Cancers

21 pages, 1889 KiB

Open AccessReview

Liquid Crystals: A Novel Approach for Cancer Detection and Treatment

by Jayalakshmi Vallamkondu^1,2,*, Edwin Bernard Corgiat³, Gollapelli Buchaiah¹, Ramesh Kandimalla^4,5 and P. Hemachandra Reddy^{4,5,6,7,8,9,10,*}

¹ Department of Physics, NIT Warangal, Telangana 506004, India

² Centre for Advanced Materials, NIT Warangal, Telangana 506004, India

³ Department of Cellular Biology, Emory University School of Medicine, Atlanta, GA 30322, USA

⁴ Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, TX 79430, USA

⁵ Neurology Department, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, TX 79430, USA

⁶ Pharmacology and Neuroscience Department, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, TX 79430, USA

⁷ Garrison Institute on Aging, South West Campus, Texas Tech University Health Sciences Center, 6630 S. Quaker Suite E, MS 7495, Lubbock, TX 79413, USA

⁸ Cell Biology and Biochemistry Department, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, TX 79430, USA

⁹ Speech, Language and Hearing Sciences Department, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, TX 79430, USA

¹⁰ Department of Public Health, Graduate School of Biomedical Sciences, 3601 4th Street, MS 9424, Lubbock, TX 79430, USA

Cancers 2018, 10(11), 462; https://doi.org/10.3390/cancers10110462 - 21 Nov 2018

Cited by 36 | Viewed by 7696

Abstract

Liquid crystals are defined as the fourth state of matter forming between solid and liquid states. Earlier the applications of liquid crystals were confined to electronic instruments, but recent research findings suggest multiple applications of liquid crystals in biology and medicine. Here, the [...] Read more.

Liquid crystals are defined as the fourth state of matter forming between solid and liquid states. Earlier the applications of liquid crystals were confined to electronic instruments, but recent research findings suggest multiple applications of liquid crystals in biology and medicine. Here, the purpose of this review article is to discuss the potential biological impacts of liquid crystals in the diagnosis and prognosis of cancer along with the risk assessment. In this review, we also discussed the recent advances of liquid crystals in cancer biomarker detection and treatment in multiple cell line models. Cases reviewed here will demonstrate that cancer diagnostics based on the multidisciplinary technology and intriguingly utilization of liquid crystals may become an alternative to regular cancer detection methodologies. Additionally, we discussed the formidable challenges and problems in applying liquid crystal technologies. Solving these problems will require great effort and the way forward is through the multidisciplinary collaboration of physicists, biologists, chemists, material-scientists, clinicians, and engineers. The triumphant outcome of these liquid crystals and their applications in cancer research would be convenient testing for the detection of cancer and may result in treating the cancer patients non-invasively. Full article

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23 pages, 26745 KiB

Open AccessEditor’s ChoiceArticle

Network Pharmacology to Unveil the Biological Basis of Health-Strengthening Herbal Medicine in Cancer Treatment

by Jiahui Zheng¹, Min Wu¹, Haiyan Wang², Shasha Li², Xin Wang¹, Yan Li³, Dong Wang² and Shao Li^1,*

¹ MOE Key Laboratory of Bioinformatics; Bioinformatics Division Biology/Center for TCM-X, BNRist, TFIDT/Department of Automation, Tsinghua University, 100084 Beijing, China

² Department of Basic Medicine, School of Medicine, Tsinghua University, 100084 Beijing, China

³ State Key Laboratory of Bioactive Substances and Functions of Nature Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 100730 Beijing, China

Cancers 2018, 10(11), 461; https://doi.org/10.3390/cancers10110461 - 21 Nov 2018

Cited by 104 | Viewed by 9325

Abstract

Health-strengthening (Fu-Zheng) herbs is a representative type of traditional Chinese medicine (TCM) widely used for cancer treatment in China, which is in contrast to pathogen eliminating (Qu-Xie) herbs. However, the commonness in the biological basis of health-strengthening herbs remains [...] Read more.

Health-strengthening (Fu-Zheng) herbs is a representative type of traditional Chinese medicine (TCM) widely used for cancer treatment in China, which is in contrast to pathogen eliminating (Qu-Xie) herbs. However, the commonness in the biological basis of health-strengthening herbs remains to be holistically elucidated. In this study, an innovative high-throughput research strategy integrating computational and experimental methods of network pharmacology was proposed, and 22 health-strengthening herbs were selected for the investigation. Additionally, 25 pathogen-eliminating herbs were included for comparison. First, based on network-based, large-scale target prediction, we analyzed the target profiles of 1446 TCM compounds. Next, the actions of 166 compounds on 420 antitumor or immune-related genes were measured using a unique high-throughput screening strategy by high-throughput sequencing, referred to as HTS². Furthermore, the structural information and the antitumor activity of the compounds in health-strengthening and pathogen-eliminating herbs were compared. Using network pharmacology analysis, we discovered that: (1) Functionally, the predicted targets of compounds from health strengthening herbs were enriched in both immune-related and antitumor pathways, similar to those of pathogen eliminating herbs. As a case study, galloylpaeoniflorin, a compound in a health strengthening herb Radix Paeoniae Alba (Bai Shao), was found to exert antitumor effects both in vivo and in vitro. Yet the inhibitory effects of the compounds from pathogen eliminating herbs on tumor cells proliferation as a whole were significantly stronger than those in health-strengthening herbs (p < 0.001). Moreover, the percentage of assay compounds in health-strengthening herbs with the predicted targets enriched in the immune-related pathways (e.g., natural killer cell mediated cytotoxicity and antigen processing and presentation) were significantly higher than that in pathogen-eliminating herbs (p < 0.05). This finding was supported by the immune-enhancing effects of a group of compounds from health-strengthening herbs indicated by differentially expressed genes in the HTS² results. (2) Compounds in the same herb may exhibit the same or distinguished mechanisms in cancer treatment, which was demonstrated as the compounds influence pathway gene expressions in the same or opposite directions. For example, acetyl ursolic acid and specnuezhenide in a health-strengthening herb Fructus Ligustri lucidi (Nv Zhen Zi) both upregulated gene expressions in T cell receptor signaling pathway. Together, this study suggested greater potentials in tumor immune microenvironment regulation and tumor prevention than in direct killing tumor cells of health-strengthening herbs generally, and provided a systematic strategy for unveiling the commonness in the biological basis of health-strengthening herbs in cancer treatment. Full article

(This article belongs to the Special Issue Application of Bioinformatics in Cancers)

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Graphical abstract

17 pages, 3785 KiB

Open AccessArticle

Fucosyl-Agalactosyl IgG₁ Induces Cholangiocarcinoma Metastasis and Early Recurrence by Activating Tumor-Associated Macrophage

by Ting-Tsung Chang¹

, Hung-Wen Tsai² and Cheng-Hsun Ho^3,*

¹ Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan

² Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan

³ Department of Medical Laboratory Science, College of Medicine, I-Shou University, Kaohsiung 82445, Taiwan

Cancers 2018, 10(11), 460; https://doi.org/10.3390/cancers10110460 - 21 Nov 2018

Cited by 9 | Viewed by 3828

Abstract

Concern over roles of serum IgG agalactosylation in chronic inflammatory diseases has been mounting for years but less touched in cancers. The present study addressed the underlying role of agalactosylated IgG beyond tumorigenesis. Liquid-chromatography-tandem mass spectrometry was leveraged for the analysis of IgG [...] Read more.

Concern over roles of serum IgG agalactosylation in chronic inflammatory diseases has been mounting for years but less touched in cancers. The present study addressed the underlying role of agalactosylated IgG beyond tumorigenesis. Liquid-chromatography-tandem mass spectrometry was leveraged for the analysis of IgG₁ and IgG₂ N-glycomes. We found that a high percentage of serum fucosyl-agalactosyl IgG₁ (IgG₁-G0F) in patients with cholangiocarcinoma was associated with poor tumor differentiation and tumor metastasis. Results from Kaplan–Meier analyses and a stepwise Cox regression analysis showed that patients with serum IgG₁-G0F ≥40% were highly correlated with poor recurrence-free survivals and overall survivals. Interestingly, patients with cholangiocarcinoma whose serum IgG₁-G0F ≥40% had more CD163+ tumor-associated macrophages in cancerous tissues than adjacent non-cancerous counterparts. In vitro assays revealed that agalactosylated IgG upregulated tumor-associated macrophage markers CD163 and CD204 in human U-937 cells and peripheral macrophages. Moreover, a positive and a negative feedback loop of transforming growth factor-β1 and interferon-γ, respectively, on IgG agalactosylation was identified using hybridoma cells and verified in sera of the patients. In conclusion, agalactosylated IgG activates tumor-associated macrophages, thereby promoting tumor metastasis and recurrence of cholangiocarcinoma. Full article

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14 pages, 1057 KiB

Open AccessArticle

Mutational Evolution in Relapsed Diffuse Large B-Cell Lymphoma

by Marcel Nijland^1,*,†

, Annika Seitz^2,†, Martijn Terpstra³, Gustaaf W. Van Imhoff¹, Philip M Kluin², Tom Van Meerten¹, Çiğdem Atayar⁴

, Léon C. Van Kempen²

, Arjan Diepstra²

, Klaas Kok³

and Anke Van den Berg²

¹ Department of Hematology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands

² Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands

³ Department of Genetics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands

⁴ Department of Pathology, Treant Caregroup, Bethesda Hospital, 7909 AA Hoogenveen, The Netherlands

^† These authors contributed equally to this work.

Cancers 2018, 10(11), 459; https://doi.org/10.3390/cancers10110459 - 20 Nov 2018

Cited by 22 | Viewed by 4799

Abstract

Current genomic models in diffuse large B-cell lymphoma (DLBCL) are based on single tumor biopsies, which might underestimate heterogeneity. Data on mutational evolution largely remains unknown. An exploratory study using whole exome sequencing on paired (primary and relapse) formalin fixed paraffin embedded DLBCL [...] Read more.

