read more.

Tumor heterogeneity, especially intratumoral heterogeneity, is a primary reason for treatment failure. A single biopsy may not reflect the complete genomic architecture of the tumor needed to make therapeutic decisions. Circulating tumor DNA (ctDNA) is believed to overcome these limitations. We analyzed concordance between ctDNA and whole-exome sequencing/whole-genome sequencing (WES/WGS) of tumor samples from patients with breast (n = 12), gastrointestinal (n = 20), lung (n = 19), and other tumor types (n = 13). Correlation in the driver, hotspot, and actionable alterations was studied. Three cases in which more-in-depth genomic analysis was required have been presented. A total 58% (37/64) of patients had at least one concordant mutation. Patients who had received systemic therapy before tissue next-generation sequencing (NGS) and ctDNA analysis showed high concordance (78% (21/27) vs. 43% (12/28) p = 0.01, respectively). Obtaining both NGS and ctDNA increased actionable alterations from 28% (18/64) to 52% (33/64) in our patients. Twenty-one patients had mutually exclusive actionable alterations seen only in either tissue NGS or ctDNA samples. Somatic hotspot mutation analysis showed significant discordance between tissue NGS and ctDNA analysis, denoting significant tumor heterogeneity in these malignancies. Increased tissue tumor mutation burden (TMB) positively correlated with the number of ctDNA mutations in patients who had received systemic therapy, but not in treatment-naïve patients. Prior systemic therapy and TMB may affect concordance and should be taken into consideration in future studies. Incorporating driver, actionable, and hotspot analysis may help to further refine the correlation between these two platforms. Tissue NGS and ctDNA are complimentary, and if done in conjunction, may increase the detection rate of actionable alterations and potentially therapeutic targets. Full article

(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)

► Show Figures

Figure 1

13 pages, 5407 KiB

Open AccessEditor’s ChoiceArticle

CD8+ and Regulatory T cells Differentiate Tumor Immune Phenotypes and Predict Survival in Locally Advanced Head and Neck Cancer

by Alessia Echarti, Markus Hecht, Maike Büttner-Herold, Marlen Haderlein, Arndt Hartmann, Rainer Fietkau and Luitpold Distel

Cancers 2019, 11(9), 1398; https://doi.org/10.3390/cancers11091398 - 19 Sep 2019

Cited by 64 | Viewed by 4646

Abstract

Background: The tumor immune status “inflamed”, “immune excluded”, and “desert” might serve as a predictive parameter. We studied these three cancer immune phenotypes while using a simple immunohistochemical algorithm. Methods: Pre-treatment tissue samples of 280 patients with locally advanced HNSCC treated with radiochemotherapy [...] Read more.

Background: The tumor immune status “inflamed”, “immune excluded”, and “desert” might serve as a predictive parameter. We studied these three cancer immune phenotypes while using a simple immunohistochemical algorithm. Methods: Pre-treatment tissue samples of 280 patients with locally advanced HNSCC treated with radiochemotherapy were analyzed. A double staining of CD8+ cytotoxic T cells (CTL) and FoxP3+ (Treg) was performed and the cell density was evaluated in the intraepithelial and stromal compartment of the tumor. Results: The classification of tumors as “immune desert” when stromal CTL were ≤ 50 cells/mm², “inflamed” when intraepithelial CTL were > 500 cells/mm², and as “excluded” when neither of these definitions met these cut off values allowed the best discrimination regarding overall survival. These groups had median OS periods of 37, 61, and 85 months, respectively. In “immune desert” and “immune excluded” tumors high Treg tended to worsen OS, but in “inflamed” tumors high Treg clearly improved OS. Conclusions: We propose that, in locally advanced HNSCC, the tumor immune state “inflamed”, “immune excluded”, and “immune desert” can be defined by intraepithelial and stromal CTL. Tregs can further subdivide these groups. The opposing effects of Tregs in the different groups might be the reason for the inconsistency of Tregs prognostic values published earlier. Full article

► Show Figures

Graphical abstract

19 pages, 23606 KiB

Open AccessArticle

γ-H2AX Foci Persistence at Chromosome Break Suggests Slow and Faithful Repair Phases Restoring Chromosome Integrity

by Michelle Ricoul, Tamizh Selvan Gnana Sekaran, Patricia Brochard, Cecile Herate and Laure Sabatier

Cancers 2019, 11(9), 1397; https://doi.org/10.3390/cancers11091397 - 19 Sep 2019

Cited by 14 | Viewed by 5609

Abstract

Many toxic agents can cause DNA double strand breaks (DSBs), which are in most cases quickly repaired by the cellular machinery. Using ionising radiation, we explored the kinetics of DNA lesion signaling and structural chromosome aberration formation at the intra- and inter-chromosomal level. [...] Read more.

Many toxic agents can cause DNA double strand breaks (DSBs), which are in most cases quickly repaired by the cellular machinery. Using ionising radiation, we explored the kinetics of DNA lesion signaling and structural chromosome aberration formation at the intra- and inter-chromosomal level. Using a novel approach, the classic Premature Chromosome Condensation (PCC) was combined with γ-H2AX immunofluorescence staining in order to unravel the kinetics of DNA damage signalisation and chromosome repair. We identified an early mechanism of DNA DSB joining that occurs within the first three hours post-irradiation, when dicentric chromosomes and chromosome exchanges are formed. The slower and significant decrease of ”deleted chromosomes” and 1 acentric telomere fragments observed until 24 h post-irradiation, leads to the conclusion that a second and error-free repair mechanism occurs. In parallel, we revealed remaining signalling of γ-H2AX foci at the site of chromosome fusion long after the chromosome rearrangement formation. Moreover there is important signalling of foci on the site of telomere and sub-telomere sequences suggesting either a different function of γ-H2AX signalling in these regions or an extreme sensibility of the telomere sequences to DNA damage that remains unrepaired 24 h post-irradiation. In conclusion, chromosome repair happens in two steps, including a last and hardly detectable one because of restoration of the chromosome integrity. Full article

(This article belongs to the Special Issue New Discoveries in Radiation Science: Selection of Papers from the 44th Congress of the European Radiation Research Society (Pécs, Hungary))

► Show Figures

Figure 1

19 pages, 886 KiB

Open AccessReview

Dendritic Cell-Based and Other Vaccination Strategies for Pediatric Cancer

by Sévérine de Bruijn, Sébastien Anguille, Joris Verlooy, Evelien L. Smits, Viggo F. van Tendeloo, Maxime de Laere, Koenraad Norga, Zwi N. Berneman and Eva Lion

Cancers 2019, 11(9), 1396; https://doi.org/10.3390/cancers11091396 - 19 Sep 2019

Cited by 14 | Viewed by 4666

Abstract

Dendritic cell-based and other vaccination strategies that use the patient’s own immune system for the treatment of cancer are gaining momentum. Most studies of therapeutic cancer vaccination have been performed in adults. However, since cancer is one of the leading causes of death [...] Read more.

