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Volume 11
Issue 5
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Cancers, Volume 11, Issue 5 (May 2019) – 149 articles

Cover Story (view full-size image): Evasion from immunosurveillance is one of the hallmarks of tumor progression in human malignancies, including breast cancer. Intensive research has helped unravel various mechanisms involved in this process, and has recently been rewarded by the advent of immune checkpoint inhibitors targeting PD-1/PD-L1 and CTLA4. Despite revolutionizing cancer management, these agents—used either as monotherapy or in combination with chemotherapy—have limits. Current efforts focus on a large number of co-stimulatory and co-inhibitory molecules involved in tumor evasion, consistent with the complexity of the tumor–host interactions. These molecules likely represent promising targets of immunotherapy and it is thus of paramount importance to understand their biology. Here, we summarize the data regarding their expression, their role in tumor evasion from immunosurveillance and ongoing clinical trials in breast cancer. [...] Read more.
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18 pages, 5843 KiB  
Article
Detecting and Tracking Circulating Tumour DNA Copy Number Profiles during First Line Chemotherapy in Oesophagogastric Adenocarcinoma
by Michael Davidson, Louise J. Barber, Andrew Woolston, Catherine Cafferkey, Sonia Mansukhani, Beatrice Griffiths, Sing-Yu Moorcraft, Isma Rana, Ruwaida Begum, Ioannis Assiotis, Nik Matthews, Sheela Rao, David Watkins, Ian Chau, David Cunningham, Naureen Starling and Marco Gerlinger
Cancers 2019, 11(5), 736; https://doi.org/10.3390/cancers11050736 - 27 May 2019
Cited by 14 | Viewed by 5004
Abstract
DNA somatic copy number aberrations (SCNAs) are key drivers in oesophagogastric adenocarcinoma (OGA). Whether minimally invasive SCNA analysis of circulating tumour (ct)DNA can predict treatment outcomes and reveal how SCNAs evolve during chemotherapy is unknown. We investigated this by low-coverage whole genome sequencing [...] Read more.
DNA somatic copy number aberrations (SCNAs) are key drivers in oesophagogastric adenocarcinoma (OGA). Whether minimally invasive SCNA analysis of circulating tumour (ct)DNA can predict treatment outcomes and reveal how SCNAs evolve during chemotherapy is unknown. We investigated this by low-coverage whole genome sequencing (lcWGS) of ctDNA from 30 patients with advanced OGA prior to first-line chemotherapy and on progression. SCNA profiles were detectable pretreatment in 23/30 (76.7%) patients. The presence of liver metastases, primary tumour in situ, or of oesophageal or junctional tumour location predicted for a high ctDNA fraction. A low ctDNA concentration associated with significantly longer overall survival. Neither chromosomal instability metrics nor ploidy correlated with chemotherapy outcome. Chromosome 2q and 8p gains before treatment were associated with chemotherapy responses. lcWGS identified all amplifications found by prior targeted tumour tissue sequencing in cases with detectable ctDNA as well as finding additional changes. SCNA profiles changed during chemotherapy, indicating that cancer cell populations evolved during treatment; however, no recurrent SCNA changes were acquired at progression. Tracking the evolution of OGA cancer cell populations in ctDNA is feasible during chemotherapy. The observation of genetic evolution warrants investigation in larger series and with higher resolution techniques to reveal potential genetic predictors of response and drivers of chemotherapy resistance. The presence of liver metastasis is a potential biomarker for the selection of patients with high ctDNA content for such studies. Full article
(This article belongs to the Special Issue Liquid Biopsy for Cancer)
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13 pages, 3281 KiB  
Article
miR551b Regulates Colorectal Cancer Progression by Targeting the ZEB1 Signaling Axis
by Kwang Seock Kim, Dongjun Jeong, Ita Novita Sari, Yoseph Toni Wijaya, Nayoung Jun, Sanghyun Lee, Ying-Gui Yang, Sae Hwan Lee and Hyog Young Kwon
Cancers 2019, 11(5), 735; https://doi.org/10.3390/cancers11050735 - 27 May 2019
Cited by 5 | Viewed by 3662
Abstract
Our current understanding of the role of microRNA 551b (miR551b) in the progression of colorectal cancer (CRC) remains limited. Here, studies using both ectopic expression of miR551b and miR551b mimics revealed that miR551b exerts a tumor suppressive effect in CRC cells. Specifically, miR551b [...] Read more.
Our current understanding of the role of microRNA 551b (miR551b) in the progression of colorectal cancer (CRC) remains limited. Here, studies using both ectopic expression of miR551b and miR551b mimics revealed that miR551b exerts a tumor suppressive effect in CRC cells. Specifically, miR551b was significantly downregulated in both patient-derived CRC tissues and CRC cell lines compared to normal tissues and non-cancer cell lines. Also, miR551b significantly inhibited the motility of CRC cells in vitro, including migration, invasion, and wound healing rates, but did not affect cell proliferation. Mechanistically, miR551b targets and inhibits the expression of ZEB1 (Zinc finger E-box-binding homeobox 1), resulting in the dysregulation of EMT (epithelial-mesenchymal transition) signatures. More importantly, miR551b overexpression was found to reduce the tumor size in a xenograft model of CRC cells in vivo. Furthermore, bioinformatic analyses showed that miR551b expression levels were markedly downregulated in the advanced-stage CRC tissues compared to normal tissues, and ZEB1 was associated with the disease progression in CRC patients. Our findings indicated that miR551b could serve as a potential diagnostic biomarker and could be utilized to improve the therapeutic outcomes of CRC patients. Full article
(This article belongs to the Special Issue Colorectal Cancers)
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10 pages, 6047 KiB  
Review
Deciphering The Potential Role of Hox Genes in Pancreatic Cancer
by Tzu-Lei Kuo, Kuang-Hung Cheng, Li-Tzong Chen and Wen-Chun Hung
Cancers 2019, 11(5), 734; https://doi.org/10.3390/cancers11050734 - 27 May 2019
Cited by 21 | Viewed by 4728
Abstract
The Hox gene family plays an important role in organogenesis and animal development. Currently, 39 Hox genes that are clustered in four chromosome regions have been identified in humans. Emerging evidence suggests that Hox genes are involved in the development of the pancreas. [...] Read more.
The Hox gene family plays an important role in organogenesis and animal development. Currently, 39 Hox genes that are clustered in four chromosome regions have been identified in humans. Emerging evidence suggests that Hox genes are involved in the development of the pancreas. However, the expression of Hox genes in pancreatic tumor tissues has been investigated in only a few studies. In addition, whether specific Hox genes can promote or suppress cancer metastasis is not clear. In this article, we first review the recent progress in studies on the role of Hox genes in pancreatic cancer. By comparing the expression profiles of pancreatic cancer cells isolated from genetically engineered mice established in our laboratory with three different proliferative and metastatic abilities, we identified novel Hox genes that exhibited tumor-promoting activity in pancreatic cancer. Finally, a potential oncogenic mechanism of the Hox genes was hypothesized. Full article
(This article belongs to the Special Issue HOX Genes in Cancer)
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8 pages, 736 KiB  
Article
Clinical Evaluation of CA72-4 for Screening Gastric Cancer in a Healthy Population: A Multicenter Retrospective Study
by Ping-Jen Hu, Ming-Yao Chen, Ming-Shun Wu, Ying-Chin Lin, Ping-Hsiao Shih, Chih-Ho Lai and Hwai-Jeng Lin
Cancers 2019, 11(5), 733; https://doi.org/10.3390/cancers11050733 - 27 May 2019
Cited by 35 | Viewed by 13513
Abstract
Early detection is important for improving the survival rate of patients with gastric cancer (GC). Serum tumor markers have been widely used for detecting GC. However, their clinical values remain controversial. This study aims to investigate the role of serum cancer antigen 72-4 [...] Read more.