Current genomic models in diffuse large B-cell lymphoma (DLBCL) are based on single tumor biopsies, which might underestimate heterogeneity. Data on mutational evolution largely remains unknown. An exploratory study using whole exome sequencing on paired (primary and relapse) formalin fixed paraffin embedded DLBCL biopsies (n = 14) of 6 patients was performed to globally assess the mutational evolution and to identify gene mutations specific for relapse samples from patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone. A minority of the mutations detected in the primary sample (median 7.6%, range 4.8–66.2%) could not be detected in the matching relapse sample. Relapsed DLBCL samples showed a mild increase of mutations (median 12.5%, range 9.4–87.6%) as compared to primary tumor biopsies. We identified 264 genes possibly related to therapy resistance, including tyrosine kinases (n = 18), (transmembrane) glycoproteins (n = 73), and genes involved in the JAK-STAT pathway (n = 7). Among the potentially resistance related genes were PIM1, SOCS1, and MYC, which have been reported to convey a risk for treatment failure. In conclusion, we show modest temporal heterogeneity between paired tumor samples with the acquisition of new mutations and identification of genes possibly related to therapy resistance. The mutational evolution could have implications for treatment decisions and development of novel targeted drugs. Full article

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24 pages, 1786 KiB

Open AccessEditor’s ChoiceReview

Aberrant RNA Splicing in Cancer and Drug Resistance

by Bi-Dar Wang^1,* and Norman H. Lee^2,*

¹ Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland Eastern Shore, Princess Anne, MD 21853, USA

² Department of Pharmacology and Physiology, School of Medicine and Health Sciences, George Washington University, GW Cancer Center, Washington, DC 20037, USA

Cancers 2018, 10(11), 458; https://doi.org/10.3390/cancers10110458 - 20 Nov 2018

Cited by 131 | Viewed by 12671

Abstract

More than 95% of the 20,000 to 25,000 transcribed human genes undergo alternative RNA splicing, which increases the diversity of the proteome. Isoforms derived from the same gene can have distinct and, in some cases, opposing functions. Accumulating evidence suggests that aberrant RNA [...] Read more.

More than 95% of the 20,000 to 25,000 transcribed human genes undergo alternative RNA splicing, which increases the diversity of the proteome. Isoforms derived from the same gene can have distinct and, in some cases, opposing functions. Accumulating evidence suggests that aberrant RNA splicing is a common and driving event in cancer development and progression. Moreover, aberrant splicing events conferring drug/therapy resistance in cancer is far more common than previously envisioned. In this review, aberrant splicing events in cancer-associated genes, namely BCL2L1, FAS, HRAS, CD44, Cyclin D1, CASP2, TMPRSS2-ERG, FGFR2, VEGF, AR and KLF6, will be discussed. Also highlighted are the functional consequences of aberrant splice variants (BCR-Abl35INS, BIM-γ, IK6, p61 BRAF V600E, CD19-∆2, AR-V7 and PIK3CD-S) in promoting resistance to cancer targeted therapy or immunotherapy. To overcome drug resistance, we discuss opportunities for developing novel strategies to specifically target the aberrant splice variants or splicing machinery that generates the splice variants. Therapeutic approaches include the development of splice variant-specific siRNAs, splice switching antisense oligonucleotides, and small molecule inhibitors targeting splicing factors, splicing factor kinases or the aberrant oncogenic protein isoforms. Full article

(This article belongs to the Special Issue Drug Resistance in Cancers)

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11 pages, 3398 KiB

Open AccessArticle

Advanced Radiation Techniques in the Treatment of Esthesioneuroblastoma: A 7-Year Single-Institution’s Clinical Experience

by Jakob Liermann^1,2,3, Mustafa Syed^1,2, Thomas Held^1,2, Denise Bernhardt^1,2,3,4,5,6, Peter Plinkert⁷, Christine Jungk⁸, Andreas Unterberg⁸, Stefan Rieken^1,2,3,4,5,6, Jürgen Debus^1,2,3,4,5,6, Klaus Herfarth^1,2,3,4,5,6 and Sebastian Adeberg^{1,2,3,4,5,6,*}

¹ Department of Radiation Oncology, Heidelberg University Hospital, 69120 Heidelberg, Germany

² Heidelberg Institute of Radiation Oncology (HIRO), 69120 Heidelberg, Germany

³ Heidelberg Ion-Beam Therapy Center (HIT), Department of Radiation Oncology, Heidelberg University Hospital, 69120 Heidelberg, Germany

⁴ National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany

⁵ Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

⁶ German Cancer Consortium (DKTK), Partner Site, 69120 Heidelberg, Germany

⁷ Department of Otolaryngology, Head and Neck Surgery, Heidelberg University Hospital, 69120 Heidelberg, Germany

⁸ Division of Neurosurgical Research, Department of Neurosurgery, Heidelberg University Hospital, 69120 Heidelberg, Germany

Cancers 2018, 10(11), 457; https://doi.org/10.3390/cancers10110457 - 20 Nov 2018

Cited by 14 | Viewed by 5153

Abstract

(1) Background: Esthesioneuroblastoma (ENB) is a rare tumor entity originating from the olfactory neuroepithelium. There is a scarcity of data about different treatment strategies. Intensity modulated radiotherapy (IMRT) and carbon ion radiotherapy (CIRT) are advanced radiation techniques that might improve local tumor control. [...] Read more.

(1) Background: Esthesioneuroblastoma (ENB) is a rare tumor entity originating from the olfactory neuroepithelium. There is a scarcity of data about different treatment strategies. Intensity modulated radiotherapy (IMRT) and carbon ion radiotherapy (CIRT) are advanced radiation techniques that might improve local tumor control. (2) Methods: This retrospective analysis contained 17 patients with ENB (Kadish stage ≥ C: 88%; n = 15). Four patients had already undergone previous radiotherapy (RT). The treatment consisted of either IMRT (n = 5), CIRT (n = 4) or a combination of both techniques (n = 8). Median follow-up was 29 months. (3) Results: In patients that had not been irradiated before (n = 13), calculated overall survival (OS) and progression free survival (PFS) rates after 48 months were 100% and 81% respectively (Kaplan-Meier estimates). Two of four patients that underwent reirradiation died after RT, presumably due to tumor progression. Besides common toxicities, five patients (30%) showed mostly asymptomatic radiation-induced brain changes, most likely due to a disturbance of the blood-brain barrier. (4) Conclusions: Our results demonstrate that IMRT, CIRT, a combined approach of IMRT and CIRT as well as reirradiation with CIRT seem to be feasible and effective treatment methods in ENB. Full article

(This article belongs to the Special Issue New Developments in Radiotherapy)

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13 pages, 673 KiB

Open AccessReview

Human Glioma Migration and Infiltration Properties as a Target for Personalized Radiation Medicine

by Michaela Wank^1,2,3

, Daniela Schilling^1,2, Thomas E. Schmid^1,2, Bernhard Meyer⁴

, Jens Gempt⁴, Melanie Barz⁴, Jürgen Schlegel⁵, Friederike Liesche⁵, Kerstin A. Kessel^1,2,3, Benedikt Wiestler⁶

, Stefanie Bette⁶, Claus Zimmer⁶ and Stephanie E. Combs^1,2,3,*

¹ Institute of Innovative Radiotherapy (iRT), Department of Radiation Sciences (DRS), Helmholtz Zentrum München, 85764 Neuherberg, Germany

² Department of Radiation Oncology, Technical University of Munich (TUM), Klinikum rechts der Isar, 81675 Munich, Germany

³ Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partner Site Munich, 81675 Munich, Germany

⁴ Department of Neurosurgery, Technical University of Munich (TUM), Klinikum rechts der Isar, 81675 Munich, Germany

⁵ Department of Neuropathology, Technical University of Munich (TUM), 81675 Munich, Germany

⁶ Department of Neuroradiology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany

Cancers 2018, 10(11), 456; https://doi.org/10.3390/cancers10110456 - 20 Nov 2018

Cited by 43 | Viewed by 4462

Abstract

Gliomas are primary brain tumors that present the majority of malignant adult brain tumors. Gliomas are subdivided into low- and high-grade tumors. Despite extensive research in recent years, the prognosis of malignant glioma patients remains poor. This is caused by naturally highly infiltrative [...] Read more.

Gliomas are primary brain tumors that present the majority of malignant adult brain tumors. Gliomas are subdivided into low- and high-grade tumors. Despite extensive research in recent years, the prognosis of malignant glioma patients remains poor. This is caused by naturally highly infiltrative capacities as well as high levels of radio- and chemoresistance. Additionally, it was shown that low linear energy transfer (LET) irradiation enhances migration and invasion of several glioma entities which might counteract today’s treatment concepts. However, this finding is discussed controversially. In the era of personalized medicine, this controversial data might be attributed to the patient-specific heterogeneity that ultimately could be used for treatment. Thus, current developments in glioma therapy should be seen in the context of intrinsic and radiation-enhanced migration and invasion. Due to the natural heterogeneity of glioma cells and different radiation responses, a personalized radiation treatment concept is suggested and alternative radiation concepts are discussed. Full article

(This article belongs to the Special Issue New Developments in Radiotherapy)

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18 pages, 3139 KiB

Open AccessArticle

Renal Cell Carcinoma Is Abrogated by p53 Stabilization through Transglutaminase 2 Inhibition

by Seon-Hyeong Lee¹, Won-Kyu Lee^1,2, Nayeon Kim^1,3, Joon Hee Kang¹, Kyung-Hee Kim⁴, Seul-Gi Kim¹, Jae-Seon Lee¹, Soohyun Lee¹, Jongkook Lee⁵

, Jungnam Joo⁶, Woo Sun Kwon⁷

, Sun Young Rha⁸ and Soo-Youl Kim^1,*

¹ Tumor Microenvironment Research Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi-do 10408, Korea

² New Drug Development Center, Osong Medical Innovation Foundation, Cheongju, Chungbuk 28160, Korea

³ Department of Chemistry, College of Science, Dongguk University, 30 Pildong-ro 2-gil, Jung-gu, Seoul 04620, Korea

⁴ Omics Core Lab, National Cancer Center, Goyang, Gyeonggi-do 10408, Korea

⁵ College of Pharmacy, Kangwon National University, Chuncheon, Gangwon-do 24341, Korea

⁶ Biometric Research Branch, Division of Cancer Epidemiology and Prevention, National Cancer Center, Goyang, Gyeonggi-do 10408, Korea

⁷ Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul 03722, Korea

⁸ Songdang Institute for Cancer Research, Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, Korea

Cancers 2018, 10(11), 455; https://doi.org/10.3390/cancers10110455 - 19 Nov 2018

Cited by 17 | Viewed by 4913

Abstract

In general, expression of transglutaminase 2 (TGase 2) is upregulated in renal cell carcinoma (RCC), resulting in p53 instability. Previous studies show that TGase 2 binds to p53 and transports it to the autophagosome. Knockdown or inhibition of TGase 2 in RCC induces [...] Read more.