Dendritic cell-based and other vaccination strategies that use the patient’s own immune system for the treatment of cancer are gaining momentum. Most studies of therapeutic cancer vaccination have been performed in adults. However, since cancer is one of the leading causes of death among children past infancy in the Western world, the hope is that this form of active specific immunotherapy can play an important role in the pediatric population as well. Since children have more vigorous and adaptable immune systems than adults, therapeutic cancer vaccines are expected to have a better chance of creating protective immunity and preventing cancer recurrence in pediatric patients. Moreover, in contrast to conventional cancer treatments such as chemotherapy, therapeutic cancer vaccines are designed to specifically target tumor cells and not healthy cells or tissues. This reduces the likelihood of side effects, which is an important asset in this vulnerable patient population. In this review, we present an overview of the different therapeutic cancer vaccines that have been studied in the pediatric population, with a main focus on dendritic cell-based strategies. In addition, new approaches that are currently being investigated in clinical trials are discussed to provide guidance for further improvement and optimization of pediatric cancer vaccines. Full article

(This article belongs to the Special Issue Tumour Associated Dendritic Cells)

► Show Figures

Figure 1

21 pages, 1286 KiB

Open AccessFeature PaperReview

Management of Small Bowel Neuroendocrine Tumors

by Vincent Larouche, Amit Akirov, Sameerah Alshehri and Shereen Ezzat

Cancers 2019, 11(9), 1395; https://doi.org/10.3390/cancers11091395 - 18 Sep 2019

Cited by 23 | Viewed by 6143

Abstract

Several important landmark trials have reshaped the landscape of non-surgical management of small bowel neuroendocrine tumors over the last few years, with the confirmation of the antitumor effect of somatostatin analogue therapy in PROMID and CLARINET trials as well as the advent of [...] Read more.

Several important landmark trials have reshaped the landscape of non-surgical management of small bowel neuroendocrine tumors over the last few years, with the confirmation of the antitumor effect of somatostatin analogue therapy in PROMID and CLARINET trials as well as the advent of therapies with significant potential such as mammalian target of rapamycin inhibitor (mTor) everolimus (RADIANT trials) and peptide receptor radionuclide therapy (PRRT) with 177-Lutetium (NETTER-1 trial). This narrative summarizes the recommended management strategies of small bowel neuroendocrine tumors. We review the main evidence behind each recommendation as well as compare and contrast four major guidelines, namely the 2016 Canadian Consensus guidelines, the 2017 North American Neuroendocrine Tumor Society guidelines, the 2018 National Comprehensive Cancer Network guidelines, and the 2016 European Neuroendocrine Tumor Society guidelines. Different clinical situations will be addressed, from loco-regional therapy to metastatic unresectable disease. Carcinoid syndrome, which is mostly managed by somatostatin analogue therapy and the serotonin antagonist telotristat etiprate for refractory diarrhea, as well as neuroendocrine carcinoma will be reviewed. However, several questions remain unanswered, such as the optimal management of neuroendocrine carcinomas or the effect of combining and sequencing of the aforementioned modalities where more randomized controlled trials are needed. Full article

(This article belongs to the Special Issue Management of Neuroendocrine Neoplasms)

► Show Figures

Figure 1

24 pages, 4028 KiB

Open AccessArticle

Interleukin4Rα (IL4Rα) and IL13Rα1 Are Associated with the Progress of Renal Cell Carcinoma through Janus Kinase 2 (JAK2)/Forkhead Box O3 (FOXO3) Pathways

by Mi-Ae Kang, Jongsung Lee, Sang Hoon Ha, Chang Min Lee, Kyoung Min Kim, Kyu Yun Jang and See-Hyoung Park

Cancers 2019, 11(9), 1394; https://doi.org/10.3390/cancers11091394 - 18 Sep 2019

Cited by 20 | Viewed by 4506

Abstract

Specific kinds of interleukin (IL) receptors are known to mediate lymphocyte proliferation and survival. However, recent reports have suggested that the high expression of IL4Rα and IL13Rα1 in tumor tissue might be associated with tumorigenesis in several kinds of tumor. We found that [...] Read more.

Specific kinds of interleukin (IL) receptors are known to mediate lymphocyte proliferation and survival. However, recent reports have suggested that the high expression of IL4Rα and IL13Rα1 in tumor tissue might be associated with tumorigenesis in several kinds of tumor. We found that a significant association between mRNA level of IL4Rα or IL13Rα1 and the poor prognosis of renal cell carcinoma (RCC) from the public database (http://www.oncolnc.org/). Then, we evaluated the clinicopathological significance of the immunohistochemical expression of IL4Rα and IL13Rα1 in 199 clear cell RCC (CCRCC) patients. The individual and co-expression patterns of IL4Rα and IL13Rα1 were significantly associated with cancer-specific survival (CSS) and relapse-free survival (RFS) in univariate analysis. Multivariate analysis indicated IL4Rα-positivity and co-expression of IL4Rα and IL13Rα1 as the independent indicators of shorter CSS and RFS of CCRCC patients. For the in vitro evaluation of the oncogenic role of IL4Rα and IL13Rα1 in RCC, we knock-downed IL4Rα or IL13Rα1 and observed that the cell proliferation rate was decreased, and the apoptosis rate was increased in A498 and ACHN cells. Furthermore, we examined the possible role of Janus kinase 2 (JAK2), well-known down-stream tyrosine kinase under the heterodimeric receptor complex of IL4Rα and IL13Rα1. Interestingly, JAK2 interacted with Forkhead box O3 (FOXO3) to cause tyrosine-phosphorylation of FOXO3. Silencing IL4Rα or JAK2 in A498 and ACHN cells reduced the interaction between JAK2 and FOXO3. Moreover, pharmacological inhibition of JAK2 induced the nuclear localization of FOXO3, leading to increase apoptosis and decrease cell proliferation rate in A498 and ACHN cells. Taken together, these results suggest that IL4Rα and IL13Rα1 might be involved in the progression of RCC through JAK2/FOXO3 pathway, and their expression might be used as the novel prognostic factor and therapeutic target for RCC patients. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma)

► Show Figures

Figure 1

17 pages, 2025 KiB

Open AccessArticle

Should Tumor Infiltrating Lymphocytes, Androgen Receptor, and FOXA1 Expression Predict the Clinical Outcome in Triple Negative Breast Cancer Patients?

by Anita Mangia, Concetta Saponaro, Alessandro Vagheggini, Giuseppina Opinto, Matteo Centonze, Chiara Vicenti, Ondina Popescu, Maria Pastena, Francesco Giotta and Nicola Silvestris

Cancers 2019, 11(9), 1393; https://doi.org/10.3390/cancers11091393 - 18 Sep 2019

Cited by 13 | Viewed by 4617

Abstract

Tumor-infiltrating lymphocytes (TILs) are a valuable indicator of the immune microenvironment that plays the central role in new anticancer drugs. TILs have a strong prognostic role in triple negative breast cancer (TNBC). Little is known about the interaction with the androgen receptor (AR) [...] Read more.