Early detection is important for improving the survival rate of patients with gastric cancer (GC). Serum tumor markers have been widely used for detecting GC. However, their clinical values remain controversial. This study aims to investigate the role of serum cancer antigen 72-4 (CA72-4) in the diagnosis of GC in a healthy population. A total of 7757 adults who underwent upper gastrointestinal endoscopy and serum CA72-4 level measurement in multicenters in Taiwan from January 2006 to August 2016 were recruited in this retrospective study. Risk factors for GC, serum tumor markers, and esophagogastroduodenoscopy (EGD) findings were evaluated. High serum levels of CA72-4 were found in 7.2% of healthy adults. CA72-4 level showed lower sensitivity (33.3%) but higher specificity (92.8%); however, the positive predictive value was quite low (0.18%). After adjustment of clinical risk factors for GC using EGD findings, gastric ulcer (adjusted odds ratio (aOR) = 2.11), gastric polyps (aOR = 1.42), and atrophic gastritis (aOR = 1.27) were significantly associated with high serum CA72-4 levels. Furthermore, both age (OR = 1.01) and Helicobacter pylori infection (OR = 1.44) exhibited a significant association with high serum CA72-4 levels. These results indicate that routine screening of CA72-4 levels for diagnosing GC in asymptomatic patients may be ineffective due to low sensitivity and low positive predictive value. The clinical utility of EGD findings along with serum CA72-4 level for screening healthy individuals with GC is warranted. Full article
(This article belongs to the Special Issue New Biomarkers in Cancers)
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18 pages, 921 KiB  
Review
Targeting Cancer Stem Cells: A Strategy for Effective Eradication of Cancer
by Masahiro Shibata and Mohammad Obaidul Hoque
Cancers 2019, 11(5), 732; https://doi.org/10.3390/cancers11050732 - 27 May 2019
Cited by 134 | Viewed by 10265
Abstract
Cancer stem cells (CSCs) are subpopulations of tumor cells with the ability to self-renew, differentiate, and initiate and maintain tumor growth, and they are considered to be the main drivers of intra- and inter-tumoral heterogeneity. While conventional chemotherapy can eradicate the majority of [...] Read more.
Cancer stem cells (CSCs) are subpopulations of tumor cells with the ability to self-renew, differentiate, and initiate and maintain tumor growth, and they are considered to be the main drivers of intra- and inter-tumoral heterogeneity. While conventional chemotherapy can eradicate the majority of non-CSC tumor cells, CSCs are often drug-resistant, leading to tumor recurrence and metastasis. The heterogeneity of CSCs is the main challenge in developing CSC-targeting therapy; therefore, we and other investigators have focused on developing novel therapeutic strategies that combine conventional chemotherapy with inhibitors of CSC-regulating pathways. Encouraging preclinical findings have suggested that CSC pathway blockade can indeed enhance cellular sensitivity to non-targeted conventional therapy, and this work has led to several ongoing clinical trials of CSC pathway inhibitors. Our studies in bladder cancer and lung adenocarcinoma have demonstrated a crucial role of YAP1, a transcriptional regulator of genes that promote cell survival and proliferation, in regulating CSC phenotypes. Moreover, using cell lines and patient-derived xenograft models, we showed that inhibition of YAP1 enhances the efficacy of conventional therapies by attenuating CSC stemness features. In this review, we summarize the therapeutic strategies for targeting CSCs in several cancers and discuss the potential and challenges of the approach. Full article
(This article belongs to the Special Issue Advances in Cancer Stem Cell Research)
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15 pages, 623 KiB  
Review
STAT3: A Promising Therapeutic Target in Multiple Myeloma
by Phyllis S. Y. Chong, Wee-Joo Chng and Sanjay de Mel
Cancers 2019, 11(5), 731; https://doi.org/10.3390/cancers11050731 - 26 May 2019
Cited by 62 | Viewed by 6733
Abstract
Multiple myeloma (MM) is an incurable plasma cell malignancy for which novel treatment options are required. Signal Transducer and Activator of Transcription 3 (STAT3) overexpression in MM appears to be mediated by a variety of factors including interleukin-6 signaling and downregulation of Src [...] Read more.
Multiple myeloma (MM) is an incurable plasma cell malignancy for which novel treatment options are required. Signal Transducer and Activator of Transcription 3 (STAT3) overexpression in MM appears to be mediated by a variety of factors including interleukin-6 signaling and downregulation of Src homology phosphatase-1 (SHP-1). STAT3 overexpression in MM is associated with an adverse prognosis and may play a role in microenvironment-dependent treatment resistance. In addition to its pro-proliferative role, STAT3 upregulates anti-apoptotic proteins and leads to microRNA dysregulation in MM. Phosphatase of regenerating liver 3 (PRL-3) is an oncogenic phosphatase which is upregulated by STAT3. PRL-3 itself promotes STAT-3 phosphorylation resulting in a positive feedback loop. PRL-3 is overexpressed in a subset of MM patients and may cooperate with STAT3 to promote survival of MM cells. Indirectly targeting STAT3 via JAK (janus associated kinase) inhibition has shown promise in early clinical trials. Specific inhibitors of STAT3 showed in vitro efficacy but have failed in clinical trials while several STAT3 inhibitors derived from herbs have been shown to induce apoptosis of MM cells in vitro. Optimising the pharmacokinetic profiles of novel STAT3 inhibitors and identifying how best to combine these agents with existing anti-myeloma therapy are key questions to be addressed in future clinical trials. Full article
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8 pages, 4642 KiB  
Case Report
Living Donor Liver Re-Transplantation for Recurrent Hepatoblastoma in the Liver Graft following Complete Eradication of Peritoneal Metastases under Indocyanine Green Fluorescence Imaging
by Nobuhiro Takahashi, Yohei Yamada, Ken Hoshino, Miho Kawaida, Teizaburo Mori, Kiyotomo Abe, Takumi Fujimura, Kentaro Matsubara, Taizo Hibi, Masahiro Shinoda, Hideaki Obara, Kyohei Isshiki, Haruko Shima, Hiroyuki Shimada, Kaori Kameyama, Yasushi Fuchimoto, Yuko Kitagawa and Tatsuo Kuroda
Cancers 2019, 11(5), 730; https://doi.org/10.3390/cancers11050730 - 26 May 2019
Cited by 28 | Viewed by 4799
Abstract
The curability of chemotherapy-resistant hepatoblastoma (HB) largely depends on the achievement of radical surgical resection. Navigation techniques utilizing indocyanine green (ICG) are a powerful tool for detecting small metastatic lesions. We herein report a patient who underwent a second living donor liver transplantation [...] Read more.
The curability of chemotherapy-resistant hepatoblastoma (HB) largely depends on the achievement of radical surgical resection. Navigation techniques utilizing indocyanine green (ICG) are a powerful tool for detecting small metastatic lesions. We herein report a patient who underwent a second living donor liver transplantation (LDLTx) for multiple recurrent HBs in the liver graft following metastasectomy for peritoneal dissemination with ICG navigation. The patient initially presented with ruptured HB at 6 years of age and underwent 3 liver resections followed by the first LDLTx with multiple sessions of chemotherapy at 11 years of age. His alpha-fetoprotein (AFP) level increased above the normal limit, and metastases were noted in the transplanted liver and peritoneum four years after the first LDLTx. The patient underwent metastasectomy of the peritoneally disseminated HBs with ICG navigation followed by the second LDLTx for multiple metastases in the transplanted liver. The patient has been recurrence-free with a normal AFP for 30 months since the second LDLTx. To our knowledge, this report is the first successful case of re-LDLTx for recurrent HBs. Re-LDLTx for recurrent HB can be performed in highly select patients, and ICG navigation is a powerful surgical tool for achieving tumor clearance. Full article
(This article belongs to the Special Issue Hepatoblastoma and Pediatric Liver Tumors)
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17 pages, 2854 KiB  
Review
Interplay Between LOX Enzymes and Integrins in the Tumor Microenvironment
by Pier Giorgio Amendola, Raphael Reuten and Janine Terra Erler
Cancers 2019, 11(5), 729; https://doi.org/10.3390/cancers11050729 - 26 May 2019
Cited by 51 | Viewed by 7130
Abstract
Members of the lysyl oxidase (LOX) family are secreted copper-dependent amine oxidases that catalyze the covalent crosslinking of collagens and elastin in the extracellular matrix (ECM), an essential process for the structural integrity of all tissues. LOX enzymes can also remodel the tumor [...] Read more.
Members of the lysyl oxidase (LOX) family are secreted copper-dependent amine oxidases that catalyze the covalent crosslinking of collagens and elastin in the extracellular matrix (ECM), an essential process for the structural integrity of all tissues. LOX enzymes can also remodel the tumor microenvironment and have been implicated in all stages of tumor initiation and progression of many cancer types. Changes in the ECM can influence several cancer cell phenotypes. Integrin adhesion complexes (IACs) physically connect cells with their microenvironment. This review article summarizes the main findings on the role of LOX proteins in modulating the tumor microenvironment, with a particular focus on how ECM changes are integrated by IACs to modulate cells behavior. Finally, we discuss how the development of selective LOX inhibitors may lead to novel and effective therapies in cancer treatment. Full article
(This article belongs to the Special Issue The Role of Integrins in Cancer)
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12 pages, 10040 KiB  
Article
TCam-2 Cells Deficient for SOX2 and FOXA2 Are Blocked in Differentiation and Maintain a Seminoma-Like Cell Fate In Vivo
by Daniel Nettersheim, Saskia Vadder, Sina Jostes, Alena Heimsoeth and Hubert Schorle
Cancers 2019, 11(5), 728; https://doi.org/10.3390/cancers11050728 - 25 May 2019
Cited by 13 | Viewed by 5382
Abstract
Testicular germ cell tumors (GCTs) are very common in young men and can be stratified into seminomas and non-seminomas. While seminomas share a similar gene expression and epigenetic profile with primordial germ cells, the stem cell population of the non-seminomas, the embryonal carcinoma [...] Read more.
Testicular germ cell tumors (GCTs) are very common in young men and can be stratified into seminomas and non-seminomas. While seminomas share a similar gene expression and epigenetic profile with primordial germ cells, the stem cell population of the non-seminomas, the embryonal carcinoma (EC), resembles malignant embryonic stem cells. Thus, ECs are able to differentiate into cells of all three germ layers (teratomas) and even extra-embryonic-tissue-like cells (yolk-sac tumor, choriocarcinoma). In the last years, we demonstrated that the cellular microenvironment considerably influences the plasticity of seminomas (TCam-2 cells). Upon a microenvironment-triggered inhibition of the BMP signaling pathway in vivo (murine flank or brain), seminomatous TCam-2 cells reprogram to an EC-like cell fate. We identified SOX2 as a key factor activated upon BMP inhibition mediating the reprogramming process by regulating pluripotency, reprogramming and epigenetic factors. Indeed, CRISPR/Cas9 SOX2-deleted TCam-2 cells were able to maintain a seminoma-cell fate in vivo for about six weeks, but after six weeks in vivo still small sub-populations initiated differentiation. Closer analyses of these differentiated clusters suggested that the pioneer factor FOXA2 might be the driving force behind this induction of differentiation, since many FOXA2 interacting genes and differentiation factors like AFP, EOMES, CDX1, ALB, HAND1, DKK, DLK1, MSX1 and PITX2 were upregulated. In this study, we generated TCam-2 cells double-deficient for SOX2 and FOXA2 using the CRISPR/Cas9 technique and xenografted those cells into the flank of nude mice. Upon loss of SOX2 and FOXA2, TCam-2 maintained a seminoma cell fate for at least twelve weeks, demonstrating that both factors are key players in the reprogramming to an EC-like cell fate. Therefore, our study adds an important piece to the puzzle of GCT development and plasticity, providing interesting insights in what can be expected in a patient, when GCT cells are confronted with different microenvironments. Full article
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21 pages, 5199 KiB  
Article
Acute Skin Damage and Late Radiation-Induced Fibrosis and Inflammation in Murine Ears after High-Dose Irradiation
by Annique C. Dombrowsky, Jannis Schauer, Matthias Sammer, Andreas Blutke, Dietrich W. M. Walsh, Benjamin Schwarz, Stefan Bartzsch, Annette Feuchtinger, Judith Reindl, Stephanie E. Combs, Günther Dollinger and Thomas E. Schmid
Cancers 2019, 11(5), 727; https://doi.org/10.3390/cancers11050727 - 25 May 2019
Cited by 15 | Viewed by 5953
Abstract
The use of different scoring systems for radiation-induced toxicity limits comparability between studies. We examined dose-dependent tissue alterations following hypofractionated X-ray irradiation and evaluated their use as scoring criteria. Four dose fractions (0, 5, 10, 20, 30 Gy/fraction) were applied daily to ear [...] Read more.
The use of different scoring systems for radiation-induced toxicity limits comparability between studies. We examined dose-dependent tissue alterations following hypofractionated X-ray irradiation and evaluated their use as scoring criteria. Four dose fractions (0, 5, 10, 20, 30 Gy/fraction) were applied daily to ear pinnae. Acute effects (ear thickness, erythema, desquamation) were monitored for 92 days after fraction 1. Late effects (chronic inflammation, fibrosis) and the presence of transforming growth factor beta 1 (TGFβ1)-expressing cells were quantified on day 92. The maximum ear thickness displayed a significant positive correlation with fractional dose. Increased ear thickness and erythema occurred simultaneously, followed by desquamation from day 10 onwards. A significant dose-dependency was observed for the severity of erythema, but not for desquamation. After 4 × 20 and 4 × 30 Gy, inflammation was significantly increased on day 92, whereas fibrosis and the abundance of TGFβ1-expressing cells were only marginally increased after 4 × 30 Gy. Ear thickness significantly correlated with the severity of inflammation and fibrosis on day 92, but not with the number of TGFβ1-expressing cells. Fibrosis correlated significantly with inflammation and fractional dose. In conclusion, the parameter of ear thickness can be used as an objective, numerical and dose-dependent quantification criterion to characterize the severity of acute toxicity and allow for the prediction of late effects. 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))
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17 pages, 1023 KiB  
Review
Epigenetic Reprogramming of TGF-β Signaling in Breast Cancer
by Sudha Suriyamurthy, David Baker, Peter ten Dijke and Prasanna Vasudevan Iyengar
Cancers 2019, 11(5), 726; https://doi.org/10.3390/cancers11050726 - 24 May 2019
Cited by 52 | Viewed by 9605
Abstract
The Transforming Growth Factor-β (TGF-β) signaling pathway has a well-documented, context-dependent role in breast cancer development. In normal and premalignant cells, it acts as a tumor suppressor. By contrast, during the malignant phases of breast cancer progression, the TGF-β signaling pathway elicits tumor [...] Read more.
The Transforming Growth Factor-β (TGF-β) signaling pathway has a well-documented, context-dependent role in breast cancer development. In normal and premalignant cells, it acts as a tumor suppressor. By contrast, during the malignant phases of breast cancer progression, the TGF-β signaling pathway elicits tumor promoting effects particularly by driving the epithelial to mesenchymal transition (EMT), which enhances tumor cell migration, invasion and ultimately metastasis to distant organs. The molecular and cellular mechanisms that govern this dual capacity are being uncovered at multiple molecular levels. This review will focus on recent advances relating to how epigenetic changes such as acetylation and methylation control the outcome of TGF-β signaling and alter the fate of breast cancer cells. In addition, we will highlight how this knowledge can be further exploited to curb tumorigenesis by selective targeting of the TGF-β signaling pathway. Full article
(This article belongs to the Special Issue Epigenetic Dysregulation in Cancer: From Mechanism to Therapy)
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10 pages, 1430 KiB  
Article
Western-Type Helicobacter pylori CagA are the Most Frequent Type in Mongolian Patients
by Tegshee Tserentogtokh, Boldbaatar Gantuya, Phawinee Subsomwong, Khasag Oyuntsetseg, Dashdorj Bolor, Yansan Erdene-Ochir, Dashdorj Azzaya, Duger Davaadorj, Tomohisa Uchida, Takeshi Matsuhisa and Yoshio Yamaoka
Cancers 2019, 11(5), 725; https://doi.org/10.3390/cancers11050725 - 24 May 2019
Cited by 18 | Viewed by 3916
Abstract
Helicobacter pylori infection possessing East-Asian-type CagA is associated with carcinogenesis. Mongolia has the highest mortality rate from gastric cancer. Therefore, we evaluated the CagA status in the Mongolian population. High risk and gastric cancer patients were determined using endoscopy and histological examination. H. [...] Read more.
Helicobacter pylori infection possessing East-Asian-type CagA is associated with carcinogenesis. Mongolia has the highest mortality rate from gastric cancer. Therefore, we evaluated the CagA status in the Mongolian population. High risk and gastric cancer patients were determined using endoscopy and histological examination. H. pylori strains were isolated from different locations in Mongolia. The CagA subtypes (East-Asian-type or Western-type, based on sequencing of Glu-Pro-Ile-Tyr-Ala (EPIYA) segments) and vacA genotypes (s and m regions) were determined using PCR-based sequencing and PCR, respectively. In total, 368 patients were examined (341 gastritis, 10 peptic ulcer, and 17 gastric cancer). Sixty-two (16.8%) strains were cagA-negative and 306 (83.1%) were cagA-positive (293 Western-type, 12 East-Asian-type, and one hybrid type). All cagA-negative strains were isolated from gastritis patients. In the gastritis group, 78.6% (268/341) had Western-type CagA, 2.9% (10/341) had East-Asian-type, and 18.2% (61/341) were cagA-negative. However, all H. pylori from gastric cancer patients possessed Western-type CagA. Histological analyses showed that East-Asian-type CagA was the most virulent strains, followed by Western-type and cagA-negative strains. This finding agreed with the current consensus. CagA-positive strains were the most virulent type. However, the fact that different CagA types can explain the high incidence of gastric cancer might be inapplicable in Mongolia. Full article
(This article belongs to the Special Issue Helicobacter pylori Associated Cancer)
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16 pages, 799 KiB  
Review
Malignant Pheochromocytomas/Paragangliomas and Ectopic Hormonal Secretion: A Case Series and Review of the Literature
by Anna Angelousi, Melpomeni Peppa, Alexandra Chrisoulidou, Krystallenia Alexandraki, Annabel Berthon, Fabio Rueda Faucz, Eva Kassi and Gregory Kaltsas
Cancers 2019, 11(5), 724; https://doi.org/10.3390/cancers11050724 - 24 May 2019
Cited by 19 | Viewed by 4451
Abstract
Malignant pheochromocytomas (PCs) and paragangliomas (PGLs) are rare neuroendocrine neoplasms defined by the presence of distant metastases. There is currently a relatively paucity of data regarding the natural history of PCs/PGLs and the optimal approach to their treatment. We retrospectively analyzed the clinical, [...] Read more.
Malignant pheochromocytomas (PCs) and paragangliomas (PGLs) are rare neuroendocrine neoplasms defined by the presence of distant metastases. There is currently a relatively paucity of data regarding the natural history of PCs/PGLs and the optimal approach to their treatment. We retrospectively analyzed the clinical, biochemical, imaging, genetic and histopathological characteristics of fourteen patients with metastatic PCs/PGLs diagnosed over 15 years, along with their response to treatment. Patients were followed-up for a median of six years (range: 1–14 years). Six patients had synchronous metastases and the remaining developed metastases after a median of four years (range 2–10 years). Genetic analysis of seven patients revealed that three harbored succinate dehydrogenase subunit B/D gene (SDHB/D) mutations. Hormonal hypersecretion occurred in 70% of patients; normetanephrine, either alone or with other concomitant hormones, was the most frequent secretory component. Patients were administered multiple first and subsequent treatments including surgery (n = 12), chemotherapy (n = 7), radionuclide therapy (n = 2) and radiopeptides (n = 5). Seven patients had stable disease, four had progressive disease and three died. Ectopic hormonal secretion is rare and commonly encountered in benign PCs. Ectopic secretion of interleukin-6 in one of our patients, prompted a literature review of ectopic hormonal secretion, particularly from metastatic PCs/PGLs. Only four cases of metastatic PC/PGLs with confirmed ectopic secretion of hormones or peptides have been described so far. Full article
(This article belongs to the Special Issue Pheochromocytoma (PHEO) and Paraganglioma (PGL))
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23 pages, 3176 KiB  
Communication
Profiling of Epigenetic Features in Clinical Samples Reveals Novel Widespread Changes in Cancer
by Roberta Noberini, Camilla Restellini, Evelyn Oliva Savoia, Francesco Raimondi, Lavinia Ghiani, Maria Giovanna Jodice, Giovanni Bertalot, Giuseppina Bonizzi, Maria Capra, Fausto Antonio Maffini, Marta Tagliabue, Mohssen Ansarin, Michela Lupia, Marco Giordano, Daniela Osti, Giuliana Pelicci, Susanna Chiocca and Tiziana Bonaldi
Cancers 2019, 11(5), 723; https://doi.org/10.3390/cancers11050723 - 24 May 2019
Cited by 20 | Viewed by 5407
Abstract
Aberrations in histone post-translational modifications (PTMs), as well as in the histone modifying enzymes (HMEs) that catalyze their deposition and removal, have been reported in many tumors and many epigenetic inhibitors are currently under investigation for cancer treatment. Therefore, profiling epigenetic features in [...] Read more.
Aberrations in histone post-translational modifications (PTMs), as well as in the histone modifying enzymes (HMEs) that catalyze their deposition and removal, have been reported in many tumors and many epigenetic inhibitors are currently under investigation for cancer treatment. Therefore, profiling epigenetic features in cancer could have important implications for the discovery of both biomarkers for patient stratification and novel epigenetic targets. In this study, we employed mass spectrometry-based approaches to comprehensively profile histone H3 PTMs in a panel of normal and tumoral tissues for different cancer types, identifying various changes, some of which appear to be a consequence of the increased proliferation rate of tumors, while others are cell-cycle independent. Histone PTM changes found in tumors partially correlate with alterations of the gene expression profiles of HMEs obtained from publicly available data and are generally lost in culture conditions. Through this analysis, we identified tumor- and subtype-specific histone PTM changes, but also widespread changes in the levels of histone H3 K9me3 and K14ac marks. In particular, H3K14ac showed a cell-cycle independent decrease in all the seven tumor/tumor subtype models tested and could represent a novel epigenetic hallmark of cancer. Full article
(This article belongs to the Collection Histone Modification in Cancer)
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18 pages, 8559 KiB  
Article
POLQ Overexpression Is Associated with an Increased Somatic Mutation Load and PLK4 Overexpression in Lung Adenocarcinoma
by Kazuya Shinmura, Hisami Kato, Yuichi Kawanishi, Katsuhiro Yoshimura, Kazuo Tsuchiya, Yoshiyuki Takahara, Seiji Hosokawa, Akikazu Kawase, Kazuhito Funai and Haruhiko Sugimura
Cancers 2019, 11(5), 722; https://doi.org/10.3390/cancers11050722 - 24 May 2019
Cited by 21 | Viewed by 5442
Abstract
DNA Polymerase Theta (POLQ) is a DNA polymerase involved in error-prone translesion DNA synthesis (TLS) and error-prone repair of DNA double-strand breaks (DSBs). In the present study, we examined whether abnormal POLQ expression may be involved in the pathogenesis of lung adenocarcinoma (LAC). [...] Read more.
DNA Polymerase Theta (POLQ) is a DNA polymerase involved in error-prone translesion DNA synthesis (TLS) and error-prone repair of DNA double-strand breaks (DSBs). In the present study, we examined whether abnormal POLQ expression may be involved in the pathogenesis of lung adenocarcinoma (LAC). First, we found overexpression of POLQ at both the mRNA and protein levels in LAC, using data from the Cancer Genome Atlas (TCGA) database and by immunohistochemical analysis of our LAC series. POLQ overexpression was associated with an advanced pathologic stage and an increased total number of somatic mutations in LAC. When H1299 human lung cancer cell clones overexpressing POLQ were established and examined, the clones showed resistance to a DSB-inducing chemical in the clonogenic assay and an increased frequency of mutations in the supF forward mutation assay. Further analysis revealed that POLQ overexpression was also positively correlated with Polo Like Kinase 4 (PLK4) overexpression in LAC, and that PLK4 overexpression in the POLQ-overexpressing H1299 cells induced centrosome amplification. Finally, analysis of the TCGA data revealed that POLQ overexpression was associated with an increased somatic mutation load and PLK4 overexpression in diverse human cancers; on the other hand, overexpressions of nine TLS polymerases other than POLQ were associated with an increased somatic mutation load at a much lower frequency. Thus, POLQ overexpression is associated with advanced pathologic stage, increased somatic mutation load, and PLK4 overexpression, the last inducing centrosome amplification, in LAC, suggesting that POLQ overexpression is involved in the pathogenesis of LAC. Full article
(This article belongs to the Special Issue Molecular Profiling of Lung Cancer)
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17 pages, 446 KiB  
Review
Integrins, CAFs and Mechanical Forces in the Progression of Cancer
by Imjoo Jang and Karen A. Beningo
Cancers 2019, 11(5), 721; https://doi.org/10.3390/cancers11050721 - 24 May 2019
Cited by 118 | Viewed by 12254
Abstract
Cells respond to both chemical and mechanical cues present within their microenvironment. Various mechanical signals are detected by and transmitted to the cells through mechanoreceptors. These receptors often contact with the extracellular matrix (ECM), where the external signals are converted into a physiological [...] Read more.
Cells respond to both chemical and mechanical cues present within their microenvironment. Various mechanical signals are detected by and transmitted to the cells through mechanoreceptors. These receptors often contact with the extracellular matrix (ECM), where the external signals are converted into a physiological response. Integrins are well-defined mechanoreceptors that physically connect the actomyosin cytoskeleton to the surrounding matrix and transduce signals. Families of α and β subunits can form a variety of heterodimers that have been implicated in cancer progression and differ among types of cancer. These heterodimers serve as the nexus of communication between the cells and the tumor microenvironment (TME). The TME is dynamic and composed of stromal cells, ECM and associated soluble factors. The most abundant stromal cells within the TME are cancer-associated fibroblasts (CAFs). Accumulating studies implicate CAFs in cancer development and metastasis through their remodeling of the ECM and release of large amounts of ECM proteins and soluble factors. Considering that the communication between cancer cells and CAFs, in large part, takes place through the ECM, the involvement of integrins in the crosstalk is significant. This review discusses the role of integrins, as the primary cell-ECM mechanoreceptors, in cancer progression, highlighting integrin-mediated mechanical communication between cancer cells and CAFs. Full article
(This article belongs to the Special Issue The Role of Integrins in Cancer)
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22 pages, 5428 KiB  
Article
Tumor Mesenchymal Stromal Cells Regulate Cell Migration of Atypical Teratoid Rhabdoid Tumor through Exosome-Mediated miR155/SMARCA4 Pathway
by Yi-Ping Yang, Phan Nguyen Nhi Nguyen, Hsin-I Ma, Wen-Jin Ho, Yi-Wei Chen, Yueh Chien, Aliaksandr A. Yarmishyn, Pin-I Huang, Wen-Liang Lo, Chien-Ying Wang, Yung-Yang Liu, Yi-Yen Lee, Chien-Min Lin, Ming-Teh Chen and Mong-Lien Wang
Cancers 2019, 11(5), 720; https://doi.org/10.3390/cancers11050720 - 24 May 2019
Cited by 22 | Viewed by 4531
Abstract
Atypical teratoid/rhabdoid tumor (ATRT) is a rare pediatric brain tumor with extremely high aggressiveness and poor prognosis. The tumor microenvironment is regulated by a complex interaction among distinct cell types, yet the crosstalk between tumor-associated mesenchymal stem cells (tMSCs) and naïve ATRT cells [...] Read more.
Atypical teratoid/rhabdoid tumor (ATRT) is a rare pediatric brain tumor with extremely high aggressiveness and poor prognosis. The tumor microenvironment is regulated by a complex interaction among distinct cell types, yet the crosstalk between tumor-associated mesenchymal stem cells (tMSCs) and naïve ATRT cells are unclear. In this study, we sought to identify the secretory factor(s) that is responsible for the tMSC-mediated regulation of ATRT migration. Comparing with ATRT cell alone, co-culture of tMSCs or addition of its conditioned medium (tMSC-CM) promoted the migration of ATRT, and this effect could be abrogated by exosome release inhibitor GW4869. The exosomes in tMSC-CM were detected by transmission electron microscope and flow cytometry. ATRT naïve cell-derived conditioned media (ATRT-CM) also enhanced the exosome secretion from tMSCs, indicating the interplay between ATRT cells and tMSCs. Microarray analysis revealed that, compared with that in bone marrow-derived MSCs, microRNA155 is the most upregulated microRNA in the tMSC-CM. Tracing the PK67-labeled exosomes secreted from tMSCs confirmed their incorporation into naïve ATRT cells. After entering ATRT cells, miR155 promoted ATRT cell migration by directly targeting SMARCA4. Knockdown of SMARCA4 mimicked the miR155-driven ATRT cell migration, whereas SMARCA4 overexpression or the delivery of exosomes with miR155 knockdown suppressed the migration. Furthermore, abrogation of exosome release with GW4869 reduced the tumorigenesis of the xenograft containing naïve ATRT cells and tMSCs in immunocompromised recipients. In conclusion, our data have demonstrated that tMSCs secreted miR155-enriched exosomes, and the exosome incorporation and miR155 delivery further promoted migration in ATRT cells via a SMARCA4-dependent mechanism. Full article
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12 pages, 2784 KiB  
Article
Changes in Ultraviolet Radiation Exposure to the Ocular Region: A Population-Based Study
by Ezekiel Weis, Sebastian Q. Vrouwe, David B. LeBaron, Matthew B. Parliament, Jerry Shields and Carol L. Shields
Cancers 2019, 11(5), 719; https://doi.org/10.3390/cancers11050719 - 24 May 2019
Cited by 7 | Viewed by 3501
Abstract
In contrast to the well-established association between ultraviolet radiation (UVR) exposure and skin cancers, the relationship between UVR and uveal malignant melanoma (UM) remains controversial. To address this controversy, we evaluated the incidence rates of cutaneous malignancies in the eyelids as a proxy [...] Read more.
In contrast to the well-established association between ultraviolet radiation (UVR) exposure and skin cancers, the relationship between UVR and uveal malignant melanoma (UM) remains controversial. To address this controversy, we evaluated the incidence rates of cutaneous malignancies in the eyelids as a proxy for UVR exposure in the ocular region using a population-based cancer registry. Overall, 74,053 cases of eyelid basal cell carcinoma (BCC) and 7890 cases of melanoma over a 26-year period (1982–2007) were analyzed. The incidence of eyelid basal cell carcinoma and uveal melanoma remained stable, whereas other cutaneous areas demonstrated an increase in the rates. A comparability test demonstrated that BCC incidence trends were significantly different between the eyelid versus both chronically exposed (males p = 0.001; females p = 0.01) and intermittently exposed skin (males and females, p = 0.0002), as well as the skin of the face (males p = 0.002; females p = 0.02). Similarly, melanoma trends were significantly different between the UM group versus both chronically exposed cutaneous melanoma (CM) (males p = 0.001; females p = 0.04) and intermittently exposed CM (males p = 0.005), as well as facial skin CM (males and females p = 0.0002). The discrepancy of cancer incidence between tumors in the peri-ocular region versus the rest of the body suggests that the peri-ocular region might have a different or unique exposure pattern to ultraviolet radiation. Full article
(This article belongs to the Special Issue Uveal Melanoma)
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16 pages, 1893 KiB  
Article
ROR1 Potentiates FGFR Signaling in Basal-Like Breast Cancer
by Gaurav Pandey, Nicholas Borcherding, Ryan Kolb, Paige Kluz, Wei Li, Sonia Sugg, Jun Zhang, Dazhi A. Lai and Weizhou Zhang
Cancers 2019, 11(5), 718; https://doi.org/10.3390/cancers11050718 - 24 May 2019
Cited by 11 | Viewed by 5603 | Correction
Abstract
Among all breast cancer types, basal-like breast cancer (BLBC) represents an aggressive subtype that lacks targeted therapy. We and others have found that receptor tyrosine kinase-like orphan receptor 1 (ROR1) is overexpressed in BLBC and other types of cancer and that ROR1 is [...] Read more.
Among all breast cancer types, basal-like breast cancer (BLBC) represents an aggressive subtype that lacks targeted therapy. We and others have found that receptor tyrosine kinase-like orphan receptor 1 (ROR1) is overexpressed in BLBC and other types of cancer and that ROR1 is significantly correlated with patient prognosis. In addition, using primary patient-derived xenografts (PDXs) and ROR1-knockout BLBC cells, we found that ROR1+ cells form tumors in immunodeficient mice. We developed an anti-ROR1 immunotoxin and found that targeting ROR1 significantly kills ROR1+ cancer cells and slows down tumor growth in ROR1+ xenografts. Our bioinformatics analysis revealed that ROR1 expression is commonly associated with the activation of FGFR-mediated signaling pathway. Further biochemical analysis confirmed that ROR1 stabilized FGFR expression at the posttranslational level by preventing its degradation. CRISPR/Cas9-mediated ROR1 knockout significantly reduced cancer cell invasion at cellular levels by lowering FGFR protein and consequent inactivation of AKT. Our results identified a novel signaling regulation from ROR1 to FGFR and further confirm that ROR1 is a potential therapeutic target for ROR1+ BLBC cells. Full article
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15 pages, 989 KiB  
Article
A Multidisciplinary Team Guided Approach to the Management of cT3 Laryngeal Cancer: A Retrospective Analysis of 104 Cases
by Filippo Marchi, Marta Filauro, Francesco Missale, Giampiero Parrinello, Fabiola Incandela, Almalina Bacigalupo, Stefania Vecchio, Cesare Piazza and Giorgio Peretti
Cancers 2019, 11(5), 717; https://doi.org/10.3390/cancers11050717 - 24 May 2019
Cited by 13 | Viewed by 4248
Abstract
The optimal treatment for T3 laryngeal carcinoma (LC) is still a matter of debate. Different therapeutic options are available: Transoral laser microsurgery (TLM), open partial horizontal laryngectomies (OPHLs), total laryngectomy (TL), and organ preservation protocols (radiation therapy (RT) or chemo-radiation (CRT)). This study [...] Read more.
The optimal treatment for T3 laryngeal carcinoma (LC) is still a matter of debate. Different therapeutic options are available: Transoral laser microsurgery (TLM), open partial horizontal laryngectomies (OPHLs), total laryngectomy (TL), and organ preservation protocols (radiation therapy (RT) or chemo-radiation (CRT)). This study aimed to retrospectively evaluate oncologic outcomes of 104 T3 LCs treated by surgery or non-surgical approaches from January 2011 to December 2016 at a single academic tertiary referral center. Each case was evaluated by a multidisciplinary team (MDT) devoted to the management of head and neck cancers. We divided the cohort into two subgroups: Group A, surgical treatment (TLM, OPHLs, TL) and Group B, non-surgical treatment (RT, CRT). For the entire cohort, two- and five-year overall survival (OS) rates were 83% and 56%, respectively. The two- and five-year disease-free survival (DFS) rates were 75% and 65%, and disease-specific survival rates were 93% and 70%, respectively. The N category was a significant independent prognosticator for OS (p = 0.02), whereas Group B was significantly and independently associated with DFS (HR 4.10, p = 0.006). Analyzing laryngo-esophageal dysfunction-free survival as an outcome, it was found that this was significantly lower in higher N categories (p = 0.04) and in cases that underwent non-surgical treatments (p = 0.002). Optimization of oncologic outcomes in T3 LCs may be obtained only by a comprehensive MDT approach, considering that different treatment options have heterogenous toxicity profiles and indications. Full article
(This article belongs to the Special Issue Emerging Concepts in Treatment of Laryngeal Cancer)
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21 pages, 4687 KiB  
Article
On the Impact of Chemo-Mechanically Induced Phenotypic Transitions in Gliomas
by Pietro Mascheroni, Juan Carlos López Alfonso, Maria Kalli, Triantafyllos Stylianopoulos, Michael Meyer-Hermann and Haralampos Hatzikirou
Cancers 2019, 11(5), 716; https://doi.org/10.3390/cancers11050716 - 24 May 2019
Cited by 9 | Viewed by 4345
Abstract
Tumor microenvironment is a critical player in glioma progression, and novel therapies for its targeting have been recently proposed. In particular, stress-alleviation strategies act on the tumor by reducing its stiffness, decreasing solid stresses and improving blood perfusion. However, these microenvironmental changes trigger [...] Read more.
Tumor microenvironment is a critical player in glioma progression, and novel therapies for its targeting have been recently proposed. In particular, stress-alleviation strategies act on the tumor by reducing its stiffness, decreasing solid stresses and improving blood perfusion. However, these microenvironmental changes trigger chemo–mechanically induced cellular phenotypic transitions whose impact on therapy outcomes is not completely understood. In this work we analyze the effects of mechanical compression on migration and proliferation of glioma cells. We derive a mathematical model of glioma progression focusing on cellular phenotypic plasticity. Our results reveal a trade-off between tumor infiltration and cellular content as a consequence of stress-alleviation approaches. We discuss how these novel findings increase the current understanding of glioma/microenvironment interactions and can contribute to new strategies for improved therapeutic outcomes. Full article
(This article belongs to the Collection Targeting Solid Tumors)
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13 pages, 5205 KiB  
Review
Integrin Regulation of CAF Differentiation and Function
by C. Michael DiPersio and Livingston Van De Water
Cancers 2019, 11(5), 715; https://doi.org/10.3390/cancers11050715 - 24 May 2019
Cited by 21 | Viewed by 5086
Abstract
Extensive remodeling of the extracellular matrix, together with paracrine communication between tumor cells and stromal cells, contribute to an “activated” tumor microenvironment that supports malignant growth and progression. These stromal cells include inflammatory cells, endothelial cells, and cancer-associated fibroblasts (CAFs). Integrins are expressed [...] Read more.
Extensive remodeling of the extracellular matrix, together with paracrine communication between tumor cells and stromal cells, contribute to an “activated” tumor microenvironment that supports malignant growth and progression. These stromal cells include inflammatory cells, endothelial cells, and cancer-associated fibroblasts (CAFs). Integrins are expressed on all tumor and stromal cell types where they regulate both cell adhesion and bidirectional signal transduction across the cell membrane. In this capacity, integrins control pro-tumorigenic cell autonomous functions such as growth and survival, as well as paracrine crosstalk between tumor cells and stromal cells. The myofibroblast-like properties of cancer-associated fibroblasts (CAFs), such as robust contractility and extracellular matrix (ECM) deposition, allow them to generate both chemical and mechanical signals that support invasive tumor growth. In this review, we discuss the roles of integrins in regulating the ability of CAFs to generate and respond to extracellular cues in the tumor microenvironment. Since functions of specific integrins in CAFs are only beginning to emerge, we take advantage of a more extensive literature on how integrins regulate wound myofibroblast differentiation and function, as some of these integrin functions are likely to extrapolate to CAFs within the tumor microenvironment. In addition, we discuss the roles that integrins play in controlling paracrine signals that emanate from epithelial/tumor cells to stimulate fibroblasts/CAFs. Full article
(This article belongs to the Special Issue The Role of Integrins in Cancer)
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17 pages, 674 KiB  
Review
Targeting the Interplay between Epithelial-to-Mesenchymal-Transition and the Immune System for Effective Immunotherapy
by Rama Soundararajan, Jared J. Fradette, Jessica M. Konen, Stacy Moulder, Xiang Zhang, Don L. Gibbons, Navin Varadarajan, Ignacio I. Wistuba, Debasish Tripathy, Chantale Bernatchez, Lauren A. Byers, Jeffrey T. Chang, Alejandro Contreras, Bora Lim, Edwin Roger Parra, Emily B. Roarty, Jing Wang, Fei Yang, Michelle Barton, Jeffrey M. Rosen and Sendurai A. Maniadd Show full author list remove Hide full author list
Cancers 2019, 11(5), 714; https://doi.org/10.3390/cancers11050714 - 24 May 2019
Cited by 86 | Viewed by 6987
Abstract
Over the last decade, both early diagnosis and targeted therapy have improved the survival rates of many cancer patients. Most recently, immunotherapy has revolutionized the treatment options for cancers such as melanoma. Unfortunately, a significant portion of cancers (including lung and breast cancers) [...] Read more.
Over the last decade, both early diagnosis and targeted therapy have improved the survival rates of many cancer patients. Most recently, immunotherapy has revolutionized the treatment options for cancers such as melanoma. Unfortunately, a significant portion of cancers (including lung and breast cancers) do not respond to immunotherapy, and many of them develop resistance to chemotherapy. Molecular characterization of non-responsive cancers suggest that an embryonic program known as epithelial-mesenchymal transition (EMT), which is mostly latent in adults, can be activated under selective pressures, rendering these cancers resistant to chemo- and immunotherapies. EMT can also drive tumor metastases, which in turn also suppress the cancer-fighting activity of cytotoxic T cells that traffic into the tumor, causing immunotherapy to fail. In this review, we compare and contrast immunotherapy treatment options of non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). We discuss why, despite breakthrough progress in immunotherapy, attaining predictable outcomes in the clinic is mostly an unsolved problem for these tumors. Although these two cancer types appear different based upon their tissues of origin and molecular classification, gene expression indicate that they possess many similarities. Patient tumors exhibit activation of EMT, and resulting stem cell properties in both these cancer types associate with metastasis and resistance to existing cancer therapies. In addition, the EMT transition in both these cancers plays a crucial role in immunosuppression, which exacerbates treatment resistance. To improve cancer-related survival we need to understand and circumvent, the mechanisms through which these tumors become therapy resistant. In this review, we discuss new information and complementary perspectives to inform combination treatment strategies to expand and improve the anti-tumor responses of currently available clinical immune checkpoint inhibitors. Full article
(This article belongs to the Special Issue Towards New Promising Discoveries for Lung Cancer Patients: A Selection of Papers from the First Joint Meeting on Lung Cancer of the FHU OncoAge (Nice, France) and the MD Anderson Cancer Center (Houston, TX, USA))
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11 pages, 1174 KiB  
Article
Potential Prognostic Role of 18F-FDG PET/CT in Invasive Epithelial Ovarian Cancer Relapse. A Preliminary Study
by Anna Myriam Perrone, Giulia Dondi, Giacomo Maria Lima, Paolo Castellucci, Marco Tesei, Sara Coluccelli, Giuseppe Gasparre, Anna Maria Porcelli, Cristina Nanni, Stefano Fanti and Pierandrea De Iaco
Cancers 2019, 11(5), 713; https://doi.org/10.3390/cancers11050713 - 23 May 2019
Cited by 11 | Viewed by 4068
Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, with relapse occurring in about 70% of advanced cases with poor prognosis. Fluorine-18-2-fluoro-2-deoxy-d-glucose PET/CT (18F-FDGPET/CT) is the most specific radiological imaging used to assess recurrence. Some intensity-based and volume-based PET parameters, [...] Read more.
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, with relapse occurring in about 70% of advanced cases with poor prognosis. Fluorine-18-2-fluoro-2-deoxy-d-glucose PET/CT (18F-FDGPET/CT) is the most specific radiological imaging used to assess recurrence. Some intensity-based and volume-based PET parameters, maximum standardized uptake values (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG), are indicated to have a correlation with treatment response. The aim of our study is to correlate these parameters with post relapse survival (PRS) and overall survival (OS) in Epithelial Ovarian Cancer (EOC) relapse. The study included 50 patients affected by EOC relapse who underwent 18F-FDGPET/CT before surgery. All imaging was reviewed and SUVmax, MTV and TLG were calculated and correlated to PRS and OS. PRS and OS were obtained from the first relapse and from the first diagnosis to the last follow up or death, respectively. SUVmax, MTV and TLG were tested in a univariate logistic regression analysis, only SUVmax demonstrated to be significantly associated to PRS and OS (p = 0.005 and p = 0.024 respectively). Multivariate analysis confirmed the results. We found a cut-off of SUVmax of 13 that defined worse or better survival (p = 0.003). In the first relapse of EOC, SUVmax is correlated to PRS and OS, and when SUVmax is greater than 13, it is an unfavorable prognostic factor. Full article
(This article belongs to the Special Issue Role of Medical Imaging in Cancers)
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13 pages, 2278 KiB  
Article
Huzhangoside A Suppresses Tumor Growth through Inhibition of Pyruvate Dehydrogenase Kinase Activity
by Choong-Hwan Kwak, Jung-Hee Lee, Eun-Yeong Kim, Chang Woo Han, Keuk-Jun Kim, Hanna Lee, MyoungLae Cho, Se Bok Jang, Cheorl-Ho Kim, Tae-Wook Chung and Ki-Tae Ha
Cancers 2019, 11(5), 712; https://doi.org/10.3390/cancers11050712 - 23 May 2019
Cited by 14 | Viewed by 4821
Abstract
Aerobic glycolysis is one of the important metabolic characteristics of many malignant tumors. Pyruvate dehydrogenase kinase (PDHK) plays a key role in aerobic glycolysis by phosphorylating the E1α subunit of pyruvate dehydrogenase (PDH). Hence, PDHK has been recognized as a molecular target for [...] Read more.
Aerobic glycolysis is one of the important metabolic characteristics of many malignant tumors. Pyruvate dehydrogenase kinase (PDHK) plays a key role in aerobic glycolysis by phosphorylating the E1α subunit of pyruvate dehydrogenase (PDH). Hence, PDHK has been recognized as a molecular target for cancer treatment. Here, we report that huzhangoside A (Hu.A), a triterpenoid glycoside compound isolated from several plants of the Anemone genus, acts as a novel PDHK inhibitor. Hu.A was found to decrease the cell viability of human breast cancer MDA-MB-231, hepatocellular carcinoma Hep3B, colon cancer HT-29, DLD-1, and murine lewis lung carcinoma LLC cell lines. The activity of PDHK1 was decreased by Hu.A in both in vitro assays and in vivo assays in DLD-1 cells. Hu.A significantly increased the oxygen consumption and decreased the secretory lactate levels in DLD-1 cells. In addition, Hu.A interacted with the ATP-binding pocket of PDHK1 without affecting the interaction of PDHK1 and pyruvate dehydrogenase complex (PDC) subunits. Furthermore, Hu.A significantly induced mitochondrial reactive oxygen species (ROS) and depolarized the mitochondrial membrane potential in DLD-1 cells. Consistently, when Hu.A was intraperitoneally injected into LLC allograft mice, the tumor growth was significantly decreased. In conclusion, Hu.A suppressed the growth of tumors in both in vitro and in vivo models via inhibition of PDHK activity. Full article
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19 pages, 10627 KiB  
Article
Novel Thienopyrimidine Derivative, RP-010, Induces β-Catenin Fragmentation and Is Efficacious against Prostate Cancer Cells
by Haneen Amawi, Noor Hussein, Sai H. S. Boddu, Chandrabose Karthikeyan, Frederick E. Williams, Charles R. Ashby, Jr., Dayanidhi Raman, Piyush Trivedi and Amit K. Tiwari
Cancers 2019, 11(5), 711; https://doi.org/10.3390/cancers11050711 - 23 May 2019
Cited by 17 | Viewed by 4582
Abstract
Thienopyrimidines containing a thiophene ring fused to pyrimidine are reported to have a wide-spectrum of anticancer efficacy in vitro. Here, we report for the first time that thieno[3,2-d]pyrimidine-based compounds, also known as the RP series, have efficacy in prostate cancer cells. [...] Read more.
Thienopyrimidines containing a thiophene ring fused to pyrimidine are reported to have a wide-spectrum of anticancer efficacy in vitro. Here, we report for the first time that thieno[3,2-d]pyrimidine-based compounds, also known as the RP series, have efficacy in prostate cancer cells. The compound RP-010 was efficacious against both PC-3 and DU145 prostate cancer (PC) cells (IC50 < 1 µM). The cytotoxicity of RP-010 was significantly lower in non-PC, CHO, and CRL-1459 cell lines. RP-010 (0.5, 1, 2, and 4 µM) arrested prostate cancer cells in G2 phase of the cell cycle, and induced mitotic catastrophe and apoptosis in both PC cell lines. Mechanistic studies suggested that RP-010 (1 and 2 µM) affected the wingless-type MMTV (Wnt)/β-catenin signaling pathway, in association with β-catenin fragmentation, while also downregulating important proteins in the pathway, including LRP-6, DVL3, and c-Myc. Interestingly, RP-010 (1 and 2 µM) induced nuclear translocation of the negative feedback proteins, Naked 1 and Naked 2, in the Wnt pathway. In addition, RP-010 (0.5, 1, 2 and 4 µM) significantly decreased the migration of PC cells in vitro. Finally, RP-010 did not produce significant toxic effects in zebrafish at concentrations of up to 6 µM. In conclusion, RP-010 may be an efficacious and relatively nontoxic anticancer compound for prostate cancer. Future mechanistic and in vivo efficacy studies are needed to optimize the hit compound RP-010 for lead optimization and clinical use. Full article
(This article belongs to the Special Issue Targeting Wnt Signaling in Cancer)
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14 pages, 1725 KiB  
Review
Detection Rate of 18F-Labeled PSMA PET/CT in Biochemical Recurrent Prostate Cancer: A Systematic Review and a Meta-Analysis
by Giorgio Treglia, Salvatore Annunziata, Daniele A. Pizzuto, Luca Giovanella, John O. Prior and Luca Ceriani
Cancers 2019, 11(5), 710; https://doi.org/10.3390/cancers11050710 - 23 May 2019
Cited by 81 | Viewed by 6440
Abstract
Background: The use of radiolabeled prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) for biochemical recurrent prostate cancer (BRPCa) is increasing worldwide. Recently, 18F-labeled PSMA agents have become available. We performed a systematic review and meta-analysis regarding the detection rate [...] Read more.
Background: The use of radiolabeled prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) for biochemical recurrent prostate cancer (BRPCa) is increasing worldwide. Recently, 18F-labeled PSMA agents have become available. We performed a systematic review and meta-analysis regarding the detection rate (DR) of 18F-labeled PSMA PET/CT in BRPCa to provide evidence-based data in this setting. Methods: A comprehensive literature search of PubMed/MEDLINE, EMBASE, and Cochrane Library databases through 23 April 2019 was performed. Pooled DR was calculated on a per-patient basis, with pooled proportion and 95% confidence interval (95% CI). Furthermore, pooled DR of 18F-PSMA PET/CT using different cut-off values of prostate-specific antigen (PSA) was obtained. Results: Six articles (645 patients) were included in the meta-analysis. The pooled DR of 18F-labeled PSMA PET/CT in BRPCa was 81% (95% CI: 71–88%). The pooled DR was 86% for PSA ≥ 0.5 ng/mL (95% CI: 78–93%) and 49% for PSA < 0.5 ng/mL (95% CI: 23–74%). Statistical heterogeneity was found. Conclusions: 18F-labeled PSMA PET/CT demonstrated a good DR in BRPCa. DR of 18F-labeled PSMA PET/CT is related to PSA values with significant lower DR in patients with PSA < 0.5 ng/mL. Prospective multicentric trials are needed to confirm these findings. Full article
(This article belongs to the Special Issue Role of Medical Imaging in Cancers)
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13 pages, 1229 KiB  
Article
Continued Weight Loss and Sarcopenia Predict Poor Outcomes in Locally Advanced Pancreatic Cancer Treated with Chemoradiation
by Patrick Naumann, Jonathan Eberlein, Benjamin Farnia, Thilo Hackert, Jürgen Debus and Stephanie E. Combs
Cancers 2019, 11(5), 709; https://doi.org/10.3390/cancers11050709 - 23 May 2019
Cited by 33 | Viewed by 4014
Abstract
Background: Surgical resection offers the best chance of survival in patients with pancreatic cancer, but those with locally advanced disease (LAPC) are usually not surgical candidates. This cohort often receives either neoadjuvant chemotherapy or chemoradiation (CRT), but unintended weight loss coupled with [...] Read more.
Background: Surgical resection offers the best chance of survival in patients with pancreatic cancer, but those with locally advanced disease (LAPC) are usually not surgical candidates. This cohort often receives either neoadjuvant chemotherapy or chemoradiation (CRT), but unintended weight loss coupled with muscle wasting (sarcopenia) can often be observed. Here, we report on the predictive value of changes in weight and muscle mass in 147 consecutive patients with LAPC treated with neoadjuvant CRT. Methods: Clinicopathologic data were obtained via a retrospective chart review. The abdominal skeletal muscle area (SMA) at the third lumbar vertebral body was determined via computer tomographic (CT) scans as a surrogate for the muscle mass and skeletal muscle index (SMI) calculated. Uni- and multi-variable statistical tests were performed to assess for impact on survival. Results: Weight loss (14.5 vs. 20.3 months; p = 0.04) and loss of muscle mass (15.1 vs. 22.2 months; p = 0.007) were associated with poor outcomes. The highest survival was observed in patients who had neither cachectic weight loss nor sarcopenia (27 months), with improved survival seen in those who ultimately received a resection (23 vs. 10 months; p < 0.001). Cox regression revealed that either continued weight loss or continued muscle wasting (SMA reduction) was predictive of poor outcomes, whereas a sarcopenic SMI was not. Conclusions: Loss of weight and lean muscle in patients with LAPC is prognostic when persistent. Therefore, both should be assessed longitudinally and considered before surgery. Full article
(This article belongs to the Special Issue Advances in Pancreatic Cancer Research)
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14 pages, 3714 KiB  
Article
Down-Regulation of Cannabinoid Type 1 (CB1) Receptor and its Downstream Signaling Pathways in Metastatic Colorectal Cancer
by Valeria Tutino, Maria Gabriella Caruso, Valentina De Nunzio, Dionigi Lorusso, Nicola Veronese, Isabella Gigante, Maria Notarnicola and Gianluigi Giannelli
Cancers 2019, 11(5), 708; https://doi.org/10.3390/cancers11050708 - 22 May 2019
Cited by 20 | Viewed by 4519
Abstract
Changes in the regulation of endocannabinoid production, together with an altered expression of their receptors are hallmarks of cancer, including colorectal cancer (CRC). Although several studies have been conducted to understand the biological role of the CB1 receptor in cancer, little is known [...] Read more.
Changes in the regulation of endocannabinoid production, together with an altered expression of their receptors are hallmarks of cancer, including colorectal cancer (CRC). Although several studies have been conducted to understand the biological role of the CB1 receptor in cancer, little is known about its involvement in the metastatic process of CRC. The aim of this study was to investigate the possible link between CB1 receptor expression and the presence of metastasis in patients with CRC, investigating the main signaling pathways elicited downstream of CB1 receptor in colon cancer. Fifty-nine consecutive patients, with histologically proven colorectal cancer, were enrolled in the study, of which 30 patients with synchronous metastasis, at first diagnosis and 29 without metastasis. A low expression of CB1 receptor were detected in primary tumor tissue of CRC patients with metastasis and consequently, we observed an alteration of CB1 receptor downstream signaling. These signaling routes were also altered in intestinal normal mucosa, suggesting that, normal mucosa surrounding the tumor provides a realistic picture of the molecules involved in tissue malignant transformation. These observations contribute to the idea that drugs able to induce CB1 receptor expression can be helpful in order to set new anticancer therapeutic strategies. Full article
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12 pages, 417 KiB  
Article
NF1 Patients Receiving Breast Cancer Screening: Insights from The Ontario High Risk Breast Screening Program
by Nika Maani, Shelley Westergard, Joanna Yang, Anabel M. Scaranelo, Stephanie Telesca, Emily Thain, Nathan F. Schachter, Jeanna M. McCuaig and Raymond H. Kim
Cancers 2019, 11(5), 707; https://doi.org/10.3390/cancers11050707 - 22 May 2019
Cited by 19 | Viewed by 5350
Abstract
Neurofibromatosis Type I (NF1) is caused by variants in neurofibromin (NF1). NF1 predisposes to a variety of benign and malignant tumor types, including breast cancer. Women with NF1 <50 years of age possess an up to five-fold increased risk of developing [...] Read more.
Neurofibromatosis Type I (NF1) is caused by variants in neurofibromin (NF1). NF1 predisposes to a variety of benign and malignant tumor types, including breast cancer. Women with NF1 <50 years of age possess an up to five-fold increased risk of developing breast cancer compared with the general population. Impaired emotional functioning is reported as a comorbidity that may influence the participation of NF1 patients in regular clinical surveillance despite their increased risk of breast and other cancers. Despite emphasis on breast cancer surveillance in women with NF1, the uptake and feasibility of high-risk screening programs in this population remains unclear. A retrospective chart review between 2014–2018 of female NF1 patients seen at the Elizabeth Raab Neurofibromatosis Clinic (ERNC) in Ontario was conducted to examine the uptake of high-risk breast cancer screening, radiologic findings, and breast cancer characteristics. 61 women with pathogenic variants in NF1 enrolled in the high-risk Ontario breast screening program (HR-OBSP); 95% completed at least one high-risk breast screening modality, and four were diagnosed with invasive breast cancer. Our findings support the integration of a formal breast screening programs in clinical management of NF1 patients. Full article
(This article belongs to the Special Issue New Insights into Neurofibromatosis)
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