In general, expression of transglutaminase 2 (TGase 2) is upregulated in renal cell carcinoma (RCC), resulting in p53 instability. Previous studies show that TGase 2 binds to p53 and transports it to the autophagosome. Knockdown or inhibition of TGase 2 in RCC induces p53-mediated apoptosis. Here, we screened a chemical library for TGase 2 inhibitors and identified streptonigrin as a potential therapeutic compound for RCC. Surface plasmon resonance and mass spectroscopy were used to measure streptonigrin binding to TGase 2. Mass spectrometry analysis revealed that streptonigrin binds to the N-terminus of TGase 2 (amino acids 95–116), which is associated with inhibition of TGase 2 activity in vitro and with p53 stabilization in RCC. The anti-cancer effects of streptonigrin on RCC cell lines were demonstrated in cell proliferation and cell death assays. In addition, a single dose of streptonigrin (0.2 mg/kg) showed marked anti-tumor effects in a preclinical RCC model by stabilizing p53. Inhibition of TGase 2 using streptonigrin increased p53 stability, which resulted in p53-mediated apoptosis of RCC. Thus, targeting TGase 2 may be a new therapeutic approach to RCC. Full article

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12 pages, 670 KiB

Open AccessArticle

Severe Neutropenia is Associated with Better Clinical Outcomes in Patients with Advanced Pancreatic Cancer Who Receive Modified FOLFIRINOX Therapy

by Yunami Yamada¹, Hironori Fujii^1,*, Daichi Watanabe¹, Hiroko Kato-Hayashi¹, Koichi Ohata¹, Ryo Kobayashi¹, Takuma Ishihara², Shinya Uemura³, Takuji Iwashita³, Masahito Shimizu³ and Akio Suzuki¹

¹ Department of Pharmacy, Gifu University Hospital, Gifu 501-1194, Japan

² Gifu University Hospital, Innovative and Clinical Research Promotion Center, Gifu University, Gifu 501-1194, Japan

³ First Department of Internal Medicine, Gifu University Hospital, Gifu 501-1194, Japan

Cancers 2018, 10(11), 454; https://doi.org/10.3390/cancers10110454 - 16 Nov 2018

Cited by 11 | Viewed by 4775

Abstract

While modified FOLFIRINOX therapy is effective for treating advanced pancreatic cancer, it frequently causes severe neutropenia. The present study investigated the effect of severe neutropenia on clinical outcomes in advanced pancreatic cancer patients who received modified FOLFIRINOX. The study subjects were 51 patients [...] Read more.

While modified FOLFIRINOX therapy is effective for treating advanced pancreatic cancer, it frequently causes severe neutropenia. The present study investigated the effect of severe neutropenia on clinical outcomes in advanced pancreatic cancer patients who received modified FOLFIRINOX. The study subjects were 51 patients (30 males and 21 females) with advanced pancreatic cancer who received modified FOLFIRINOX (2h bolus injection of oxaliplatin at 85 mg/m², 2 h bolus injection of L-leucovorin at 200 mg/m², 90min bolus injection of irinotecan at 150 mg/m², followed by continuous infusion of 5-fluorouracil for 46 h at 2400 mg/m² without bolus 5-fluorouracil) during the period from January 2014 to May 2018. No patients had prior history of chemotherapy. Adverse events, including neutropenia, were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. Median overall survival (OS) was the primary endpoint, while median time to treatment failure (TTF), overall response rate (ORR), and the incidence of other adverse events were secondary endpoints. Severe neutropenia (grade ≥3) occurred in 39 patients (76.4%), and Cox proportional hazard analysis identified high total bilirubin level as a significant risk factor. Median duration of OS was significantly longer in patients with severe neutropenia than in those without it (21.3 months versus 8.9 months, p = 0.020). Moreover, there was a significant correlation between OS and the grade of neutropenia (r = 0.306, p = 0.029). ORR tended to be higher, though not significantly, in patients with severe neutropenia. In contrast, the incidence rates of other adverse events were not different between the two groups. Severe neutropenia is an independent predictor of prognosis in advanced pancreatic cancer patients received modified FOLFIRINOX therapy. Full article

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21 pages, 545 KiB

Open AccessReview

Non-Coding Variants in BRCA1 and BRCA2 Genes: Potential Impact on Breast and Ovarian Cancer Predisposition

by Elizabeth Santana dos Santos^1,2,3

, François Lallemand^3,4, Leslie Burke⁵, Dominique Stoppa-Lyonnet^3,6,7

, Melissa Brown⁵, Sandrine M. Caputo^3,4

and Etienne Rouleau^8,*

¹ A.C.Camargo Cancer Center, São Paulo 01509-010, Brazil

² Department of Oncology, Center for Translational Oncology, Cancer Institute of the State of São Paulo—ICESP, São Paulo 01246-000, Brazil

³ Department of Genetics, Institut Curie, 75005 Paris, France

⁴ Institut Curie, Paris Sciences Lettres Research University, 75230 Paris, France

⁵ School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia

⁶ Department of Genetics at Institut Curie, Université Paris Descartes, 75006 Paris, France

⁷ INSERM U830, Institut Curie, 75248 Paris, France

⁸ Institut Gustave Roussy, 94805 Villejuif, France

Cancers 2018, 10(11), 453; https://doi.org/10.3390/cancers10110453 - 16 Nov 2018

Cited by 22 | Viewed by 8430

Abstract

BRCA1 and BRCA2 are major breast cancer susceptibility genes whose pathogenic variants are associated with a significant increase in the risk of breast and ovarian cancers. Current genetic screening is generally limited to BRCA1/2 exons and intron/exon boundaries. Most identified pathogenic [...] Read more.

BRCA1 and BRCA2 are major breast cancer susceptibility genes whose pathogenic variants are associated with a significant increase in the risk of breast and ovarian cancers. Current genetic screening is generally limited to BRCA1/2 exons and intron/exon boundaries. Most identified pathogenic variants cause the partial or complete loss of function of the protein. However, it is becoming increasingly clear that variants in these regions only account for a small proportion of cancer risk. The role of variants in non-coding regions beyond splice donor and acceptor sites, including those that have no qualitative effect on the protein, has not been thoroughly investigated. The key transcriptional regulatory elements of BRCA1 and BRCA2 are housed in gene promoters, untranslated regions, introns, and long-range elements. Within these sequences, germline and somatic variants have been described, but the clinical significance of the majority is currently unknown and it remains a significant clinical challenge. This review summarizes the available data on the impact of variants on non-coding regions of BRCA1/2 genes and their role on breast and ovarian cancer predisposition. Full article

(This article belongs to the Special Issue BRCA Mutations and Cancer)

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17 pages, 2658 KiB

Open AccessArticle

Externalized Keratin 8: A Target at the Interface of Microenvironment and Intracellular Signaling in Colorectal Cancer Cells

by Marie Alexandra Albaret^1,2

, Claudine Vermot-Desroches³, Arnaud Paré^1,2,4, Jean-Xavier Roca-Martinez¹, Lucie Malet^1,2, Jad Esseily¹, Laetitia Gerossier¹, Johan Brière¹, Nathalie Pion¹, Virginie Marcel¹

, Frédéric Catez¹

, Geneviève De Souza^1,2, Boris Vuillermoz³, Franck Doerflinger³, Emilie Lavocat³, Olivier Subiger³, Carine Rousset³, Corinne Bresson³, Elodie Mandon⁵, Anass Jawhari⁵, Pierre Falson⁶, Mélissa Jasmin¹

, Yohann Coute⁷

, Hichem-Claude Mertani¹

, Pierre Saintigny^1,2,8,† and Jean-Jacques Diaz^1,*,†

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¹ Univ Lyon, Université Claude Bernard Lyon 1, INSERM U1052, CNRS UMR5286, Centre Léon Bérard, Cancer Research Center of Lyon, 69008 Lyon, France

² Department of Translational Research and Innovation, Centre Léon Bérard, 69373 Lyon, France

³ iDD Biotech Bâtiment Accinov 317 avenue Jean Jaurès, 69007 Lyon, France

⁴ Service de Chirurgie Maxillo-Faciale, Centre Hospitalier Universitaire, 37170 Tours, France

⁵ CALIXAR Functional Membrane Proteins For Life, 60 avenue Rockefeller, 69008 Lyon, France

⁶ Laboratory of Molecular Microbiology and Structural Biochemistry, CNRS UMR 5086, IBCP, 69367 Lyon, France

⁷ Biosciences and Biotechnology Institute of Grenoble-Laboratoire Biologie à Grande Echelle (BIG-BGE) U1038 INSERM/CEA/UGA, Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA) Grenoble, F-38054 Grenoble CEDEX 9, France

⁸ Department of Medical Oncology, Centre Léon Bérard, 69373 Lyon, France

^† Co-senior authors: Pierre Saintigny and Jean-Jacques Diaz.

Cancers 2018, 10(11), 452; https://doi.org/10.3390/cancers10110452 - 16 Nov 2018

Cited by 4 | Viewed by 4179

Abstract

Accumulating evidence supports the remarkable presence at the membrane surface of cancer cells of proteins, which are normally expressed in the intracellular compartment. Although these proteins, referred to as externalized proteins, represent a highly promising source of accessible and druggable targets for cancer [...] Read more.

Accumulating evidence supports the remarkable presence at the membrane surface of cancer cells of proteins, which are normally expressed in the intracellular compartment. Although these proteins, referred to as externalized proteins, represent a highly promising source of accessible and druggable targets for cancer therapy, the mechanisms via which they impact cancer biology remain largely unexplored. The aim of this study was to expose an externalized form of cytokeratin 8 (eK8) as a key player of colorectal tumorigenesis and characterize its mode of action. To achieve this, we generated a unique antagonist monoclonal antibody (D-A10 MAb) targeting an eight-amino-acid-long domain of eK8, which enabled us to ascertain the pro-tumoral activity of eK8 in both KRAS-mutant and wild-type colorectal cancers (CRC). We showed that this pro-tumoral activity involves a bidirectional eK8-dependent control of caspase-mediated apoptosis in vivo and of the plasminogen-induced invasion process in cellulo. Furthermore, we demonstrated that eK8 is anchored at the plasma membrane supporting this dual function. We, therefore, identified eK8 as an innovative therapeutic target in CRC and provided a unique MAb targeting eK8 that displays anti-neoplastic activities that could be useful to treat CRC, including those harboring KRAS mutations. Full article

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12 pages, 1211 KiB

Open AccessArticle

Targeted Therapy-Resistant Melanoma Cells Acquire Transcriptomic Similarities with Human Melanoblasts

by Lionel Larribère^1,2,*, Silke Kuphal³, Christos Sachpekidis⁴, Sachindra^1,2,5, Laura Hüser^1,2, Anja Bosserhoff³

and Jochen Utikal^1,2

¹ Skin Cancer Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

² Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, 68167 Mannheim, Germany

³ Institute of Biochemistry, Emil-Fischer-Center, Friedrich Alexander University Erlangen-Nuremberg, D-91054 Erlangen, Germany

⁴ Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

⁵ Department of Hepatology and Gastroenterology, Charité-University Medical Center Berlin, 10117 Berlin, Germany

Cancers 2018, 10(11), 451; https://doi.org/10.3390/cancers10110451 - 16 Nov 2018

Cited by 12 | Viewed by 5327

Abstract

The mechanisms of adaptive and acquired drug resistance in tumors are not completely understood. So far, gene amplifications or mutations, leading to the reactivation of the MAPK or PI3K pathways have been described. In this study, we used two different methods to generate [...] Read more.