Tumor-infiltrating lymphocytes (TILs) are a valuable indicator of the immune microenvironment that plays the central role in new anticancer drugs. TILs have a strong prognostic role in triple negative breast cancer (TNBC). Little is known about the interaction with the androgen receptor (AR) and forkhead box A1 (FOXA1). We analyzed the relationships between TIL levels, AR, and FOXA1 expression and their clinical significance in TNBC patients. Further, we investigated their interaction with other biomarkers like programmed cell death ligand-1 (PD-L1), breast cancer type 1 susceptibility protein (BRCA1), poly (ADP-Ribose) polymerase 1 (PARP1), and Na+/H+ exchanger regulatory factor 1 (NHERF1). The expression of the proteins was evaluated by immunohistochemistry in 124 TNBC samples. TILs were performed adhering to International TILs Working Group 2014 criteria. Cox proportional hazards models were also used to identify risk factors associated with poor prognosis. Multivariate analysis identified TILs as independent prognostic factor of disease free survival (DFS; p = 0.045). A Kaplan–Meyer analysis revealed that the patients with high TILs had a better DFS compared to patients with low TILs (p = 0.037), and the phenotypes TILs−/AR+ and TILs−/FOXA1− had a worse DFS (p = 0.032, p = 0.001 respectively). AR was associated with FOXA1 expression (p = 0.007), and the tumors FOXA1+ presented low levels of TILs (p = 0.028). A poor DFS was observed for AR+/FOXA1+ tumors compared to other TNBCs (p = 0.0117). Low TILs score was associated with poor patients’ survival, and TILs level in combination with AR or FOXA1 expression affected patient’s clinical outcome. In addition, AR+/FOXA1+ phenotype identified a specific subgroup of TNBC patients with poor prognosis. These data may suggest new ways of therapeutic intervention to support current treatments. Full article

(This article belongs to the Special Issue New Insights into Breast and Endometrial Cancer)

► Show Figures

Figure 1

17 pages, 2430 KiB

Open AccessArticle

TWIST1 Heterodimerization with E12 Requires Coordinated Protein Phosphorylation to Regulate Periostin Expression

by Svetlana A. Mikheeva, Nathan D. Camp, Lei Huang, Antrix Jain, Sung Yun Jung, Naze G. Avci, Mari Tokita, Alejandro Wolf-Yadlin, Jing Zhang, Stephen J. Tapscott, Robert C. Rostomily and Andrei M. Mikheev

Cancers 2019, 11(9), 1392; https://doi.org/10.3390/cancers11091392 - 18 Sep 2019

Cited by 4 | Viewed by 3510

Abstract

Diffuse invasion into adjacent brain matter by glioblastoma (GBM) is largely responsible for their dismal prognosis. Previously, we showed that the TWIST1 (TW) bHLH transcription factor and its regulated gene periostin (POSTN) promote invasive phenotypes of GBM cells. Since TW functional [...] Read more.

Diffuse invasion into adjacent brain matter by glioblastoma (GBM) is largely responsible for their dismal prognosis. Previously, we showed that the TWIST1 (TW) bHLH transcription factor and its regulated gene periostin (POSTN) promote invasive phenotypes of GBM cells. Since TW functional effects are regulated by phosphorylation and dimerization, we investigated how phosphorylation of serine 68 in TW regulates TW dimerization, POSTN expression, and invasion in glioma cells. Compared with wild-type TW, the hypophosphorylation mutant, TW(S68A), impaired TW heterodimerization with the E12 bHLH transcription factor and cell invasion in vitro but had no effect on TW homodimerization. Overexpression of TW:E12 forced dimerization constructs (FDCs) increased glioma cell invasion and upregulated pro-invasive proteins, including POSTN, in concert with cytoskeletal reorganization. By contrast, TW:TW homodimer FDCs inhibited POSTN expression and cell invasion in vitro. Further, phosphorylation of analogous PXSP phosphorylation sites in TW:E12 FDCs (TW S68 and E12 S139) coordinately regulated POSTN and PDGFRa mRNA expression. These results suggested that TW regulates pro-invasive phenotypes in part through coordinated phosphorylation events in TW and E12 that promote heterodimer formation and regulate downstream targets. This new mechanistic understanding provides potential therapeutic strategies to inhibit TW-POSTN signaling in GBM and other cancers. Full article

► Show Figures

Figure 1

4 pages, 169 KiB

Open AccessEditorial

Pheochromocytoma (PHEO) and Paraganglioma (PGL)

by Karel Pacak and David Taïeb

Cancers 2019, 11(9), 1391; https://doi.org/10.3390/cancers11091391 - 18 Sep 2019

Cited by 6 | Viewed by 3936

Abstract

This series of 23 articles (17 original articles, six reviews) is presented by international leaders in pheochromocytoma and paraganglioma (PPGL) [...] Full article

(This article belongs to the Special Issue Pheochromocytoma (PHEO) and Paraganglioma (PGL))

13 pages, 2987 KiB

Open AccessArticle

Docetaxel Combined with Thymoquinone Induces Apoptosis in Prostate Cancer Cells via Inhibition of the PI3K/AKT Signaling Pathway

by Santosh Kumar Singh, Tejumola Apata, Jennifer B. Gordetsky and Rajesh Singh

Cancers 2019, 11(9), 1390; https://doi.org/10.3390/cancers11091390 - 18 Sep 2019

Cited by 44 | Viewed by 4937

Abstract

Toxicity and the development of resistance by cancer cells are impediments for docetaxel (DTX), a primary drug for treating prostate cancer (PCa). Since the combination of DTX with natural compounds can increase its effectiveness by reducing its toxic concentrations, we evaluated a combination [...] Read more.