The mechanisms of adaptive and acquired drug resistance in tumors are not completely understood. So far, gene amplifications or mutations, leading to the reactivation of the MAPK or PI3K pathways have been described. In this study, we used two different methods to generate human melanoblasts: (1) via differentiation from induced pluripotent stem cells (iPSCs) and (2) via dedifferentiation from melanocytes. The melanoblast transcriptomes were then compared to the transcriptome of MAPK inhibitor-resistant melanoma cells. We observed that the expression of genes associated with cell cycle control, DNA damage control, metabolism, and cancer was altered in both melanoblast populations and in both adaptive and acquired resistant melanoma samples, compared to drug-sensitive samples. However, genes involved in antigen presentation and cellular movement were only regulated in the melanoblast populations and in the acquired resistant melanoma samples, compared to the drug-sensitive samples. Moreover, melanocyte-derived melanoblasts and adaptive resistant melanoma samples were characterized by different expression levels of certain transcription factors or genes involved in the CDK5 pathway. In conclusion, we show here that in vitro models of human melanoblasts are very important tools to comprehend the expression profiles of drug-resistant melanoma. Full article

(This article belongs to the Collection Drug Resistance and Novel Therapies in Cancers)

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19 pages, 524 KiB

Open AccessReview

Cancer-Associated Thrombosis in Cirrhotic Patients with Hepatocellular Carcinoma

by Alberto Zanetto^1,†

, Elena Campello^2,†

, Luca Spiezia²

, Patrizia Burra¹

, Paolo Simioni^2,* and Francesco Paolo Russo¹

¹ Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 Padua, Italy

² Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, Padua University Hospital, 35128 Padua, Italy

^† These Authors equally contributed to the manuscript.

Cancers 2018, 10(11), 450; https://doi.org/10.3390/cancers10110450 - 16 Nov 2018

Cited by 59 | Viewed by 5804

Abstract

It is common knowledge that cancer patients are more prone to develop venous thromboembolic complications (VTE). It is therefore not surprising that patients with hepatocellular carcinoma (HCC) present with a significant risk of VTE, with the portal vein being the most frequent site [...] Read more.

It is common knowledge that cancer patients are more prone to develop venous thromboembolic complications (VTE). It is therefore not surprising that patients with hepatocellular carcinoma (HCC) present with a significant risk of VTE, with the portal vein being the most frequent site (PVT). However, patients with HCC are peculiar as both cancer and liver cirrhosis are conditions that can perturb the hemostatic balance towards a prothrombotic state. Because HCC-related hypercoagulability is not clarified at all, the aim of the present review is to summarize the currently available knowledge on epidemiology and pathogenesis of non-malignant thrombotic complications in patients with liver cirrhosis and HCC. They are at increased risk to develop both PVT and non-splanchnic VTE, indicating that both local and systemic factors can foster the development of site-specific thrombosis. Recent studies have suggested multiple and often interrelated mechanisms through which HCC can tip the hemostatic balance of liver cirrhosis towards hypercoagulability. Described mechanisms include increased fibrinogen concentration/polymerization, thrombocytosis, and release of tissue factor-expressing extracellular vesicles. Currently, there are no specific guidelines on the use of thromboprophylaxis in this unique population. There is the urgent need of prospective studies assessing which patients have the highest prothrombotic profile and would therefore benefit from early thromboprophylaxis. Full article

(This article belongs to the Special Issue The Role of Thrombosis and Haemostasis in Cancer)

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18 pages, 8306 KiB

Open AccessArticle

Cyclopeptide RA-V Inhibits Organ Enlargement and Tumorigenesis Induced by YAP Activation

by Xinyan Ji¹

, Lihua Song², Li Sheng³, Anhui Gao³, Yang Zhao¹, Shixun Han¹, Yuchao Zhang¹, Chu Zhu¹, Simeng Zhao⁴, Zhe Wang², Bohan Xu¹, Li Li⁵, Jia Li^3,6,*, Ninghua Tan^2,4,* and Bin Zhao^1,*

¹ MOE Key Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China

² School of Traditional Chinese Pharmacy and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China

³ The National Center for Drug Screening, 189 Guoshoujing Road, Shanghai 201203, China

⁴ State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China

⁵ Institute of Aging Research, Hangzhou Normal University, Hangzhou 311121, China

⁶ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

Cancers 2018, 10(11), 449; https://doi.org/10.3390/cancers10110449 - 16 Nov 2018

Cited by 20 | Viewed by 5056

Abstract

The Hippo pathway restricts organ size during development and its inactivation plays a crucial role in cancer. Yes-associated protein (YAP) and its paralog transcriptional coactivator with PSD-95/Dlg/ZO-1 (PDZ)-binding motif (TAZ) are transcription co-activators and effectors of the Hippo pathway mediating aberrant enlargement of [...] Read more.

The Hippo pathway restricts organ size during development and its inactivation plays a crucial role in cancer. Yes-associated protein (YAP) and its paralog transcriptional coactivator with PSD-95/Dlg/ZO-1 (PDZ)-binding motif (TAZ) are transcription co-activators and effectors of the Hippo pathway mediating aberrant enlargement of organs and tumor growth upon Hippo pathway inactivation. It has been demonstrated that genetic inactivation of YAP could be an effective approach to inhibit tumorigenesis. In order to identify pharmacological inhibitors of YAP, we screened a library of 52,683 compounds using a YAP-specific reporter assay. In this screen we identified cyclopeptide RA-V (deoxybouvardin) as a specific inhibitor of YAP and TAZ but not other reporters. Unexpectedly, later experiments demonstrated that RA-V represses the protein but not mRNA levels of YAP target genes. Nevertheless, RA-V strongly blocks liver enlargement induced by Mst1/2 knockout. Furthermore, RA-V not only inhibits liver tumorigenesis induced by YAP activation, but also induces regression of established tumors. We found that RA-V inhibits dedifferentiation and proliferation, while inducing apoptosis of hepatocytes. Furthermore, RA-V also induces apoptosis and inhibits proliferation of macrophages in the microenvironment, which are essential for YAP-induced tumorigenesis. RA-V is thus a drug candidate for cancers involving YAP/TAZ activation. Full article

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13 pages, 2384 KiB

Open AccessArticle

Targeting the MYC Oncogene in Burkitt Lymphoma through HSP90 Inhibition

by Candace J. Poole¹

, Wenli Zheng¹, Haesung Lee¹, Danielle Young¹, Atul Lodh¹, Ahmed Chadli² and Jan Van Riggelen^1,*

¹ Department of Biochemistry and Molecular Biology, Augusta University, 1410 Laney-Walker Blvd., Augusta, GA 30912, USA

² Georgia Cancer Center, Augusta University, 1410 Laney-Walker Blvd., Augusta, GA 30912, USA

Cancers 2018, 10(11), 448; https://doi.org/10.3390/cancers10110448 - 16 Nov 2018

Cited by 17 | Viewed by 6021

Abstract

Overexpression of the MYC oncogene is a key feature of many human malignancies including Burkitt lymphoma. While MYC is widely regarded to be a promising therapeutic target, a clinically effective MYC inhibitor is still elusive. Here, we report an alternative strategy, targeting MYC [...] Read more.

Overexpression of the MYC oncogene is a key feature of many human malignancies including Burkitt lymphoma. While MYC is widely regarded to be a promising therapeutic target, a clinically effective MYC inhibitor is still elusive. Here, we report an alternative strategy, targeting MYC indirectly through inhibition of the HSP90 machinery. We found that inhibition of HSP90 function reduces MYC expression in human Burkitt lymphoma through suppression of MYC transcription and destabilization of MYC protein, thereby diminishing the proliferation of tumor cells. Consistently, treatment of Burkitt lymphoma cell lines with HSP90 inhibitors (17-AAG or 17-DMAG) was accompanied by downregulation of canonical MYC target genes. Combination treatment with 17-DMAG and the proteasome inhibitor, MG-132, led to accumulation of MYC protein, indicating that upon HSP90 inhibition, MYC is degraded by the proteasome. Using co-immunoprecipitation, we furthermore demonstrated a direct interaction between MYC and HSP90, indicating that MYC is an HSP90 client protein in Burkitt lymphoma. Together, we report here the use of HSP90 inhibitors as an alternative approach to target the MYC oncogene and its network in Burkitt lymphoma. Full article

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14 pages, 1781 KiB

Open AccessEditor’s ChoiceReview

Lipid Metabolic Reprogramming in Hepatocellular Carcinoma

by Hayato Nakagawa^*, Yuki Hayata, Satoshi Kawamura, Tomoharu Yamada, Naoto Fujiwara and Kazuhiko Koike

Department of Gastroenterology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

Cancers 2018, 10(11), 447; https://doi.org/10.3390/cancers10110447 - 15 Nov 2018

Cited by 133 | Viewed by 11432

Abstract

Metabolic reprogramming for adaptation to the local environment has been recognized as a hallmark of cancer. Although alterations in fatty acid (FA) metabolism in cancer cells have received less attention compared to other metabolic alterations such as glucose or glutamine metabolism, recent studies [...] Read more.