Toxicity and the development of resistance by cancer cells are impediments for docetaxel (DTX), a primary drug for treating prostate cancer (PCa). Since the combination of DTX with natural compounds can increase its effectiveness by reducing its toxic concentrations, we evaluated a combination of thymoquinone (TQ) with DTX and determined its cytotoxicity against PCa cells (DU145 and C4-2B). This combination, in a concentration-dependent manner, resulted in synergistic cytotoxicity and apoptosis in comparison to either DTX or TQ alone. In addition, inhibition of cell survival pathways by PI3K/AKT inhibitors conferred sensitivity of DU145 and C4-2B cells to the combination as compared to the individual drugs. Moreover, the combined drugs (DTX+TQ) with inhibitors of PI3K/AKT increased the expression of pro-apoptotic markers (BAX and BID) along with caspase-3, PARP and decreased expression of the anti-apoptotic marker, BCL-XL. These data show that, for PCa cells, the cytotoxic effect of the DTX and TQ combination correlates with a block of the PI3K/AKT signaling pathway. These findings indicate that the combination of DTX and TQ, by blocking of the PI3K/AKT pathway, will improve the survival rate and quality of life of PCa patients. Full article

(This article belongs to the Special Issue Prostate Cancer: Past, Present, and Future)

► Show Figures

Figure 1

29 pages, 2121 KiB

Open AccessReview

Heat Shock Proteins and Ovarian Cancer: Important Roles and Therapeutic Opportunities

by Abdullah Hoter and Hassan Y. Naim

Cancers 2019, 11(9), 1389; https://doi.org/10.3390/cancers11091389 - 18 Sep 2019

Cited by 50 | Viewed by 6995

Abstract

Ovarian cancer is a serious cause of death in gynecological oncology. Delayed diagnosis and poor survival rates associated with late stages of the disease are major obstacles against treatment efforts. Heat shock proteins (HSPs) are stress responsive molecules known to be crucial in [...] Read more.

Ovarian cancer is a serious cause of death in gynecological oncology. Delayed diagnosis and poor survival rates associated with late stages of the disease are major obstacles against treatment efforts. Heat shock proteins (HSPs) are stress responsive molecules known to be crucial in many cancer types including ovarian cancer. Clusterin (CLU), a unique chaperone protein with analogous oncogenic criteria to HSPs, has also been proven to confer resistance to anti-cancer drugs. Indeed, these chaperone molecules have been implicated in diagnosis, prognosis, metastasis and aggressiveness of various cancers. However, relative to other cancers, there is limited body of knowledge about the molecular roles of these chaperones in ovarian cancer. In the current review, we shed light on the diverse roles of HSPs as well as related chaperone proteins like CLU in the pathogenesis of ovarian cancer and elucidate their potential as effective drug targets. Full article

► Show Figures

Figure 1

14 pages, 262 KiB

Open AccessReview

BRAF Inhibitors in Thyroid Cancer: Clinical Impact, Mechanisms of Resistance and Future Perspectives

by Fabiana Crispo, Tiziana Notarangelo, Michele Pietrafesa, Giacomo Lettini, Giovanni Storto, Alessandro Sgambato, Francesca Maddalena and Matteo Landriscina

Cancers 2019, 11(9), 1388; https://doi.org/10.3390/cancers11091388 - 18 Sep 2019

Cited by 77 | Viewed by 6109

Abstract

The Kirsten rat sarcoma viral oncogene homolog (RAS)/v-raf-1 murine leukemia viral oncogene homolog 1 (RAF)/mitogen-activated protein kinase 1 (MAPK) signaling cascade is the most important oncogenic pathway in human cancers. Tumors leading mutations in the gene encoding for v-raf murine sarcoma viral oncogene [...] Read more.

The Kirsten rat sarcoma viral oncogene homolog (RAS)/v-raf-1 murine leukemia viral oncogene homolog 1 (RAF)/mitogen-activated protein kinase 1 (MAPK) signaling cascade is the most important oncogenic pathway in human cancers. Tumors leading mutations in the gene encoding for v-raf murine sarcoma viral oncogene homolog B (BRAF) serine-threonine kinase are reliant on the MAPK signaling pathway for their growth and survival. Indeed, the constitutive activation of MAPK pathway results in continuous stimulation of cell proliferation, enhancement of the apoptotic threshold and induction of a migratory and metastatic phenotype. In a clinical perspective, this scenario opens to the possibility of targeting BRAF pathway for therapy. Thyroid carcinomas (TCs) bearing BRAF mutations represent approximately 29–83% of human thyroid malignancies and, differently from melanomas, are less sensitive to BRAF inhibitors and develop primary or acquired resistance due to mutational events or activation of alternative signaling pathways able to reactivate ERK signaling. In this review, we provide an overview on the current knowledge concerning the mechanisms leading to resistance to BRAF inhibitors in human thyroid carcinomas and discuss the potential therapeutic strategies, including combinations of BRAF inhibitors with other targeted agents, which might be employed to overcome drug resistance and potentiate the activity of single agent BRAF inhibitors. Full article

(This article belongs to the Special Issue Thyroid Cancer)

13 pages, 925 KiB

Open AccessArticle

Prognostic Factors for Event-Free Survival in Pediatric Patients with Hepatoblastoma Based on the 2017 PRETEXT and CHIC-HS Systems

by Hee Mang Yoon, Jisun Hwang, Kyung Won Kim, Jung-Man Namgoong, Dae Yeon Kim, Kyung-Nam Koh, Hyery Kim and Young Ah Cho

Cancers 2019, 11(9), 1387; https://doi.org/10.3390/cancers11091387 - 18 Sep 2019

Cited by 15 | Viewed by 3433

Abstract

This study aimed to evaluate the prognostic value of variables used in the 2017 PRE-Treatment EXTent of tumor (PRETEXT) system and the Children’s Hepatic tumors International Collaboration-Hepatoblastoma Stratification (CHIC-HS) system in pediatric patients with hepatoblastoma. A retrospective analysis of data from the pediatric [...] Read more.

This study aimed to evaluate the prognostic value of variables used in the 2017 PRE-Treatment EXTent of tumor (PRETEXT) system and the Children’s Hepatic tumors International Collaboration-Hepatoblastoma Stratification (CHIC-HS) system in pediatric patients with hepatoblastoma. A retrospective analysis of data from the pediatric hepatoblastoma registry of a tertiary referral center was conducted to evaluate the clinical and imaging variables (annotation factors) of the PRETEXT staging system. The primary outcome was event-free survival (EFS). Data from 84 patients (mean age: 2.9 ± 3.5 years) identified between 1998 and 2017 were included. Univariable Cox proportional hazards analysis revealed that PRETEXT annotation factors P (portal vein involvement), F (multifocality of tumor), and M (distant metastasis) showed a significant negative association with EFS. Multivariable Cox proportional hazard analysis showed that factor F was the strongest predictor (HR (hazard ratio), 2.908; 95% CI (confidence interval), 1.061–7.972; p = 0.038), whereas factor M showed borderline significance (HR, 2.416; 95% CI, 0.918–6.354; p = 0.074). The prediction model based on F and M (F + M) showed good performance to predict EFS (C-statistic, 0.734; 95% CI, 0.612–0.854). In conclusion, the PRETEXT annotation factor F was the strongest predictor of EFS, and the F + M model showed good performance to predict EFS in pediatric patients with hepatoblastoma. Full article

(This article belongs to the Special Issue Hepatoblastoma and Pediatric Liver Tumors)

► Show Figures

Figure 1

2 pages, 147 KiB

Open AccessReply

Reply to Comment on “Osteopontin, Macrophage Migration Inhibitory Factor and Anti-Interleukin-8 Autoantibodies Complement CA125 for Detection of Early Stage Ovarian Cancer” Cancers 2019, 11, 596: Markers for Early Detection of Ovarian Cancer

by Jing Guo, Zhen Lu and Robert C. Bast, Jr.

Cancers 2019, 11(9), 1386; https://doi.org/10.3390/cancers11091386 - 18 Sep 2019

Cited by 1 | Viewed by 2160

Abstract

We appreciate Mor et al [...] Full article

15 pages, 2474 KiB

Open AccessArticle

XIST-Promoter Demethylation as Tissue Biomarker for Testicular Germ Cell Tumors and Spermatogenesis Quality

by João Lobo, Sandra P. Nunes, Ad J. M. Gillis, Daniela Barros-Silva, Vera Miranda-Gonçalves, Annette van den Berg, Mariana Cantante, Rita Guimarães, Rui Henrique, Carmen Jerónimo and Leendert H. J. Looijenga

Cancers 2019, 11(9), 1385; https://doi.org/10.3390/cancers11091385 - 17 Sep 2019

Cited by 24 | Viewed by 3637

Abstract

Background: The event of X chromosome inactivation induced by XIST, which is physiologically observed in females, is retained in testicular germ cell tumors (TGCTs), as a result of a supernumerary X chromosome constitution. X chromosome inactivation also occurs in male germline, specifically [...] Read more.

Background: The event of X chromosome inactivation induced by XIST, which is physiologically observed in females, is retained in testicular germ cell tumors (TGCTs), as a result of a supernumerary X chromosome constitution. X chromosome inactivation also occurs in male germline, specifically during spermatogenesis. We aimed to analyze the promoter methylation status of XIST in a series of TGCT tissues, representative cell lines, and testicular parenchyma. Methods: Two independent cohorts were included, comprising a total of 413 TGCT samples, four (T)GCT cell lines, and 86 testicular parenchyma samples. The relative amount of methylated and demethylated XIST promoter fragments was assessed by quantitative methylation-specific PCR (qMSP) and more sensitive high-resolution melting (HRM) methylation analyses. Results: Seminomas showed a lower amount of methylated XIST fragments as compared to non-seminomas or normal testis (p < 0.0001), allowing for a good discrimination among these groups (area under the curve 0.83 and 0.81, respectively). Seminomas showed a significantly higher content of demethylated XIST as compared to non-seminomas. The percentage of demethylated XIST fragment in cell lines reflected their chromosomal constitution (number of extra X chromosomes). A novel and strong positive correlation between the Johnsen’s score and XIST demethylation was identified (r = 0.75, p < 0.0001). Conclusions: The X chromosome inactivation event and demethylated XIST promoter are promising biomarkers for TGCTs and for assessing spermatogenesis quality. Full article

(This article belongs to the Special Issue Germ Cell Tumors)

► Show Figures

Figure 1

12 pages, 3679 KiB

Open AccessArticle

Molecular Mechanisms Underlying Yatein-Induced Cell-Cycle Arrest and Microtubule Destabilization in Human Lung Adenocarcinoma Cells

by Shang-Tse Ho, Chi-Chen Lin, Yu-Tang Tung and Jyh-Horng Wu

Cancers 2019, 11(9), 1384; https://doi.org/10.3390/cancers11091384 - 17 Sep 2019

Cited by 10 | Viewed by 3304

Abstract

Yatein is an antitumor agent isolated from Calocedrus formosana Florin leaves extract. In our previous study, we found that yatein inhibited the growth of human lung adenocarcinoma A549 and CL1-5 cells by inducing intrinsic and extrinsic apoptotic pathways. To further uncover the effects [...] Read more.

Yatein is an antitumor agent isolated from Calocedrus formosana Florin leaves extract. In our previous study, we found that yatein inhibited the growth of human lung adenocarcinoma A549 and CL1-5 cells by inducing intrinsic and extrinsic apoptotic pathways. To further uncover the effects and mechanisms of yatein-induced inhibition on A549 and CL1-5 cell growth, we evaluated yatein-mediated antitumor activity in vivo and the regulatory effects of yatein on cell-cycle progression and microtubule dynamics. Flow cytometry and western blotting revealed that yatein induces G₂/M arrest in A549 and CL1-5 cells. Yatein also destabilized microtubules and interfered with microtubule dynamics in the two cell lines. Furthermore, we evaluated the antitumor activity of yatein in vivo using a xenograft mouse model and found that yatein treatment altered cyclin B/Cdc2 complex expression and significantly inhibited tumor growth. Taken together, our results suggested that yatein effectively inhibited the growth of A549 and CL1-5 cells possibly by disrupting cell-cycle progression and microtubule dynamics. Full article

(This article belongs to the Special Issue Role of Natural Bioactive Compounds in the Rise and Fall of Cancers)

► Show Figures

Graphical abstract

14 pages, 13127 KiB

Open AccessArticle

Encapsulated Carbenoxolone Reduces Lung Metastases

by Adi Karsch-Bluman, Shimrit Avraham, Miri Assayag, Ouri Schwob and Ofra Benny

Cancers 2019, 11(9), 1383; https://doi.org/10.3390/cancers11091383 - 17 Sep 2019

Cited by 11 | Viewed by 3277

Abstract

Carbenoxolone is an anti-inflammatory compound and a derivate of a natural substance from the licorice plant. We previously showed that carbenoxolone reduces the metastatic burden in the lungs of mice through its antagonistic effect on high mobility group box 1 (HMGB1). To further [...] Read more.

Carbenoxolone is an anti-inflammatory compound and a derivate of a natural substance from the licorice plant. We previously showed that carbenoxolone reduces the metastatic burden in the lungs of mice through its antagonistic effect on high mobility group box 1 (HMGB1). To further enhance carbenoxolone’s activity and localization in the lungs, thereby reducing the potential adverse side effects resulting from systemic exposure, we developed a poly(lactic-co-glycolic acid) (PLGA) slow-release system for pulmonary delivery which maintains drug activity in-vitro, as demonstrated in the anoikis assay. Both systemic and intranasal administrations of carbenoxolone effectively minimize metastatic formation in a lung colonization model in mice. Our results show a decrease in the metastatic burden in the lung tissue. Notably, the therapeutic effect of a single intranasal administration of 25 mg/kg carbenoxolone, in the form of drug-loaded particles, had a similar effect in reducing metastatic lesions in the lungs to that of a 10-fold dose of the free drug via intraperitoneal injections, three times per week over the course of four weeks. These data offer new means to potentiate the anti-cancer activity of carbenoxolone and simultaneously reduce the requirement for high dosage administration; the upshot substantially improves therapeutic effect and avoidance of side effects. Full article

► Show Figures

Figure 1

15 pages, 834 KiB

Open AccessReview

Radioiodine-Refractory Thyroid Cancer: Molecular Basis of Redifferentiation Therapies, Management, and Novel Therapies

by Mohamed Aashiq, Deborah A. Silverman, Shorook Na’ara, Hideaki Takahashi and Moran Amit

Cancers 2019, 11(9), 1382; https://doi.org/10.3390/cancers11091382 - 17 Sep 2019

Cited by 104 | Viewed by 11357

Abstract

Recurrent, metastatic disease represents the most frequent cause of death for patients with thyroid cancer, and radioactive iodine (RAI) remains a mainstay of therapy for these patients. Unfortunately, many thyroid cancer patients have tumors that no longer trap iodine, and hence are refractory [...] Read more.