Metabolic reprogramming for adaptation to the local environment has been recognized as a hallmark of cancer. Although alterations in fatty acid (FA) metabolism in cancer cells have received less attention compared to other metabolic alterations such as glucose or glutamine metabolism, recent studies have uncovered the importance of lipid metabolic reprogramming in carcinogenesis. Obesity and nonalcoholic steatohepatitis (NASH) are well-known risk factors of hepatocellular carcinoma (HCC), and individuals with these conditions exhibit an increased intake of dietary FAs accompanied by enhanced lipolysis of visceral adipose tissue due to insulin resistance, resulting in enormous exogenous FA supplies to hepatocytes via the portal vein and lymph vessels. This “lipid-rich condition” is highly characteristic of obesity- and NASH-driven HCC. Although the way in which HCC cells adapt to such a condition and exploit it to aid their progression is not understood, we recently obtained new insights into this mechanism through lipid metabolic reprogramming. In addition, accumulating evidence supports the importance of lipid metabolic reprogramming in various situations of hepatocarcinogenesis. Thus, in this review, we discuss the latest findings regarding the role of FA metabolism pathways in hepatocarcinogenesis, focusing on obesity- and NASH-driven lipid metabolic reprogramming. Full article

(This article belongs to the Special Issue Obesity as a Risk Factor for Cancer)

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15 pages, 6154 KiB

Open AccessArticle

Tumor-Targeted Immunotherapy by Using Primary Adipose-Derived Stem Cells and an Antigen-Specific Protein Vaccine

by Jui-Hua Lu^1,2, Bou-Yue Peng^3,4, Chun-Chao Chang^5,6, Navneet Kumar Dubey^7,8, Wen-Cheng Lo^9,10, Hsin-Chung Cheng³, Joseph R. Wang¹¹, Hong-Jian Wei^2,12,*

and Win-Ping Deng^2,3,13,*

¹ Graduate Institute of Biomedical Materials and Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 110, Taiwan

² Stem Cell Research Center, College of Oral Medicine, Taipei Medical University, Taipei 110, Taiwan

³ School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 110, Taiwan

⁴ Department of Dentistry, Taipei Medical University Hospital, Taipei 110, Taiwan

⁵ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 110i, Taiwan

⁶ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Medical University School of Medicine, Taipei 110, Taiwan

⁷ Ceramics and Biomaterials Research Group, Advanced Institute of Materials Science, Ton Duc Thang University, Ho Chi Minh City 700000, Vietnam

⁸ Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City 700000, Vietnam

⁹ Department of Neurosurgery, Taipei Medical University Hospital, Taipei 110, Taiwan

¹⁰ Division of Neurosurgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan

¹¹ Department of Periodontics, College of Dental Medicine, Columbia University, New York 10032, USA

¹² School of Dental Technology, College of Oral Medicine, Taipei Medical University, Taipei 110, Taiwan

¹³ Graduate Institute of Basic Medicine, Fu Jen Catholic University, New Taipei City 110, Taiwan

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Cancers 2018, 10(11), 446; https://doi.org/10.3390/cancers10110446 - 15 Nov 2018

Cited by 19 | Viewed by 4829

Abstract

Cancer is a leading cause of mortality and a major public health problem worldwide. For biological therapy against cancer, we previously developed a unique immunotherapeutic platform by combining mesenchymal stem cells with an antigen-specific protein vaccine. However, this system possesses a few limitations, [...] Read more.

Cancer is a leading cause of mortality and a major public health problem worldwide. For biological therapy against cancer, we previously developed a unique immunotherapeutic platform by combining mesenchymal stem cells with an antigen-specific protein vaccine. However, this system possesses a few limitations, such as improperly immortalized mesenchymal stem cells (MSCs) along with transfected oncogenic antigens in them. To overcome the limitations of this platform for future clinical application, we freshly prepared primary adipose-derived stem cells (ADSCs) and modified the E7’ antigen (E7’) as a non-oncogenic protein. Either subcutaneously co-inoculated with cancer cells or systemically administered after tumor growth, ADSC labeled with enhanced green fluorescent protein (eGFP) and combined with modified E7’ (ADSC-E7’-eGFP) cells showed significant antitumor activity when combined with the protein vaccine in both colon and lung cancer in mice. Specifically, this combined therapy inhibited tumor through inducing cell apoptosis. The significantly reduced endothelial cell markers, CD31 and vascular endothelial growth factor (VEGF), indicated strongly inhibited tumor angiogenesis. The activated immune system was demonstrated through the response of CD4+ T and natural killer (NK) cells, and a notable antitumor activity might be contributed by CD8+ T cells. Conclusively, these evidences imply that this promising immunotherapeutic platform might be a potential candidate for the future clinical application against cancer. Full article

(This article belongs to the Special Issue Cancer Vaccines: Research and Applications)

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10 pages, 991 KiB

Open AccessArticle

Pharmacokinetics of Sublingually Delivered Fentanyl in Head and Neck Cancer Patients Treated with Curatively Aimed Chemo or Bioradiotherapy

by Evelien J. M. Kuip^1,2,3,*, Wendy H. Oldenmenger¹, Esther Oomen-de Hoop¹, Gerda M. Verduijn⁴, Martine F. Thijs-Visser¹, Peter De Bruijn¹, Esther Van Meerten¹, Stijn L. W. Koolen^1,5, Ron H. J. Mathijssen¹ and Carin C. D. Van der Rijt^1,6

¹ Department of Medical Oncology, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands

² Department of Medical Oncology, Radboud University Medical Center, Geert Grooteplein Zuid 8, 6500 HB Nijmegen, The Netherlands

³ Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6500 HB Nijmegen, The Netherlands

⁴ Department of Radiation Oncology, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands

⁵ Department of Hospital Pharmacy, Erasmus MC, University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands

⁶ Netherlands Comprehensive Cancer Organisation, Godebaldkwartier 419, 3511 DT Utrecht, The Netherlands

Cancers 2018, 10(11), 445; https://doi.org/10.3390/cancers10110445 - 15 Nov 2018

Cited by 2 | Viewed by 3875

Abstract

Over 90% of patients treated for head and neck cancer with curatively aimed chemo or bioradiotherapy will develop painful mucositis and xerostomia. Sublingually delivered fentanyl (SDL) is a rapid acting opioid to treat breakthrough pain. It is unclear how SDL is absorbed by [...] Read more.

Over 90% of patients treated for head and neck cancer with curatively aimed chemo or bioradiotherapy will develop painful mucositis and xerostomia. Sublingually delivered fentanyl (SDL) is a rapid acting opioid to treat breakthrough pain. It is unclear how SDL is absorbed by the mucosa of these patients. Therefore, the aim of this study was to investigate the effects of mucositis and xerostomia on the absorption of SDL. Thirteen patients who received chemo or bioradiotherapy (RT), were given a single dose of fentanyl: Before start of RT, 3 and 6 weeks after start of RT, and 6 weeks after finishing RT. Pharmacokinetic samples were taken. The primary endpoint was the relative difference (RD) between systemic exposure to fentanyl (area under the curve; AUC) at baseline (AUC_baseline) and fentanyl AUC in the presence of mucositis grade ≥2. The secondary endpoint was the RD between AUC_baseline and fentanyl AUC in the presence of xerostomia, which were analyzed by means of a paired t-test on log-transformed data. Mucositis resulted in a 12.7% higher AUC (n = 13; 95% CI: −10.7% to +42.2%, p = 0.29) compared to baseline levels and xerostomia resulted in a 22.4% lower AUC (n = 8; 95% CI: −51.9% to +25.3%, p = 0.25) compared to baseline levels. Mucositis grade ≥2 or xerostomia caused by chemo or bioradiotherapy does not significantly alter the systemic exposure to SDL. Patients with pain during and after chemo or bioradiotherapy may be safely treated with SDL. Full article

(This article belongs to the Special Issue Cancer Pains)

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18 pages, 871 KiB

Open AccessReview

Molecular Mechanisms Regulating Organ-Specific Metastases in Epithelial Ovarian Carcinoma

by Maria V. Barbolina

Department of Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA

Cancers 2018, 10(11), 444; https://doi.org/10.3390/cancers10110444 - 15 Nov 2018

Cited by 45 | Viewed by 6913

Abstract

Epithelial ovarian carcinoma is the most predominant type of ovarian carcinoma, the deadliest gynecologic malignancy. It is typically diagnosed late when the cancer has already metastasized. Transcoelomic metastasis is the most predominant mechanism of dissemination from epithelial ovarian carcinoma, although both hematogenously and [...] Read more.

Epithelial ovarian carcinoma is the most predominant type of ovarian carcinoma, the deadliest gynecologic malignancy. It is typically diagnosed late when the cancer has already metastasized. Transcoelomic metastasis is the most predominant mechanism of dissemination from epithelial ovarian carcinoma, although both hematogenously and lymphogenously spread metastases also occur. In this review, we describe molecular mechanisms known to regulate organ-specific metastasis from epithelial ovarian carcinoma. We begin by discussing the sites colonized by metastatic ovarian carcinoma and rank them in the order of prevalence. Next, we review the mechanisms regulating the transcoelomic metastasis. Within this chapter, we specifically focus on the mechanisms that were demonstrated to regulate peritoneal adhesion—one of the first steps in the transcoelomic metastatic cascade. Furthermore, we describe mechanisms of the transcoelomic metastasis known to regulate colonization of specific sites within the peritoneal cavity, including the omentum. Mechanisms underlying hematogenous and lymphogenous metastatic spread are less comprehensively studied in ovarian cancer, and we summarize mechanisms that were identified to date. Lastly, we discuss the outcomes of the clinical trials that attempted to target some of the mechanisms described in this review. Full article

(This article belongs to the Special Issue The Tumor Microenvironment of High Grade Serous Ovarian Cancer)

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16 pages, 3838 KiB

Open AccessArticle

MiR-375 Regulation of LDHB Plays Distinct Roles in Polyomavirus-Positive and -Negative Merkel Cell Carcinoma

by Satendra Kumar^1,2,†, Hong Xie^1,2,3,†

, Patrick Scicluna^1,2,4, Linkiat Lee^1,2, Viveca Björnhagen⁵, Anders Höög^1,2,6

, Catharina Larsson^1,2,6 and Weng-Onn Lui^1,2,*

¹ Department of Oncology-Pathology, Karolinska Institutet, SE-17176 Stockholm, Sweden

² Cancer Center Karolinska, Karolinska University Hospital, SE-17176 Stockholm, Sweden

³ Tianjin Life Science Research Center and Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China

⁴ Department of Cell and Molecular Biology, Karolinska Institutet, SE-17165 Stockholm, Sweden

⁵ Department of Reconstructive Plastic Surgery, Karolinska University Hospital, SE-17176 Stockholm, Sweden

⁶ Department of Clinical Pathology and Cytology, Karolinska University Hospital, SE-17176 Stockholm, Sweden

^† These authors contributed equally to this work.

Cancers 2018, 10(11), 443; https://doi.org/10.3390/cancers10110443 - 14 Nov 2018

Cited by 31 | Viewed by 4457

Abstract

MicroRNA-375 (miR-375) is deregulated in multiple tumor types and regulates important targets involved in tumorigenesis and metastasis. This miRNA is highly expressed in Merkel cell carcinoma (MCC) compared to normal skin and other non-MCC skin cancers, and its expression is high [...] Read more.

MicroRNA-375 (miR-375) is deregulated in multiple tumor types and regulates important targets involved in tumorigenesis and metastasis. This miRNA is highly expressed in Merkel cell carcinoma (MCC) compared to normal skin and other non-MCC skin cancers, and its expression is high in Merkel cell polyomavirus (MCPyV)-positive (MCPyV+) and low in MCPyV-negative (MCPyV−) MCC tumors. In this study, we characterized the function and target of miR-375 in MCPyV+ and MCPyV− MCC cell lines. Ectopic expression of miR-375 in MCPyV− MCC cells resulted in decreased cell proliferation and migration, as well as increased cell apoptosis and cell cycle arrest. However, in MCPyV+ MCC cells, inhibition of miR-375 expression reduced cell growth and induced apoptosis. Additionally, the expression of lactate dehydrogenase B (LDHB), a known target of miR-375, was inversely correlated with miR-375. Silencing of LDHB reduced cell growth in MCPyV− cell lines, while its silencing in MCPyV+ cell lines rescued the cell growth effect mediated by miR-375 inhibition. Together, our results suggest dual roles of miR-375 and LDHB in MCPyV and non-MCPyV-associated MCCs. We propose that LDHB could be a therapeutic target in MCC and different strategies should be applied in virus- and non-virus-associated MCCs. Full article

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18 pages, 2537 KiB

Open AccessArticle

Spectrum and Prevalence of Pathogenic Variants in Ovarian Cancer Susceptibility Genes in a Group of 333 Patients

by Magdalena Koczkowska¹, Natalia Krawczynska^1,2

, Maciej Stukan³, Alina Kuzniacka^1,2, Izabela Brozek¹, Marcin Sniadecki⁴, Jaroslaw Debniak⁴, Dariusz Wydra⁴, Wojciech Biernat⁵

, Piotr Kozlowski⁶, Janusz Limon⁷, Bartosz Wasag^1,2

and Magdalena Ratajska^1,*

¹ Department of Biology and Medical Genetics, Medical University of Gdansk, Debinki 1 St., 80-210 Gdansk, Poland

² Laboratory of Clinical Genetics, University Clinical Centre, Smoluchowskiego 17 St., 80-952 Gdansk, Poland

³ Department of Gynecologic Oncology, Gdynia Oncology Center, Powstania Styczniowego 1 St., 81-519 Gdynia, Poland

⁴ Department of Gynaecology, Gynaecological Oncology and Gynaecological Endocrinology, Medical University of Gdansk, Kliniczna 1A St., 80-219 Gdansk, Poland

⁵ Department of Pathology, Medical University of Gdansk, Smoluchowskiego 17 St., 80-952 Gdansk, Poland

⁶ Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14 St., 61-704 Poznan, Poland

⁷ The Gdansk section of the Polish Academy of Sciences, Jaskowa Dolina 31 St., 80-286 Gdansk, Poland

Cancers 2018, 10(11), 442; https://doi.org/10.3390/cancers10110442 - 14 Nov 2018

Cited by 33 | Viewed by 6126

Abstract

Constitutional loss-of-function pathogenic variants in the tumor suppressor genes BRCA1 and BRCA2 are widely associated with an elevated risk of ovarian cancer (OC). As only ~15% of OC individuals carry the BRCA1/2 pathogenic variants, the identification of other potential OC-susceptibility genes is of [...] Read more.

Constitutional loss-of-function pathogenic variants in the tumor suppressor genes BRCA1 and BRCA2 are widely associated with an elevated risk of ovarian cancer (OC). As only ~15% of OC individuals carry the BRCA1/2 pathogenic variants, the identification of other potential OC-susceptibility genes is of great clinical importance. Here, we established the prevalence and spectrum of the germline pathogenic variants in the BRCA1/2 and 23 other cancer-related genes in a large Polish population of 333 unselected OC cases. Approximately 21% of cases (71/333) carried the BRCA1/2 pathogenic or likely pathogenic variants, with c.5266dup (p.Gln1756Profs*74) and c.3700_3704del (p.Val1234Glnfs*8) being the most prevalent. Additionally, ~6% of women (20/333) were carriers of the pathogenic or likely pathogenic variants in other cancer-related genes, with NBN and CHEK2 reported as the most frequently mutated, accounting for 1.8% (6/333) and 1.2% (4/333) of cases, respectively. We also found ten pathogenic or likely pathogenic variants in other genes: 1/333 in APC, 1/333 in ATM, 2/333 in BLM, 1/333 in BRIP1, 1/333 in MRE11A, 2/333 in PALB2, 1/333 in RAD50, and 1/333 in RAD51C, accounting for 50% of all detected variants in moderate- and low-penetrant genes. Our findings confirmed the presence of the additional OC-associated genes in the Polish population that may improve the personalized risk assessment of these individuals. Full article

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23 pages, 1985 KiB

Open AccessEditor’s ChoiceReview

Impacts of Cancer on Platelet Production, Activation and Education and Mechanisms of Cancer-Associated Thrombosis

by Léa Plantureux¹

, Diane Mège^1,2, Lydie Crescence¹, Françoise Dignat-George¹, Christophe Dubois¹

and Laurence Panicot-Dubois^1,*

¹ Aix Marseille Univ, INSERM 1263, INRA 1260, C2VN, Faculty of pharmacy, 27 Boulevard Jean Moulin, 13385 Marseille, France

² Department of Digestive Surgery, Timone University Hospital, 13385 Marseille, France

Cancers 2018, 10(11), 441; https://doi.org/10.3390/cancers10110441 - 14 Nov 2018

Cited by 87 | Viewed by 9978

Abstract

Platelets are small anucleate cells that are traditionally described as the major effectors of hemostasis and thrombosis. However, increasing evidence indicates that platelets play several roles in the progression of malignancies and in cancer-associated thrombosis. A notable cross-communication exists between platelets and cancer [...] Read more.

Platelets are small anucleate cells that are traditionally described as the major effectors of hemostasis and thrombosis. However, increasing evidence indicates that platelets play several roles in the progression of malignancies and in cancer-associated thrombosis. A notable cross-communication exists between platelets and cancer cells. On one hand, cancer can “educate” platelets, influencing their RNA profiles, the numbers of circulating platelets and their activation states. On the other hand, tumor-educated platelets contain a plethora of active biomolecules, including platelet-specific and circulating ingested biomolecules, that are released upon platelet activation and participate in the progression of malignancy. The numerous mechanisms by which the primary tumor induces the production, activation and aggregation of platelets (also known as tumor cell induced platelet aggregation, or TCIPA) are directly related to the pro-thrombotic state of cancer patients. Moreover, the activation of platelets is critical for tumor growth and successful metastatic outbreak. The development or use of existing drugs targeting the activation of platelets, adhesive proteins responsible for cancer cell-platelet interactions and platelet agonists should be used to reduce cancer-associated thrombosis and tumor progression. Full article

(This article belongs to the Special Issue The Role of Thrombosis and Haemostasis in Cancer)

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33 pages, 2436 KiB

Open AccessReview

Epigenetic Regulation by lncRNAs: An Overview Focused on UCA1 in Colorectal Cancer

by Bernadette Neve^*

, Nicolas Jonckheere

, Audrey Vincent

and Isabelle Van Seuningen

Inserm UMR-S 1172, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc), Team “Mucins, Epithelial Differentiation and Carcinogenesis”; University Lille; CHU Lille, 59045, Lille CEDEX, France

Cancers 2018, 10(11), 440; https://doi.org/10.3390/cancers10110440 - 14 Nov 2018

Cited by 45 | Viewed by 7134 | Correction

Abstract

Colorectal cancers have become the second leading cause of cancer-related deaths. In particular, acquired chemoresistance and metastatic lesions occurring in colorectal cancer are a major challenge for chemotherapy treatment. Accumulating evidence shows that long non-coding (lncRNAs) are involved in the initiation, progression, and [...] Read more.

Colorectal cancers have become the second leading cause of cancer-related deaths. In particular, acquired chemoresistance and metastatic lesions occurring in colorectal cancer are a major challenge for chemotherapy treatment. Accumulating evidence shows that long non-coding (lncRNAs) are involved in the initiation, progression, and metastasis of cancer. We here discuss the epigenetic mechanisms through which lncRNAs regulate gene expression in cancer cells. In the second part of this review, we focus on the role of lncRNA Urothelial Cancer Associated 1 (UCA1) to integrate research in different types of cancer in order to decipher its putative function and mechanism of regulation in colorectal cancer cells. UCA1 is highly expressed in cancer cells and mediates transcriptional regulation on an epigenetic level through the interaction with chromatin modifiers, by direct regulation via chromatin looping and/or by sponging the action of a diversity of miRNAs. Furthermore, we discuss the role of UCA1 in the regulation of cell cycle progression and its relation to chemoresistance in colorectal cancer cells. Full article

(This article belongs to the Special Issue Colorectal Cancers)

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24 pages, 5369 KiB

Open AccessArticle

The Role of the Anti-Aging Protein Klotho in IGF-1 Signaling and Reticular Calcium Leak: Impact on the Chemosensitivity of Dedifferentiated Liposarcomas

by Vanessa Delcroix^1,2,*

, Olivier Mauduit^1,3,4

, Nolwenn Tessier^4,5, Anaïs Montillaud^1,2, Tom Lesluyes^1,3,†, Thomas Ducret^2,6, Frédéric Chibon^1,3,†

, Fabien Van Coppenolle^4,5, Sylvie Ducreux^4,5

and Pierre Vacher^1,2,*

¹ INSERM U1218, F-33076 Bordeaux, France

² Department of Life and Health Sciences, University of Bordeaux, F-33000 Bordeaux, France

³ Department of Pathology, Bergonié Cancer Institute, F-33076 Bordeaux, France

⁴ University of Lyon, F-69361 Lyon CEDEX 07, France

⁵ Univ-Lyon, CarMeN laboratory, Inserm U1060, INRA U1397, Université Claude Bernard Lyon 1, INSA Lyon, Hospital Cardiology, B13 Building, Lyon East, F-69500 Bron, France

⁶ INSERM U1045, Centre de Recherche Cardio-Thoracique de Bordeaux (CRCTB), F-33000 Bordeaux, France

^† Current affiliations: INSERM U1037, Cancer Research Center of Toulouse (CRCT) and Department of Pathology, Institut Claudius Regaud, IUCT-Oncopole, F-31037 Toulouse, France.

Cancers 2018, 10(11), 439; https://doi.org/10.3390/cancers10110439 - 14 Nov 2018

Cited by 22 | Viewed by 6875

Abstract

By inhibiting Insulin-Like Growth Factor-1-Receptor (IGF-1R) signaling, Klotho (KL) acts like an aging- and tumor-suppressor. We investigated whether KL impacts the aggressiveness of liposarcomas, in which IGF-1R signaling is frequently upregulated. Indeed, we observed that a higher KL expression in liposarcomas is associated [...] Read more.

By inhibiting Insulin-Like Growth Factor-1-Receptor (IGF-1R) signaling, Klotho (KL) acts like an aging- and tumor-suppressor. We investigated whether KL impacts the aggressiveness of liposarcomas, in which IGF-1R signaling is frequently upregulated. Indeed, we observed that a higher KL expression in liposarcomas is associated with a better outcome for patients. Moreover, KL is downregulated in dedifferentiated liposarcomas (DDLPS) compared to well-differentiated tumors and adipose tissue. Because DDLPS are high-grade tumors associated with poor prognosis, we examined the potential of KL as a tool for overcoming therapy resistance. First, we confirmed the attenuation of IGF-1-induced calcium (Ca²⁺)-response and Extracellular signal-Regulated Kinase 1/2 (ERK1/2) phosphorylation in KL-overexpressing human DDLPS cells. KL overexpression also reduced cell proliferation, clonogenicity, and increased apoptosis induced by gemcitabine, thapsigargin, and ABT-737, all of which are counteracted by IGF-1R-dependent signaling and activate Ca²⁺-dependent endoplasmic reticulum (ER) stress. Then, we monitored cell death and cytosolic Ca²⁺-responses and demonstrated that KL increases the reticular Ca²⁺-leakage by maintaining TRPC6 at the ER and opening the translocon. Only the latter is necessary for sensitizing DDLPS cells to reticular stressors. This was associated with ERK1/2 inhibition and could be mimicked with IGF-1R or MEK inhibitors. These observations provide a new therapeutic strategy in the management of DDLPS. Full article

(This article belongs to the Special Issue Ion Channels in Cancer)

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Graphical abstract

15 pages, 4669 KiB

Open AccessArticle

Humanization of the Prostate Microenvironment Reduces Homing of PC3 Prostate Cancer Cells to Human Tissue-Engineered Bone

by Jacqui A. McGovern^1,†

, Abbas Shafiee^1,2,†

, Ferdinand Wagner^1,3, Christoph A. Lahr¹

, Marietta Landgraf¹

, Christoph Meinert¹

, Elizabeth D. Williams⁴

, Pamela J. Russell⁴, Judith A. Clements⁴, Daniela Loessner^1,5, Boris M. Holzapfel^1,4,6, Gail P. Risbridger^7,8 and Dietmar W. Hutmacher^1,4,9,*

¹ Centre in Regenerative Medicine, Institute of Health and Biomedical Innovation, Queensland University of Technology (QUT), 60 Musk Avenue, Kelvin Grove, Brisbane, QLD 4059, Australia

² UQ Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, QLD 4102, Australia

³ Department of Pediatric Surgery, Dr. von Hauner Children’s Hospital, Ludwig-Maximilians-University of Munich, Lindwurmstraße 4, 80337 Munich, Germany

⁴ Australian Prostate Cancer Research Centre—Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, QLD 4102, Australia

⁵ Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK

⁶ Orthopedic Center for Musculoskeletal Research, University of Wuerzburg, Brettreichstraße 11, 97072 Wuerzburg, Germany

⁷ Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 2800, Australia

⁸ Prostate Cancer Research Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia

⁹ ARC Industrial Transformation Training Centre In Additive Biomanufacturing, Queensland University of Technology (QUT), 60 Musk Avenue, Kelvin Grove, Brisbane, QLD 4059, Australia

^† These authors contributed equally to this work.

Cancers 2018, 10(11), 438; https://doi.org/10.3390/cancers10110438 - 13 Nov 2018

Cited by 18 | Viewed by 5327

Abstract

The primary tumor microenvironment is inherently important in prostate cancer (PCa) initiation, growth and metastasis. However, most current PCa animal models are based on the injection of cancer cells into the blood circulation and bypass the first steps of the metastatic cascade, hence [...] Read more.

The primary tumor microenvironment is inherently important in prostate cancer (PCa) initiation, growth and metastasis. However, most current PCa animal models are based on the injection of cancer cells into the blood circulation and bypass the first steps of the metastatic cascade, hence failing to investigate the influence of the primary tumor microenvironment on PCa metastasis. Here, we investigated the spontaneous metastasis of PC3 human PCa cells from humanized prostate tissue, containing cancer-associated fibroblasts (CAFs) and prostate lymphatic and blood vessel endothelial cells (BVECs), to humanized tissue-engineered bone constructs (hTEBCs) in NOD-SCID IL2Rγ^null (NSG) mice. The hTEBC formed a physiologically mature organ bone which allowed homing of metastatic PCa cells. Humanization of prostate tissue had no significant effect on the tumor burden at the primary site over the 4 weeks following intraprostatic injection, yet reduced the incidence and burden of metastases in the hTEBC. Spontaneous PCa metastases were detected in the lungs and spleen with no significant differences between the humanized and non-humanized prostate groups. A significantly greater metastatic tumor burden was observed in the liver when metastasis occurred from the humanized prostate. Together, our data suggests that the presence of human-derived CAFs and BVECs in the primary PCa microenvironment influences selectively the metastatic and homing behavior of PC3 cells in this model. Our orthotopic and humanized PCa model developed via convergence of cancer research and tissue engineering concepts provides a platform to dissect mechanisms of species-specific PCa bone metastasis and to develop precision medicine strategies. Full article

(This article belongs to the Special Issue Targeting Bone Metastasis in Cancer)

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19 pages, 3560 KiB

Open AccessArticle

CCND1 Splice Variant as A Novel Diagnostic and Predictive Biomarker for Thyroid Cancer

by Sora Jeon^1,2,3

, Yourha Kim^1,2,3, Young Mun Jeong^1,2,3, Ja Seong Bae^3,4 and Chan Kwon Jung^1,2,3,*

¹ Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea

² Department of Biomedicine & Health Sciences, Graduate School, The Catholic University of Korea, Seoul 06591, Korea

³ Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea

⁴ Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea

Cancers 2018, 10(11), 437; https://doi.org/10.3390/cancers10110437 - 13 Nov 2018

Cited by 36 | Viewed by 7061

Abstract

Cyclin D1 protein is aberrantly overexpressed in thyroid cancers, but mutations of the CCND1 gene are rare in these tumors. We investigated the CCND1 rs9344 (G870A) polymorphism and the expression profiles of wild-type CCND1a and shortened oncogenic isoform CCND1b at the mRNA and [...] Read more.

Cyclin D1 protein is aberrantly overexpressed in thyroid cancers, but mutations of the CCND1 gene are rare in these tumors. We investigated the CCND1 rs9344 (G870A) polymorphism and the expression profiles of wild-type CCND1a and shortened oncogenic isoform CCND1b at the mRNA and protein levels in 286 thyroid tumors. Genotype AA of rs9344 was associated with high expression of CCND1b mRNA and was more frequently found in thyroid cancer than in benign tumors. The mRNA expression levels of CCND1b were higher in papillary thyroid carcinoma (PTC) than in benign or other malignant tumors. However, the expression of CCND1a mRNA showed no association with the parameters. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was distinguished from PTC by low expression of CCND1b at mRNA and protein levels. We further observed that cyclin D1b immunostaining helped to avoid the misdiagnosis of classic PTC with predominant follicular pattern as NIFTP in a separate cohort. Nuclear cyclin D1b expression was associated with aggressive clinicopathologic features in PTC. These findings suggest that cyclin D1b overexpression can be used as a diagnostic and predictive biomarker in thyroid tumors and may be functionally involved in the development and progression of the disease. Full article

(This article belongs to the Special Issue Thyroid Cancer)

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Graphical abstract

23 pages, 1962 KiB

Open AccessArticle

Focal Adhesion Genes Refine the Intermediate-Risk Cytogenetic Classification of Acute Myeloid Leukemia

by Victor Pallarès^1,2

, Montserrat Hoyos^1,2, M. Carmen Chillón³

, Eva Barragán⁴

, M. Isabel Prieto Conde³, Marta Llop⁴, Aïda Falgàs¹, María Virtudes Céspedes^1,5, Pau Montesinos⁴, Josep F. Nomdedeu², Salut Brunet², Miguel Ángel Sanz⁴, Marcos González-Díaz³, Jorge Sierra^2,6,7,*, Ramon Mangues^1,5,6,*,†

and Isolda Casanova^1,5,6,†

¹ Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Sant Antoni Maria Claret 167, Pavelló 11, 2n pis, 08025 Barcelona, Spain

² Department of Hematology, Hospital de la Santa Creu i Sant Pau, Mas Casanovas nº 90, 08041 Barcelona, Spain

³ Servicio de Hematología, IBSAL-Hospital Universitario, Centro de Investigación del Cáncer (CIC)-IBMCC, Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Universidad de Salamanca, 37007 Salamanca, Spain

⁴ Hematology Department, Hospital Universitari i Politècnic La Fe, Department of Medicine, University of Valencia, and Centro de Investigación Biomédica en Red de Cáncer, Instituto Carlos III, 46026 Valencia, Spain

⁵ CIBER en Bioinginiería, Biomateriales y Nanomedicina (CIBER-BBN), 08025 Barcelona, Spain

⁶ Josep Carreras Leukemia Research Institute, 08021 Barcelona, Spain

⁷ Hematology Department, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain

^† These authors contributed equally to this work as senior authors.

Cancers 2018, 10(11), 436; https://doi.org/10.3390/cancers10110436 - 13 Nov 2018

Cited by 8 | Viewed by 4443

Abstract

In recent years, several attempts have been made to identify novel prognostic markers in patients with intermediate-risk acute myeloid leukemia (IR-AML), to implement risk-adapted strategies. The non-receptor tyrosine kinases are proteins involved in regulation of cell growth, adhesion, migration and apoptosis. They associate [...] Read more.

In recent years, several attempts have been made to identify novel prognostic markers in patients with intermediate-risk acute myeloid leukemia (IR-AML), to implement risk-adapted strategies. The non-receptor tyrosine kinases are proteins involved in regulation of cell growth, adhesion, migration and apoptosis. They associate with metastatic dissemination in solid tumors and poor prognosis. However, their role in haematological malignancies has been scarcely studied. We hypothesized that PTK2/FAK, PTK2B/PYK2, LYN or SRC could be new prognostic markers in IR-AML. We assessed PTK2, PTK2B, LYN and SRC gene expression in a cohort of 324 patients, adults up to the age of 70, classified in the IR-AML cytogenetic group. Univariate and multivariate analyses showed that PTK2B, LYN and PTK2 gene expression are independent prognostic factors in IR-AML patients. PTK2B and LYN identify a patient subgroup with good prognosis within the cohort with non-favorable FLT3/NPM1 combined mutations. In contrast, PTK2 identifies a patient subgroup with poor prognosis within the worst prognosis cohort who display non-favorable FLT3/NPM1 combined mutations and underexpression of PTK2B or LYN. The combined use of these markers can refine the highly heterogeneous intermediate-risk subgroup of AML patients, and allow the development of risk-adapted post-remission chemotherapy protocols to improve their response to treatment. Full article

(This article belongs to the Collection Kinases and Cancer)

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36 pages, 607 KiB

Open AccessReview

Next-Generation Service Delivery: A Scoping Review of Patient Outcomes Associated with Alternative Models of Genetic Counseling and Genetic Testing for Hereditary Cancer

by Jeanna M. McCuaig^1,2,3,*, Susan Randall Armel^1,2, Melanie Care^2,4,5, Alexandra Volenik^1,2, Raymond H. Kim^1,6

and Kelly A. Metcalfe^3,7

¹ Familial Cancer Clinic, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada

² Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada

³ Lawrence S. Bloomberg Faculty of Nursing, University of Toronto, Toronto, ON M5T 1P8, Canada

⁴ Division of Cardiology, Department of Medicine, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, ONM5G 2C4, Canada

⁵ Genome Diagnostics, Toronto General Hospital, University Health Network, Toronto, ON M5G 2C4, Canada

⁶ Department of Medicine, Division of Medical Oncology and Hematology, University of Toronto, Toronto, ON M5S 1A8, Canada

⁷ Women’s College Research Institute, Women’s College Hospital, Toronto, ON M5G 1N8, Canada

Cancers 2018, 10(11), 435; https://doi.org/10.3390/cancers10110435 - 13 Nov 2018

Cited by 82 | Viewed by 7054

Abstract

The combination of increased referral for genetic testing and the current shortage of genetic counselors has necessitated the development and implementation of alternative models of genetic counseling and testing for hereditary cancer assessment. The purpose of this scoping review is to provide an [...] Read more.

The combination of increased referral for genetic testing and the current shortage of genetic counselors has necessitated the development and implementation of alternative models of genetic counseling and testing for hereditary cancer assessment. The purpose of this scoping review is to provide an overview of the patient outcomes that are associated with alternative models of genetic testing and genetic counseling for hereditary cancer, including germline-only and tumor testing models. Seven databases were searched, selecting studies that were: (1) full-text articles published ≥2007 or conference abstracts published ≥2015, and (2) assessing patient outcomes of an alternative model of genetic counseling or testing. A total of 79 publications were included for review and synthesis. Data-charting was completed using a data-charting form that was developed by the study team for this review. Seven alternative models were identified, including four models that involved a genetic counselor: telephone, telegenic, group, and embedded genetic counseling models; and three models that did not: mainstreaming, direct, and tumor-first genetic testing models. Overall, these models may be an acceptable alternative to traditional models on knowledge, patient satisfaction, psychosocial measures, and the uptake of genetic testing; however, particular populations may be better served by traditional in-person genetic counseling. As precision medicine initiatives continue to advance, institutions should consider the implementation of new models of genetic service delivery, utilizing a model that will best serve the needs of their unique patient populations. Full article

(This article belongs to the Special Issue BRCA Mutations and Cancer)

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17 pages, 614 KiB

Open AccessArticle

Better Progression-Free Survival in Elderly Patients with Stage IV Lung Adenocarcinoma Harboring Uncommon Epidermal Growth Factor Receptor Mutations Treated with the First-line Tyrosine Kinase Inhibitors

by Ming-Ju Tsai^1,2,3,4,5, Jen-Yu Hung^1,2,3,4,5, Mei-Hsuan Lee¹, Chia-Yu Kuo^1,6, Yu-Chen Tsai^1,6, Ying-Ming Tsai^1,3,6, Ta-Chih Liu^3,5,7, Chih-Jen Yang^1,2,3,4,*

, Ming-Shyan Huang^8,9 and Inn-Wen Chong^1,4

¹ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No.100, Tz-You 1st Road, Kaohsiung 807, Taiwan

² Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 80145, Taiwan

³ Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan

⁴ Department of Respiratory Care, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan

⁵ Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan

⁶ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan

⁷ Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan

⁸ E-DA Cancer Hospital, Kaohsiung 82445, Taiwan

⁹ School of Medicine, I-Shou University, Kaohsiung 82445, Taiwan

Cancers 2018, 10(11), 434; https://doi.org/10.3390/cancers10110434 - 13 Nov 2018

Cited by 12 | Viewed by 4485

Abstract

Patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutations usually have a good response rate (RR) and longer progression-free survival (PFS) to EGFR tyrosine kinase inhibitors (TKIs). However, the treatment efficacy to uncommon EGFR mutations remains controversial. We, [...] Read more.

Patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutations usually have a good response rate (RR) and longer progression-free survival (PFS) to EGFR tyrosine kinase inhibitors (TKIs). However, the treatment efficacy to uncommon EGFR mutations remains controversial. We, therefore, performed a retrospective study, screening 2958 patients. A total of 67 patients with lung adenocarcinoma harboring uncommon EGFR mutations were enrolled and 57 patients with stage IV diseases receiving a first-line EGFR TKI were included for further analyses. The patients were classified into 27 (47%) “a single sensitizing uncommon mutation”, 7 (12%) “multiple sensitizing mutations”, 5 (9%) “a sensitizing mutation and a resistant uncommon mutation”, and 18 (32%) “other resistant uncommon mutations”. No significant difference was noted in PFS or overall survival (OS) between groups. Patients receiving different first-line EGFR TKIs had similar PFS and OS. The elder patients had a significantly poorer performance status than the younger patients but a significantly longer PFS than the younger patients (median PFS: 10.5 vs. 5.5 months, p = 0.0320). In conclusion, this is the first study to identify that elderly patients with stage IV lung adenocarcinoma harboring uncommon EGFR mutation might have a longer PFS. Large-scale prospective studies are mandatory to prove our findings. Full article

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28 pages, 564 KiB

Open AccessEditor’s ChoiceReview

Cell Origins of High-Grade Serous Ovarian Cancer

by Jaeyeon Kim^1,3,*, Eun Young Park¹, Olga Kim¹, Jeanne M. Schilder^2,3, Donna M. Coffey⁴, Chi-Heum Cho⁵ and Robert C. Bast⁶

¹ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA

² Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN 46202, USA

³ Indiana University Melvin & Bren Simon Cancer Center, Indianapolis, IN 46202, USA

⁴ Department of Pathology and Genomic Medicine, Houston Methodist and Weill Cornell Medical College, Houston, TX 77030, USA

⁵ Department of Obstetrics and Gynecology, School of Medicine, Keimyung University, Daegu 41931, Korea

⁶ Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

Cancers 2018, 10(11), 433; https://doi.org/10.3390/cancers10110433 - 12 Nov 2018

Cited by 192 | Viewed by 21414

Abstract

High-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), is the most common and deadliest type of ovarian cancer. HGSC appears to arise from the ovary, fallopian tube, or peritoneum. As most HGSC cases present with widespread peritoneal metastases, it is [...] Read more.

High-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), is the most common and deadliest type of ovarian cancer. HGSC appears to arise from the ovary, fallopian tube, or peritoneum. As most HGSC cases present with widespread peritoneal metastases, it is often not clear where HGSC truly originates. Traditionally, the ovarian surface epithelium (OSE) was long believed to be the origin of HGSC. Since the late 1990s, the fallopian tube epithelium has emerged as a potential primary origin of HGSC. Particularly, serous tubal intraepithelial carcinoma (STIC), a noninvasive tumor lesion formed preferentially in the distal fallopian tube epithelium, was proposed as a precursor for HGSC. It was hypothesized that STIC lesions would progress, over time, to malignant and metastatic HGSC, arising from the fallopian tube or after implanting on the ovary or peritoneum. Many clinical studies and several mouse models support the fallopian tube STIC origin of HGSC. Current evidence indicates that STIC may serve as a precursor for HGSC in high-risk women carrying germline BRCA1 or 2 mutations. Yet not all STIC lesions appear to progress to clinical HGSCs, nor would all HGSCs arise from STIC lesions, even in high-risk women. Moreover, the clinical importance of STIC remains less clear in women in the general population, in which 85–90% of all HGSCs arise. Recently, increasing attention has been brought to the possibility that many potential precursor or premalignant lesions, though composed of microscopically—and genetically—cancerous cells, do not advance to malignant tumors or lethal malignancies. Hence, rigorous causal evidence would be crucial to establish that STIC is a bona fide premalignant lesion for metastatic HGSC. While not all STICs may transform into malignant tumors, these lesions are clearly associated with increased risk for HGSC. Identification of the molecular characteristics of STICs that predict their malignant potential and clinical behavior would bolster the clinical importance of STIC. Also, as STIC lesions alone cannot account for all HGSCs, other potential cellular origins of HGSC need to be investigated. The fallopian tube stroma in mice, for instance, has been shown to be capable of giving rise to metastatic HGSC, which faithfully recapitulates the clinical behavior and molecular aspect of human HGSC. Elucidating the precise cell(s) of origin of HGSC will be critical for improving the early detection and prevention of ovarian cancer, ultimately reducing ovarian cancer mortality. Full article

(This article belongs to the Special Issue The Tumor Microenvironment of High Grade Serous Ovarian Cancer)

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