Recurrent, metastatic disease represents the most frequent cause of death for patients with thyroid cancer, and radioactive iodine (RAI) remains a mainstay of therapy for these patients. Unfortunately, many thyroid cancer patients have tumors that no longer trap iodine, and hence are refractory to RAI, heralding a poor prognosis. RAI-refractory (RAI-R) cancer cells result from the loss of thyroid differentiation features, such as iodide uptake and organification. This loss of differentiation features correlates with the degree of mitogen-activated protein kinase (MAPK) activation, which is higher in tumors with BRAF (B-Raf proto-oncogene) mutations than in those with RTK (receptor tyrosine kinase) or RAS (rat sarcoma) mutations. Hence, inhibition of the mitogen-activated protein kinase kinase-1 and -2 (MEK-1 and -2) downstream of RAF (rapidly accelerated fibrosarcoma) could sensitize RAI refractivity in thyroid cancer. However, a significant hurdle is the development of secondary tumor resistance (escape mechanisms) to these drugs through upregulation of tyrosine kinase receptors or another alternative signaling pathway. The sodium iodide symporter (NIS) is a plasma membrane glycoprotein, a member of solute carrier family 5A (SLC5A5), located on the basolateral surfaces of the thyroid follicular epithelial cells, which mediates active iodide transport into thyroid follicular cells. The mechanisms responsible for NIS loss of function in RAI-R thyroid cancer remains unclear. In a study of patients with recurrent thyroid cancer, expression levels of specific ribosomal machinery—namely PIGU (phosphatidylinositol glycan anchor biosynthesis class U), a subunit of the GPI (glycosylphosphatidylinositol transamidase complex—correlated with RAI avidity in radioiodine scanning, NIS levels, and biochemical response to RAI treatment. Here, we review the proposed mechanisms for RAI refractivity and the management of RAI-refractive metastatic, recurrent thyroid cancer. We also describe novel targeted systemic agents that are in use or under investigation for RAI-refractory disease, their mechanisms of action, and their adverse events. Full article

(This article belongs to the Special Issue Thyroid Cancer)

► Show Figures

Figure 1

13 pages, 3011 KiB

Open AccessArticle

BRAF Mutations Classes I, II, and III in NSCLC Patients Included in the SLLIP Trial: The Need for a New Pre-Clinical Treatment Rationale

by Jillian Wilhelmina Paulina Bracht, Niki Karachaliou, Trever Bivona, Richard B. Lanman, Iris Faull, Rebecca J. Nagy, Ana Drozdowskyj, Jordi Berenguer, Manuel Fernandez-Bruno, Miguel Angel Molina-Vila and Rafael Rosell

Cancers 2019, 11(9), 1381; https://doi.org/10.3390/cancers11091381 - 17 Sep 2019

Cited by 53 | Viewed by 11138

Abstract

BRAF V600 mutations have been found in 1–2% of non-small-cell lung cancer (NSCLC) patients, with Food and Drug Administration (FDA) approved treatment of dabrafenib plus trametinib and progression free survival (PFS) of 10.9 months. However, 50–80% of BRAF mutations in lung cancer are [...] Read more.

BRAF V600 mutations have been found in 1–2% of non-small-cell lung cancer (NSCLC) patients, with Food and Drug Administration (FDA) approved treatment of dabrafenib plus trametinib and progression free survival (PFS) of 10.9 months. However, 50–80% of BRAF mutations in lung cancer are non-V600, and can be class II, with intermediate to high kinase activity and RAS independence, or class III, with impaired kinase activity, upstream signaling dependence, and consequently, sensitivity to receptor tyrosine kinase (RTK) inhibitors. Plasma cell-free DNA (cfDNA) of 185 newly diagnosed advanced lung adenocarcinoma patients (Spanish Lung Liquid versus Invasive Biopsy Program, SLLIP, NCT03248089) was examined for BRAF and other alterations with a targeted cfDNA next-generation sequencing (NGS) assay (Guardant360®, Guardant Health Inc., CA, USA), and results were correlated with patient outcome. Cell viability with single or combined RAF, MEK, and SHP2 inhibitors was assessed in cell lines with BRAF class I, II, and III mutations. Out of 185 patients, 22 had BRAF alterations (12%) of which seven patients harbored amplifications (32%) and 17 had BRAF mutations (77%). Of the BRAF mutations, four out of 22 (18%) were V600E and 18/22 (82%) were non-V600. In vitro results confirmed sensitivity of class III and resistance of class I and II BRAF mutations, and BRAF wild type cells to SHP2 inhibition. Concomitant MEK or RAF and SHP2 inhibition showed synergistic effects, especially in the class III BRAF-mutant cell line. Our study indicates that the class of the BRAF mutation may have clinical implications and therefore should be defined in the clinical practice and used to guide therapeutic decisions. Full article

(This article belongs to the Special Issue Oncogenic Forms of BRAF as Cancer Driver Genes)

► Show Figures

Graphical abstract

19 pages, 7860 KiB

Open AccessFeature PaperArticle

by Patrizia Gasparini, Orazio Fortunato, Loris De Cecco, Michela Casanova, Maria Federica Iannó, Andrea Carenzo, Giovanni Centonze, Massimo Milione, Paola Collini, Mattia Boeri, Matteo Dugo, Chiara Gargiuli, Mavis Mensah, Miriam Segale, Luca Bergamaschi, Stefano Chiaravalli, Maria Luisa Sensi, Maura Massimino, Gabriella Sozzi and Andrea Ferrari

Cancers 2019, 11(9), 1380; https://doi.org/10.3390/cancers11091380 - 17 Sep 2019

Cited by 16 | Viewed by 3612

Abstract

Adolescents and young adults (AYA) with rhabdomyosarcoma (RMS) form a subgroup of patients whose optimal clinical management and access to care remain a challenge and whose survival lacks behind that of children diagnosed with histologically similar tumors. Understanding the tumor biology that differentiates [...] Read more.

Adolescents and young adults (AYA) with rhabdomyosarcoma (RMS) form a subgroup of patients whose optimal clinical management and access to care remain a challenge and whose survival lacks behind that of children diagnosed with histologically similar tumors. Understanding the tumor biology that differentiates children from AYA-RMS could provide critical information and drive new initiatives to improve the final outcome. MicroRNA (miRNA) and gene expression profiling (GEP) was evaluated in a RMS cohort of 49 tumor and 15 non-neoplastic tissues. miRNAs analysis identified miR-223 over-expression and miR-431 down-regulation in AYA, validated by Real-Time PCR and miRNA in situ hybridization (ISH). GEP analysis detected 793 age-correlated genes in tumors, of which 194 were anti-correlated. NOTCH2, FGFR1/2 were significantly down-modulated in AYA-RMS. miR-223 was associated with up-regulation of epithelial mesenchymal translation (EMT) and inflammatory pathways, whereas miR-431 was correlated to myogenic differentiation and muscle metabolism. GEP showed an increase in genes associated with CD4 memory resting cells and a decrease in genes associated with γδ T-cells in AYA-RMS. Immunohistochemistry (IHC) analysis demonstrated an increase of infiltrated CD4, CD8, and neutrophils in AYA-RMS tumors. Our results show that aggressiveness of AYA-RMS could be explained by differences in microenvironmental signal modulation mediated by tumor cells, suggesting a fundamental role of immune contexture in AYA-RMS development. Full article

► Show Figures

Figure 1

24 pages, 449 KiB

Open AccessReview

Observations on Solitary Versus Multiple Isolated Pancreatic Metastases of Renal Cell Carcinoma: Another Indication of a Seed and Soil Mechanism?

by Franz Sellner

Cancers 2019, 11(9), 1379; https://doi.org/10.3390/cancers11091379 - 17 Sep 2019

Cited by 10 | Viewed by 2865

Abstract

Isolated pancreas metastases are a rare type of metastasis of renal cell carcinoma, characterized by the presence of pancreatic metastases, while all other organs remain unaffected. In a previous study, we determined arguments from the literature which (a) indicate a systemic–haematogenic metastasis route [...] Read more.

Isolated pancreas metastases are a rare type of metastasis of renal cell carcinoma, characterized by the presence of pancreatic metastases, while all other organs remain unaffected. In a previous study, we determined arguments from the literature which (a) indicate a systemic–haematogenic metastasis route (uniform distribution of the metastases across the pancreas and independence of the metastatic localization in the pancreas of the side of the renal carcinoma); and (b) postulate a high impact of a seed and soil mechanism (SSM) on isolated pancreatic metastasis of renal cell carcinoma (isPM) as an explanation for exclusive pancreatic metastases, despite a systemic haematogenous tumor cell embolization. The objective of the study presented was to search for further arguments in favor of an SSM with isPM. For that purpose, the factor’s histology, grading, and singular/multiple pancreas metastases were analyzed on the basis of 814 observations published up to 2018. While histology and grading allowed for no conclusions regarding the importance of an SSM, the comparison of singular/multiple pancreas metastases produced arguments in favor of an SSM: 1. The multiple pancreas metastases observed in 38.1% prove that multiple tumor cell embolisms occur with isPM, the exclusive “maturation” of which in the pancreas requires an SSM; 2. The survival rates (SVR), which are consistent with singular and multiple pancreas metastases (despite the higher total tumor load with the latter), prove that the metastasized tumor cells are not able to survive in all other organs because of an SSM, which results in identical SVR when the pancreatic foci are treated adequately. Full article

(This article belongs to the Special Issue Cancer Invasion and Metastasis)

► Show Figures

Figure 1

14 pages, 7217 KiB

Open AccessArticle

CYP17A1 Maintains the Survival of Glioblastomas by Regulating SAR1-Mediated Endoplasmic Reticulum Health and Redox Homeostasis

by Hong-Yi Lin, Chiung-Yuan Ko, Tzu-Jen Kao, Wen-Bin Yang, Yu-Ting Tsai, Jian-Ying Chuang, Siou-Lian Hu, Pei-Yu Yang, Wei-Lun Lo and Tsung-I Hsu

Cancers 2019, 11(9), 1378; https://doi.org/10.3390/cancers11091378 - 16 Sep 2019

Cited by 28 | Viewed by 3934

Abstract

Cytochrome P450 (CYP) 17A1 is an important steroidogenic enzyme harboring 17α-hydroxylase and performing 17,20 lyase activities in multiple steps of steroid hormone synthesis, including dehydroepiandrosterone (DHEA) biosynthesis. Previously, we showed that CYP17A1-mediated DHEA production clearly protects glioblastomas from temozolomide-induced apoptosis, leading to drug [...] Read more.

Cytochrome P450 (CYP) 17A1 is an important steroidogenic enzyme harboring 17α-hydroxylase and performing 17,20 lyase activities in multiple steps of steroid hormone synthesis, including dehydroepiandrosterone (DHEA) biosynthesis. Previously, we showed that CYP17A1-mediated DHEA production clearly protects glioblastomas from temozolomide-induced apoptosis, leading to drug resistance. Herein, we attempt to clarify whether the inhibition of CYP17A1 has a tumor-suppressive effect, and to determine the steroidogenesis-independent functions of CYP17A1 in glioblastomas. Abiraterone, an inhibitor of CYP17A1, significantly inhibits the proliferation of A172, T98G, and PT#3 (the primary glioblastoma cells) by inducing apoptosis. In parallel, abiraterone potently suppresses tumor growth in mouse models through transplantation of PT#3 cells to the back or to the brain. Based on evidence that abiraterone induces endoplasmic reticulum (ER) stress, followed by the accumulation of reactive oxygen species (ROS), CYP17A1 is important for ER health and redox homeostasis. To confirm our hypothesis, we showed that CYP17A1 overexpression prevents the initiation of ER stress and attenuates ROS production by regulating SAR1a/b expression. Abiraterone dissociates SAR1a/b from ER-localized CYP17A1, and induces SAR1a/b ubiquitination, leading to degradation. Furthermore, SAR1 overexpression rescues abiraterone-induced apoptosis and impairs redox homeostasis. In addition to steroid hormone synthesis, CYP17A1 associates with SAR1a/b to regulate protein processing and maintain ER health in glioblastomas. Full article

► Show Figures

Figure 1

11 pages, 1576 KiB

Open AccessArticle

MALDI-MSI as a Complementary Diagnostic Tool in Cytopathology: A Pilot Study for the Characterization of Thyroid Nodules

by Giulia Capitoli, Isabella Piga, Stefania Galimberti, Davide Leni, Angela Ida Pincelli, Mattia Garancini, Francesca Clerici, Allia Mahajneh, Virginia Brambilla, Andrew Smith, Fulvio Magni and Fabio Pagni

Cancers 2019, 11(9), 1377; https://doi.org/10.3390/cancers11091377 - 16 Sep 2019

Cited by 26 | Viewed by 4958

Abstract

The present study applies for the first time as Matrix-Assisted Laser Desorption/Ionization (MALDI) Mass Spectrometry Imaging (MSI) on real thyroid Fine Needle Aspirations (FNAs) to test its possible complementary role in routine cytology in the diagnosis of thyroid nodules. The primary aim is [...] Read more.

The present study applies for the first time as Matrix-Assisted Laser Desorption/Ionization (MALDI) Mass Spectrometry Imaging (MSI) on real thyroid Fine Needle Aspirations (FNAs) to test its possible complementary role in routine cytology in the diagnosis of thyroid nodules. The primary aim is to evaluate the potential employment of MALDI-MSI in cytopathology, using challenging samples such as needle washes. Firstly, we designed a statistical model based on the analysis of Regions of Interest (ROIs), according to the morphological triage performed by the pathologist. Successively, the capability of the model to predict the classification of the FNAs was validated in a different group of patients on ROI and pixel-by-pixel approach. Results are very promising and highlight the possibility to introduce MALDI-MSI as a complementary tool for the diagnostic characterization of thyroid nodules. Full article

(This article belongs to the Special Issue Thyroid Cancer)

► Show Figures

Figure 1

9 pages, 444 KiB

Open AccessArticle

Impact of Surgery on Long-Term Results of Hearing in Neurofibromatosis Type-2 Associated Vestibular Schwannomas

by Isabel Gugel, Florian Grimm, Marina Liebsch, Julian Zipfel, Christian Teuber, Lan Kluwe, Victor-Felix Mautner, Marcos Tatagiba and Martin Ulrich Schuhmann

Cancers 2019, 11(9), 1376; https://doi.org/10.3390/cancers11091376 - 16 Sep 2019

Cited by 17 | Viewed by 3191

Abstract

Hearing preservation is a major goal in the treatment of neurofibromatosis type 2 (NF2) associated vestibular schwannoma (VS), particularly in children and adolescents. In this study, we retrospectively reviewed hearing and volumetry data sets of 39 operated tumors (ears) in 23 patients under [...] Read more.

Hearing preservation is a major goal in the treatment of neurofibromatosis type 2 (NF2) associated vestibular schwannoma (VS), particularly in children and adolescents. In this study, we retrospectively reviewed hearing and volumetry data sets of 39 operated tumors (ears) in 23 patients under the age of 25 and in a follow-up period of 21 to 167 months. Hearing data over a compatible period on 20 other tumors, which did not receive surgery due to their less aggressive nature, were included for comparison. Surgery was carried out via a retrosigmoid approach with the brainstem auditory evoked potential (BAEP) guide. Immediately after surgery, functional hearing was maintained in 82% of ears. Average hearing scores were better in the non-surgery ears. However, the hearing scores in both groups worsened gradually with a similar dynamic during the 42-month postoperative follow-up period. No accelerated impairment of hearing was evident for the operated cases. Rather, the gap between the two hearing deterioration lines tended to close at the end of the follow-up period. Our result suggested that the BAEP-guided surgery did not cause additional hearing deterioration in the long-term and seemed to slow down hearing deterioration of those tumors that were initially more aggressive. Full article

(This article belongs to the Special Issue New Insights into Neurofibromatosis)

► Show Figures

Figure 1

15 pages, 725 KiB

Open AccessFeature PaperReview

The Immune Microenvironment of Breast Cancer Progression

by Helen Tower, Meagan Ruppert and Kara Britt

Cancers 2019, 11(9), 1375; https://doi.org/10.3390/cancers11091375 - 16 Sep 2019

Cited by 73 | Viewed by 18218

Abstract

Inflammation is now recognized as a hallmark of cancer. Genetic changes in the cancer cell are accepted as the match that lights the fire, whilst inflammation is seen as the fuel that feeds the fire. Once inside the tumour, the immune cells secrete [...] Read more.

Inflammation is now recognized as a hallmark of cancer. Genetic changes in the cancer cell are accepted as the match that lights the fire, whilst inflammation is seen as the fuel that feeds the fire. Once inside the tumour, the immune cells secrete cytokines that kick-start angiogenesis to ferry in much-needed oxygen and nutrients that encourage the growth of tumours. There is now irrefutable data demonstrating that the immune contexture of breast tumours can influence growth and metastasis. A higher immune cell count in invasive breast cancer predicts prognosis and response to chemotherapy. We are beginning now to define the specific innate and adaptive immune cells present in breast cancer and their role not just in the progression of invasive disease, but also in the development of pre-invasive lesions and their transition to malignant tumours. This review article focusses on the immune cells present in early stage breast cancer and their relationship with the immunoediting process involved in tumour advancement. Full article

(This article belongs to the Special Issue Metastatic Progression and Tumour Heterogeneity)

► Show Figures

Figure 1

24 pages, 2929 KiB

Open AccessReview

Targeting Autophagy for Overcoming Resistance to Anti-EGFR Treatments

by Yoojung Kwon, Misun Kim, Hyun Suk Jung, Youngmi Kim and Dooil Jeoung

Cancers 2019, 11(9), 1374; https://doi.org/10.3390/cancers11091374 - 16 Sep 2019

Cited by 64 | Viewed by 8842

Abstract

Epidermal growth factor receptor (EGFR) plays critical roles in cell proliferation, tumorigenesis, and anti-cancer drug resistance. Overexpression and somatic mutations of EGFR result in enhanced cancer cell survival. Therefore, EGFR can be a target for the development of anti-cancer therapy. Patients with cancers, [...] Read more.

Epidermal growth factor receptor (EGFR) plays critical roles in cell proliferation, tumorigenesis, and anti-cancer drug resistance. Overexpression and somatic mutations of EGFR result in enhanced cancer cell survival. Therefore, EGFR can be a target for the development of anti-cancer therapy. Patients with cancers, including non-small cell lung cancers (NSCLC), have been shown to response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and anti-EGFR antibodies. However, resistance to these anti-EGFR treatments has developed. Autophagy has emerged as a potential mechanism involved in the acquired resistance to anti-EGFR treatments. Anti-EGFR treatments can induce autophagy and result in resistance to anti-EGFR treatments. Autophagy is a programmed catabolic process stimulated by various stimuli. It promotes cellular survival under these stress conditions. Under normal conditions, EGFR-activated phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling inhibits autophagy while EGFR/rat sarcoma viral oncogene homolog (RAS)/mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) signaling promotes autophagy. Thus, targeting autophagy may overcome resistance to anti-EGFR treatments. Inhibitors targeting autophagy and EGFR signaling have been under development. In this review, we discuss crosstalk between EGFR signaling and autophagy. We also assess whether autophagy inhibition, along with anti-EGFR treatments, might represent a promising approach to overcome resistance to anti-EGFR treatments in various cancers. In addition, we discuss new developments concerning anti-autophagy therapeutics for overcoming resistance to anti-EGFR treatments in various cancers. Full article

(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling in Cancer)

► Show Figures

Graphical abstract

Journal Menu

Journal Browser

Cancers, Volume 11, Issue 9 (September 2019) – 188 articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI