Cancers

18 pages, 3844 KiB

Open AccessArticle

High-Fat Diet-Induced Obese Effects of Adipocyte-Specific CXCR2 Conditional Knockout in the Peritoneal Tumor Microenvironment of Ovarian Cancer

by Deokyeong Choe, Eun-Sook Lee, Alicia Beeghly-Fadiel, Andrew J. Wilson, Margaret M. Whalen, Samuel E. Adunyah and Deok-Soo Son

Cancers 2021, 13(19), 5033; https://doi.org/10.3390/cancers13195033 - 8 Oct 2021

Cited by 5 | Viewed by 2943

Abstract

Obesity contributes to ovarian cancer (OC) progression via tumorigenic chemokines. Adipocytes and OC cells highly express CXCR2, and its ligands CXCL1/8, respectively, indicating that the CXCL1/8-CXCR2 axis is a molecular link between obesity and OC. Here, we investigated how the adipocyte-specific CXCR2 conditional [...] Read more.

Obesity contributes to ovarian cancer (OC) progression via tumorigenic chemokines. Adipocytes and OC cells highly express CXCR2, and its ligands CXCL1/8, respectively, indicating that the CXCL1/8-CXCR2 axis is a molecular link between obesity and OC. Here, we investigated how the adipocyte-specific CXCR2 conditional knockout (cKO) affected the peritoneal tumor microenvironment of OC in a high-fat diet (HFD)-induced obese mouse model. We first generated adipocyte-specific CXCR2 cKO in mice: adipose tissues were not different in crown-like structures and adipocyte size between the wild-type (WT) and cKO mice but expressed lower levels of CCL2/6 compared to the obese WT mice. HFD-induced obese mice had a shorter survival time than lean mice. Particularly, obese WT and cKO mice developed higher tumors and ascites burdens, respectively. The ascites from the obese cKO mice showed increased vacuole clumps but decreased the floating tumor burden, tumor-attached macrophages, triglyceride, free fatty acid, CCL2, and TNF levels compared to obese WT mice. A tumor analysis revealed that obese cKO mice attenuated inflammatory areas, PCNA, and F4/80 compared to obese WT mice, indicating a reduced tumor burden, and there were positive relationships between the ascites and tumor parameters. Taken together, the adipocyte-specific CXCR2 cKO was associated with obesity-induced ascites despite a reduced tumor burden, likely altering the peritoneal tumor microenvironment of OC. Full article

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18 pages, 2257 KiB

Open AccessFeature PaperReview

The Cellular Prion Protein and the Hallmarks of Cancer

by Sophie Mouillet-Richard, Alexandre Ghazi and Pierre Laurent-Puig

Cancers 2021, 13(19), 5032; https://doi.org/10.3390/cancers13195032 - 8 Oct 2021

Cited by 14 | Viewed by 3473

Abstract

Beyond its causal involvement in a group of neurodegenerative diseases known as Transmissible Spongiform Encephalopathies, the cellular prion protein PrP^C is now taking centre stage as an important contributor to cancer progression in various types of solid tumours. The prion cancer research [...] Read more.

Beyond its causal involvement in a group of neurodegenerative diseases known as Transmissible Spongiform Encephalopathies, the cellular prion protein PrP^C is now taking centre stage as an important contributor to cancer progression in various types of solid tumours. The prion cancer research field has progressively expanded in the last few years and has yielded consistent evidence for an involvement of PrP^C in cancer cell proliferation, migration and invasion, therapeutic resistance and cancer stem cell properties. Most recent data have uncovered new facets of the biology of PrP^C in cancer, ranging from its control on enzymes involved in immune tolerance to its radio-protective activity, by way of promoting angiogenesis. In the present review, we aim to summarise the body of literature dedicated to the study of PrP^C in relation to cancer from the perspective of the hallmarks of cancer, the reference framework defined by Hanahan and Weinberg. Full article

(This article belongs to the Special Issue Feature Paper from Journal Reviewers)

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14 pages, 1264 KiB

Open AccessArticle

Optimization of SPIO Injection for Sentinel Lymph Node Dissection in a Rat Model

by Mirjam C. L. Peek, Kohei Saeki, Kaichi Ohashi, Shinichi Chikaki, Rose Baker, Takayuki Nakagawa, Moriaki Kusakabe, Michael Douek and Masaki Sekino

Cancers 2021, 13(19), 5031; https://doi.org/10.3390/cancers13195031 - 8 Oct 2021

Cited by 7 | Viewed by 2160

Abstract

The magnetic technique, consisting of a magnetic tracer and a handheld magnetometer, is a promising alternative technique for sentinel lymph node dissection (SLND) and was shown to be non-inferior to the standard technique in terms of identification rates. In this study, injection characteristics [...] Read more.

The magnetic technique, consisting of a magnetic tracer and a handheld magnetometer, is a promising alternative technique for sentinel lymph node dissection (SLND) and was shown to be non-inferior to the standard technique in terms of identification rates. In this study, injection characteristics (iron dose, dilution, time course and massaging) were evaluated to optimize magnetic tracer uptake in the sentinel lymph nodes (SLN) in a rat hindleg model. 202 successful SLNDs were performed. Iron uptake in the SLN is proportional (10% utilization rate) to the injection dose between 20 and 200 μg, showing a plateau uptake of 80 μg in the SLN around 1000 μg injection. Linear regression showed that time had a higher impact than dilution, on the SLN iron uptake. Massaging showed no significant change in iron uptake. The amount of residual iron at the injection site was also proportional to the injection dose without any plateau. Time was a significant factor for wash-out of residual iron. From these results, preoperative injection may be advantageous for SLN detection as well as reduction in residual iron at the injection site by potential decrease in required injection dose. Full article

(This article belongs to the Special Issue Prospects from Diagnosis to Treatment in Cancer Using Magnetic Methods)

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14 pages, 6324 KiB

Open AccessArticle

Methylation Drivers and Prognostic Implications in Sinonasal Poorly Differentiated Carcinomas

by Laura Libera, Giorgia Ottini, Nora Sahnane, Fabiana Pettenon, Mario Turri-Zanoni, Alessia Lambertoni, Anna Maria Chiaravalli, Federico Leone, Paolo Battaglia, Paolo Castelnuovo, Silvia Uccella, Daniela Furlan, Carla Facco and Fausto Sessa

Cancers 2021, 13(19), 5030; https://doi.org/10.3390/cancers13195030 - 8 Oct 2021

Cited by 16 | Viewed by 2465

Abstract

Background: Poorly differentiated sinonasal carcinomas (PDSNCs) are rare and aggressive malignancies, which include squamous cell carcinoma (SCC), sinonasal undifferentiated carcinoma (SNUC), and neuroendocrine carcinomas (NEC). Several epigenetic markers have been suggested to support the histopathological classification, predict prognosis, and guide therapeutic decision. Indeed, [...] Read more.

Background: Poorly differentiated sinonasal carcinomas (PDSNCs) are rare and aggressive malignancies, which include squamous cell carcinoma (SCC), sinonasal undifferentiated carcinoma (SNUC), and neuroendocrine carcinomas (NEC). Several epigenetic markers have been suggested to support the histopathological classification, predict prognosis, and guide therapeutic decision. Indeed, molecularly distinct subtypes of sinonasal carcinomas, including SMARCB1-INI1 or SMARCA4 deficient sinonasal carcinoma, isocitrate dehydrogenase (IDH)-mutant SNUC, ARID1A mutant PDSNCs, and NUT carcinomas, have recently been proposed as separate entities. Identification of aberrant DNA methylation levels associated with these specific epigenetic driver genes could be useful for prognostic and therapeutic purpose. Methods: Histopathological review and immunohistochemical study was performed on 53 PDSNCs. Molecular analysis included mutational profile by NGS, Sanger sequencing, and MLPA analyses, and global DNA methylation profile using LINE-1 bisulfite-PCR and pyrosequencing analysis. Results: Nine SWI/SNF complex defective cases and five IDH2 p.Arg172x cases were identified. A significant correlation between INI-1 or IDH2 defects and LINE-1 hypermethylation was observed (p = 0.002 and p = 0.032, respectively), which were associated with a worse prognosis (p = 0.007). Conclusions: Genetic and epigenetic characterization of PDSNCs should be performed to identify distinct prognostic entities, which deserved a tailored clinical treatment. Full article

(This article belongs to the Special Issue Sinonasal Cancer: Improving Classification, Stratification and Therapeutic Options)

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15 pages, 3806 KiB

Open AccessArticle

Effect of Peptide Receptor Radionuclide Therapy in Combination with Temozolomide against Tumor Angiogenesis in a Glioblastoma Model

by Sang Hee Lee, Ji Young Choi, Jae Ho Jung, In Ho Song, Hyun Soo Park, Nunzio Denora, Francesco Leonetti, Sang Eun Kim and Byung Chul Lee

Cancers 2021, 13(19), 5029; https://doi.org/10.3390/cancers13195029 - 8 Oct 2021

Cited by 1 | Viewed by 1926

Abstract

Cell adhesion receptor integrin α_vβ₃ is a promising biomarker for developing tumor-angiogenesis targeted theranostics. In this study, we aimed to examine the therapeutic potential of peptide receptor radionuclide therapy (PRRT) with ¹⁸⁸Re-IDA-D-[c(RGDfK)]₂ (11.1 MBq). The results showed that [...] Read more.

Cell adhesion receptor integrin α_vβ₃ is a promising biomarker for developing tumor-angiogenesis targeted theranostics. In this study, we aimed to examine the therapeutic potential of peptide receptor radionuclide therapy (PRRT) with ¹⁸⁸Re-IDA-D-[c(RGDfK)]₂ (11.1 MBq). The results showed that the tumor volume was significantly decreased by 81% compared with the vehicle-treated group in U87-MG xenografts. The quantitative in vivo anti-angiogenic responses of PRRT were obtained using ^99mTc-IDA-D-[c(RGDfK)]₂ SPECT and corresponded to the measured tumor volume. PRRT combined with temozolomide (TMZ) resulted in a 93% reduction in tumor volume, which was markedly greater than that of each agent used individually. In addition, histopathological characterization showed that PRRT combined with TMZ was superior to PRRT or TMZ alone, even when TMZ was used at half dose. Overall, our results indicated that integrin-targeted PRRT and TMZ combined therapy might be a new medical tool for the effective treatment of glioblastoma. Full article

(This article belongs to the Special Issue Radiotherapy and Chemotherapy for Cancers)

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23 pages, 1616 KiB

Open AccessReview

Pancreatic Cancer Microenvironment and Cellular Composition: Current Understandings and Therapeutic Approaches

by Linh-Huyen Truong and Siim Pauklin

Cancers 2021, 13(19), 5028; https://doi.org/10.3390/cancers13195028 - 8 Oct 2021

Cited by 47 | Viewed by 8885

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human solid tumors, despite great efforts in improving therapeutics over the past few decades. In PDAC, the distinct characteristic of the tumor microenvironment (TME) is the main barrier for developing effective treatments. PDAC [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human solid tumors, despite great efforts in improving therapeutics over the past few decades. In PDAC, the distinct characteristic of the tumor microenvironment (TME) is the main barrier for developing effective treatments. PDAC TME is characterized by a dense stroma, cancer-associated fibroblasts, and immune cells populations that crosstalk to the subpopulations of neoplastic cells that include cancer stem cells (CSCs). The heterogeneity in TME is also exhibited in the diversity and dynamics of acellular components, including the Extracellular matrix (ECM), cytokines, growth factors, and secreted ligands to signaling pathways. These contribute to drug resistance, metastasis, and relapse in PDAC. However, clinical trials targeting TME components have often reported unexpected results and still have not benefited patients. The failures in those trials and various efforts to understand the PDAC biology demonstrate the highly heterogeneous and multi-faceted TME compositions and the complexity of their interplay within TME. Hence, further functional and mechanistic insight is needed. In this review, we will present a current understanding of PDAC biology with a focus on the heterogeneity in TME and crosstalk among its components. We also discuss clinical challenges and the arising therapeutic opportunities in PDAC research. Full article

(This article belongs to the Special Issue Tumor Microenvironment of Pancreatic Cancer)

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22 pages, 30520 KiB

Open AccessArticle

Transcription Factor RBPJL Is Able to Repress Notch Target Gene Expression but Is Non-Responsive to Notch Activation

by Leiling Pan, Philipp Hoffmeister, Aleksandra Turkiewicz, N. N. Duyen Huynh, Andreas Große-Berkenbusch, Uwe Knippschild, J. Christof M. Gebhardt, Bernd Baumann, Tilman Borggrefe and Franz Oswald

Cancers 2021, 13(19), 5027; https://doi.org/10.3390/cancers13195027 - 8 Oct 2021

Cited by 6 | Viewed by 3736

Abstract

The Notch signaling pathway is an evolutionary conserved signal transduction cascade present in almost all tissues and is required for embryonic and postnatal development, as well as for stem cell maintenance, but it is also implicated in tumorigenesis including pancreatic cancer and leukemia. [...] Read more.

The Notch signaling pathway is an evolutionary conserved signal transduction cascade present in almost all tissues and is required for embryonic and postnatal development, as well as for stem cell maintenance, but it is also implicated in tumorigenesis including pancreatic cancer and leukemia. The transcription factor RBPJ forms a coactivator complex in the presence of a Notch signal, whereas it represses Notch target genes in the absence of a Notch stimulus. In the pancreas, a specific paralog of RBPJ, called RBPJL, is expressed and found as part of the heterotrimeric PTF1-complex. However, the function of RBPJL in Notch signaling remains elusive. Using molecular modeling, biochemical and functional assays, as well as single-molecule time-lapse imaging, we show that RBPJL and RBPJ, despite limited sequence homology, possess a high degree of structural similarity. RBPJL is specifically expressed in the exocrine pancreas, whereas it is mostly undetectable in pancreatic tumour cell lines. Importantly, RBPJL is not able to interact with Notch−1 to −4 and it does not support Notch-mediated transactivation. However, RBPJL can bind to canonical RBPJ DNA elements and shows migration dynamics comparable to that of RBPJ in the nuclei of living cells. Importantly, RBPJL is able to interact with SHARP/SPEN, the central corepressor of the Notch pathway. In line with this, RBPJL is able to fully reconstitute transcriptional repression at Notch target genes in cells lacking RBPJ. Together, RBPJL can act as an antagonist of RBPJ, which renders cells unresponsive to the activation of Notch. Full article

(This article belongs to the Section Molecular Cancer Biology)

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30 pages, 16667 KiB

Open AccessReview

Immune Therapies for Myelodysplastic Syndromes and Acute Myeloid Leukemia

by Sargam Kapoor, Grace Champion, Aparna Basu, Anu Mariampillai and Matthew J. Olnes

Cancers 2021, 13(19), 5026; https://doi.org/10.3390/cancers13195026 - 8 Oct 2021

Cited by 7 | Viewed by 3885

Abstract

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematologic malignancies arising from the bone marrow. Despite recent advances in treating these diseases, patients with higher-risk MDS and AML continue to have a poor prognosis with limited survival. It has long been recognized [...] Read more.

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematologic malignancies arising from the bone marrow. Despite recent advances in treating these diseases, patients with higher-risk MDS and AML continue to have a poor prognosis with limited survival. It has long been recognized that there is an immune component to the pathogenesis of MDS and AML, but until recently, immune therapies have played a limited role in treating these diseases. Immune suppressive therapy exhibits durable clinical responses in selected patients with MDS, but the question of which patients are most suitable for this treatment remains unclear. Over the past decade, there has been remarkable progress in identifying genomic features of MDS and AML, which has led to an improved discernment of the molecular pathogenesis of these diseases. An improved understanding of immune and inflammatory molecular mechanisms of MDS and AML have also recently revealed novel therapeutic targets. Emerging treatments for MDS and AML include monoclonal antibodies such as immune checkpoint inhibitors, bispecific T-cell-engaging antibodies, antibody drug conjugates, vaccine therapies, and cellular therapeutics including chimeric antigen receptor T-cells and NK cells. In this review, we provide an overview of the current understanding of immune dysregulation in MDS and AML and an update on novel immune therapies for these bone marrow malignancies. Full article

(This article belongs to the Special Issue Immune Therapies for Hematologic Malignancies)

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17 pages, 2002 KiB

Open AccessArticle

RBL1/p107 Expression Levels Are Modulated by Multiple Signaling Pathways

by Elisa Ventura, Carmelina Antonella Iannuzzi, Francesca Pentimalli, Antonio Giordano and Andrea Morrione

Cancers 2021, 13(19), 5025; https://doi.org/10.3390/cancers13195025 - 8 Oct 2021

Cited by 8 | Viewed by 3214

Abstract

The members of the retinoblastoma (RB) protein family, RB1/p105, retinoblastoma-like (RBL)1/p107 and RBL2/p130 are critical modulators of the cell cycle and their dysregulation has been associated with tumor initiation and progression. The activity of RB proteins is regulated by numerous pathways including oncogenic [...] Read more.

The members of the retinoblastoma (RB) protein family, RB1/p105, retinoblastoma-like (RBL)1/p107 and RBL2/p130 are critical modulators of the cell cycle and their dysregulation has been associated with tumor initiation and progression. The activity of RB proteins is regulated by numerous pathways including oncogenic signaling, but the molecular mechanisms of these functional interactions are not fully defined. We previously demonstrated that RBL2/p130 is a direct target of AKT and it is a key mediator of the apoptotic process induced by AKT inhibition. Here we demonstrated that RBL1/p107 levels are only minorly modulated by the AKT signaling pathway. In contrast, we discovered that RBL1/p107 levels are regulated by multiple pathways linked directly or indirectly to Ca²⁺-dependent signaling. Inhibition of the multifunctional calcium/calmodulin-dependent kinases (CaMKs) significantly reduced RBL1/p107 expression levels and phosphorylation, increased RBL1/p107 nuclear localization and led to cell cycle arrest in G0/G1. Targeting the Ca²⁺-dependent endopeptidase calpain stabilized RBL1/p107 levels and counteracted the reduction of RBL1/p107 levels associated with CaMKs inhibition. Thus, these novel observations suggest a complex regulation of RBL1/p107 expression involving different components of signaling pathways controlled by Ca²⁺ levels, including CaMKs and calpain, pointing out a significant difference with the mechanisms modulating the close family member RBL2/p130. Full article

(This article belongs to the Special Issue Multiple Roles of the RB Family of Tumor Suppressors and Implications for Cancer Therapy)

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18 pages, 6058 KiB

Open AccessArticle

RAS Mediates BET Inhibitor-Endued Repression of Lymphoma Migration and Prognosticates a Novel Proteomics-Based Subgroup of DLBCL through Its Negative Regulator IQGAP3

by Chih-Cheng Chen, Chia-Chen Hsu, Sung-Lin Chen, Po-Han Lin, Ju-Pei Chen, Yi-Ru Pan, Cih-En Huang, Ying-Ju Chen, Yi-Yang Chen, Yu-Ying Wu and Muh-Hwa Yang

Cancers 2021, 13(19), 5024; https://doi.org/10.3390/cancers13195024 - 7 Oct 2021

Cited by 5 | Viewed by 2812

Abstract

Phenotypic heterogeneity and molecular diversity make diffuse large B-cell lymphoma (DLBCL) a challenging disease. We recently illustrated that amoeboid movement plays an indispensable role in DLBCL dissemination and inadvertently identified that the inhibitor of bromodomain and extra-terminal (BET) proteins JQ1 could repress DLBCL [...] Read more.

Phenotypic heterogeneity and molecular diversity make diffuse large B-cell lymphoma (DLBCL) a challenging disease. We recently illustrated that amoeboid movement plays an indispensable role in DLBCL dissemination and inadvertently identified that the inhibitor of bromodomain and extra-terminal (BET) proteins JQ1 could repress DLBCL migration. To explore further, we dissected the impacts of BET inhibition in DLBCL. We found that JQ1 abrogated amoeboid movement of DLBCL cells through both restraining RAS signaling and suppressing MYC-mediated RhoA activity. We also demonstrated that BET inhibition resulted in the upregulation of a GTPase regulatory protein, the IQ motif containing GTPase activating protein 3 (IQGAP3). IQGAP3 similarly exhibited an inhibitory effect on RAS activity in DLBCL cells. Through barcoded mRNA/protein profiling in clinical samples, we identified a specific subgroup of DLBCL tumors with enhanced phosphatidylinositol-3-kinase (PI3K) activity, which led to an inferior survival in these patients. Strikingly, a lower IQGAP3 expression level further portended those with PI3K-activated DLBCL a very dismal outcome. The inhibition of BET and PI3K signaling activity led to effective suppression of DLBCL dissemination in vivo. Our study provides an important insight into the ongoing efforts of targeting BET proteins as a therapeutic approach for DLBCL. Full article

(This article belongs to the Special Issue Molecular Advances in Diffuse Large B-Cell Lymphoma)

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15 pages, 1034 KiB

Open AccessArticle

MET Amplification in Non-Small Cell Lung Cancer (NSCLC)—A Consecutive Evaluation Using Next-Generation Sequencing (NGS) in a Real-World Setting

by Christoph Schubart, Robert Stöhr, Lars Tögel, Florian Fuchs, Horia Sirbu, Gerhard Seitz, Ruth Seggewiss-Bernhardt, Rumo Leistner, William Sterlacci, Michael Vieth, Christoph Seidl, Michael Mugler, Markus Kapp, Wolfgang Hohenforst-Schmidt, Arndt Hartmann, Florian Haller and Ramona Erber

Cancers 2021, 13(19), 5023; https://doi.org/10.3390/cancers13195023 - 7 Oct 2021

Cited by 27 | Viewed by 4570

Abstract

In non-small cell lung cancer (NSCLC), approximately 1–3% of cases harbor an increased gene copy number (GCN) of the MET gene. This alteration can be due to de novo amplification of the MET gene or can represent a secondary resistance mechanism in response [...] Read more.

In non-small cell lung cancer (NSCLC), approximately 1–3% of cases harbor an increased gene copy number (GCN) of the MET gene. This alteration can be due to de novo amplification of the MET gene or can represent a secondary resistance mechanism in response to targeted therapies. To date, the gold standard method to evaluate the GCN of MET is fluorescence in situ hybridization (FISH). However, next-generation sequencing (NGS) is becoming more relevant to optimize therapy by revealing the mutational profile of each NSCLC. Using evaluable n = 205 NSCLC cases of a consecutive cohort, this study addressed the question of whether an amplicon based NGS assay can completely replace the FISH method regarding the classification of MET GCN status. Out of the 205 evaluable cases, only n = 9 cases (43.7%) of n = 16 high-level MET amplified cases assessed by FISH were classified as amplified by NGS. Cases harboring a MET GCN > 10 showed the best concordance when comparing FISH versus NGS (80%). This study confirms that an amplicon-based NGS assessment of the MET GCN detects high-level MET amplified cases harboring a MET GCN > 10 but fails to detect the various facets of MET gene amplification in the context of a therapy-induced resistance mechanism. Full article

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17 pages, 2144 KiB

Open AccessArticle

Aberrant Signaling Pathways in Sinonasal Intestinal-Type Adenocarcinoma

by Cristina Riobello, Paula Sánchez-Fernández, Virginia N. Cabal, Rocío García-Marín, Laura Suárez-Fernández, Blanca Vivanco, Verónica Blanco-Lorenzo, César Álvarez Marcos, Fernando López, José Luis Llorente and Mario A. Hermsen

Cancers 2021, 13(19), 5022; https://doi.org/10.3390/cancers13195022 - 7 Oct 2021

Cited by 9 | Viewed by 2829

Abstract

Sinonasal intestinal-type adenocarcinoma (ITAC) is strongly related to occupational exposure to wood and leather dust, however, little is known on the genetic alterations involved in tumor development and progression. The aim of this study was to identify tumorigenic signaling pathways affected by gene [...] Read more.

Sinonasal intestinal-type adenocarcinoma (ITAC) is strongly related to occupational exposure to wood and leather dust, however, little is known on the genetic alterations involved in tumor development and progression. The aim of this study was to identify tumorigenic signaling pathways affected by gene mutations and their relation to clinical features. We applied whole exome sequencing of 120 cancer-related genes in 50 ITACs and analyzed the signaling activity of four specific pathways frequently affected by mutations. Genes involved in DNA damage response showed somatic mutations in 30% of cases, including four tumors that also harbored germline mutations. Genes in Wnt, MAPK and PI3K pathways harbored mutations in 20%, 20% and 24% of cases, respectively. Mutations and copy number gains in receptor tyrosine kinases possibly affecting MAPK and PI3K pathways occurred in 44% of cases. Expression of key pathway proteins showed no correlation to mutations in these pathways, except for nuclear β-catenin and APC/CTNNB1 mutation. No specific gene mutation, mutated pathway, nor pathway activity level showed correlation to clinical data or survival. In addition, a similar mutational profile was observed among histological subtypes. The wide spectrum of gene mutations suggests that ITAC is a genetically heterogeneous without specific characterizing gene mutations. Full article

(This article belongs to the Special Issue Sinonasal Cancer: Improving Classification, Stratification and Therapeutic Options)

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14 pages, 28966 KiB

Open AccessArticle

ACKR4 in Tumor Cells Regulates Dendritic Cell Migration to Tumor-Draining Lymph Nodes and T-Cell Priming

by Dechen Wangmo, Prem K. Premsrirut, Ce Yuan, William S. Morris, Xianda Zhao and Subbaya Subramanian

Cancers 2021, 13(19), 5021; https://doi.org/10.3390/cancers13195021 - 7 Oct 2021

Cited by 15 | Viewed by 3606

Abstract

Colorectal cancer (CRC) is one of the most common malignancies in both morbidity and mortality. Immune checkpoint blockade (ICB) treatments have been successful in a portion of mismatch repair-deficient (dMMR) CRC patients but have failed in mismatch repair-proficient (pMMR) CRC patients. Atypical Chemokine [...] Read more.

Colorectal cancer (CRC) is one of the most common malignancies in both morbidity and mortality. Immune checkpoint blockade (ICB) treatments have been successful in a portion of mismatch repair-deficient (dMMR) CRC patients but have failed in mismatch repair-proficient (pMMR) CRC patients. Atypical Chemokine Receptor 4 (ACKR4) is implicated in regulating dendritic cell (DC) migration. However, the roles of ACKR4 in CRC development and anti-tumor immunoregulation are not known. By analyzing human CRC tissues, transgenic animals, and genetically modified CRC cells lines, our study revealed an important function of ACKR4 in maintaining CRC immune response. Loss of ACKR4 in CRC is associated with poor immune infiltration in the tumor microenvironment. More importantly, loss of ACKR4 in CRC tumor cells, rather than stromal cells, restrains the DC migration and antigen presentation to the tumor-draining lymph nodes (TdLNs). Moreover, tumors with ACKR4 knockdown become less sensitive to immune checkpoint blockade. Finally, we identified that microRNA miR-552 negatively regulates ACKR4 expression in human CRC. Taken together, our studies identified a novel and crucial mechanism for the maintenance of the DC-mediated T-cell priming in the TdLNs. These new findings demonstrate a novel mechanism leading to immunosuppression and ICB treatment resistance in CRC. Full article

(This article belongs to the Special Issue Cancer Immunology)

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18 pages, 42324 KiB

Open AccessArticle

TBX2 Drives Neuroendocrine Prostate Cancer through Exosome-Mediated Repression of miR-200c-3p

by Girijesh Kumar Patel, Sayanika Dutta, Mosharaf Mahmud Syed, Sabarish Ramachandran, Monica Sharma, Venkatesh Rajamanickam, Vadivel Ganapathy, David J. DeGraff, Kevin Pruitt, Manisha Tripathi and Srinivas Nandana

Cancers 2021, 13(19), 5020; https://doi.org/10.3390/cancers13195020 - 7 Oct 2021

Cited by 10 | Viewed by 3869

Abstract

Deciphering the mechanisms that drive transdifferentiation to neuroendocrine prostate cancer (NEPC) is crucial to identifying novel therapeutic strategies against this lethal and aggressive subtype of advanced prostate cancer (PCa). Further, the role played by exosomal microRNAs (miRs) in mediating signaling mechanisms that propagate [...] Read more.

Deciphering the mechanisms that drive transdifferentiation to neuroendocrine prostate cancer (NEPC) is crucial to identifying novel therapeutic strategies against this lethal and aggressive subtype of advanced prostate cancer (PCa). Further, the role played by exosomal microRNAs (miRs) in mediating signaling mechanisms that propagate the NEPC phenotype remains largely elusive. The unbiased differential miR expression profiling of human PCa cells genetically modulated for TBX2 expression led to the identification of miR-200c-3p. Our findings have unraveled the TBX2/miR-200c-3p/SOX2/N-MYC signaling axis in NEPC transdifferentiation. Mechanistically, we found that: (1) TBX2 binds to the promoter and represses the expression of miR-200c-3p, a miR reported to be lost in castrate resistant prostate cancer (CRPC), and (2) the repression of miR-200c-3p results in the increased expression of its targets SOX2 and N-MYC. In addition, the rescue of mir-200c-3p in the context of TBX2 blockade revealed that miR-200c-3p is the critical intermediary effector in TBX2 regulation of SOX2 and N-MYC. Further, our studies show that in addition to the intracellular mode, TBX2/miR-200c-3p/SOX2/N-MYC signaling can promote NEPC transdifferentiation via exosome-mediated intercellular mechanism, an increasingly recognized and key mode of propagation of the NEPC phenotype. Full article

(This article belongs to the Special Issue Stromal-Epithelial Interactions in Cancer Progression and Therapy Response)

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22 pages, 5040 KiB

Open AccessArticle

Targeting Ovarian Carcinoma with TSP-1:CD47 Antagonist TAX2 Activates Anti-Tumor Immunity

by Albin Jeanne, Thomas Sarazin, Magalie Charlé, Catherine Moali, Caroline Fichel, Camille Boulagnon-Rombi, Maïté Callewaert, Marie-Christine Andry, Eric Diesis, Frédéric Delolme, Damien Rioult and Stéphane Dedieu

Cancers 2021, 13(19), 5019; https://doi.org/10.3390/cancers13195019 - 7 Oct 2021

Cited by 21 | Viewed by 4622

Abstract

TAX2 peptide is a cyclic peptide that acts as an orthosteric antagonist for thrombospondin-1 (TSP-1) interaction with CD47. TAX2 was first described for its anti-angiogenic activities and showed anti-cancer efficacy in numerous preclinical models. Here, we aimed at providing an extensive molecular characterization [...] Read more.

TAX2 peptide is a cyclic peptide that acts as an orthosteric antagonist for thrombospondin-1 (TSP-1) interaction with CD47. TAX2 was first described for its anti-angiogenic activities and showed anti-cancer efficacy in numerous preclinical models. Here, we aimed at providing an extensive molecular characterization of TAX2 mode of action, while evaluating its potential in ovarian cancer therapy. Multidisciplinary approaches were used to qualify a TAX2 drug candidate in terms of stability, solubility and potency. Then, efficacy studies, together with benchmark experiments, were performed in relevant mouse models of ovarian carcinoma. TAX2 peptide appears to be stable and soluble in clinically relevant solvents, while displaying a favorable safety profile. Moreover, clinical data mining allowed for the identification of TSP-1 as a relevant pharmacological target in ovarian cancer. In mice, TAX2 therapy inhibits ovarian tumor growth and metastatic dissemination, while activating anti-cancer adaptive immunity. Interestingly, TAX2 also synergizes when administered in combination with anti-PD-1 immune checkpoint inhibitiors. Altogether, our data expose TAX2 as an optimized candidate with advanced preclinical characterization. Using relevant syngeneic ovarian carcinoma models, we highlighted TAX2’s ability to convert poorly immunogenic tumors into ones displaying effective anti-tumor T-cell immunity. Full article

(This article belongs to the Collection Matrix Effectors and Cancer)

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14 pages, 3926 KiB

Open AccessArticle

Immunonutritive Scoring for Patients with Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization: Evaluation of the CALLY Index

by Lukas Müller, Felix Hahn, Aline Mähringer-Kunz, Fabian Stoehr, Simon Johannes Gairing, Maurice Michel, Friedrich Foerster, Arndt Weinmann, Peter Robert Galle, Jens Mittler, Daniel Pinto dos Santos, Michael Bernhard Pitton, Christoph Düber and Roman Kloeckner

Cancers 2021, 13(19), 5018; https://doi.org/10.3390/cancers13195018 - 7 Oct 2021

Cited by 25 | Viewed by 2872

Abstract

The novel CRP–albumin–lymphocyte (CALLY) index is an improved immunonutritive scoring system, based on serum C-reactive protein (CRP), serum albumin, and the lymphocyte count. It has shown promise as a prognostic index for patients with hepatocellular carcinoma (HCC) undergoing resections. This study evaluated the [...] Read more.

The novel CRP–albumin–lymphocyte (CALLY) index is an improved immunonutritive scoring system, based on serum C-reactive protein (CRP), serum albumin, and the lymphocyte count. It has shown promise as a prognostic index for patients with hepatocellular carcinoma (HCC) undergoing resections. This study evaluated the prognostic ability of the CALLY index for patients with HCC undergoing transarterial chemoembolization (TACE). We retrospectively identified 280 treatment-naïve patients with HCC that underwent an initial TACE at our institution, between 2010 and 2020. We compared the CALLY index to established risk factors in univariate and multivariate regression analyses for associations with median overall survival (OS). A low CALLY score was associated with low median OS (low vs. high CALLY: 9.0 vs. 24.0 months, p < 0.001). In the multivariate analysis, the CALLY index remained an independent prognostic predictor (p = 0.008). Furthermore, all factors of the CALLY index reached significance in univariate and in-depth multivariate analyses. However, the concordance index (C-index) of the CALLY index (0.60) was similar to the C-indices of established immunonutritive and inflammation scoring systems (range: 0.54 to 0.63). In conclusion, the CALLY index showed promise as a stratification tool for patients with HCC undergoing TACE. Notably, the CALLY index was not superior to other immunonutritive and inflammation scoring systems in predicting the median OS. Thus, future studies should re-evaluate the mathematical calculation of the index, particularly the contributions of individual parameters. Full article

(This article belongs to the Special Issue Assessing and Influencing Prognosis in Hepatocellular Carcinoma)

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13 pages, 1512 KiB

Open AccessSystematic Review

Survival in Advanced-Stage Epithelial Ovarian Cancer Patients with Cardiophrenic Lymphadenopathy Who Underwent Cytoreductive Surgery: A Systematic Review and Meta-Analysis

by Malika Kengsakul, Gatske M. Nieuwenhuyzen-de Boer, Anna H. J. Bijleveld, Suwasin Udomkarnjananun, Stephen J. Kerr, Christa D. Niehot and Heleen J. van Beekhuizen

Cancers 2021, 13(19), 5017; https://doi.org/10.3390/cancers13195017 - 7 Oct 2021

Cited by 7 | Viewed by 2959

Abstract

Purpose: To evaluate the clinical outcomes of enlarged cardiophrenic lymph node (CPLN) in advanced-stage epithelial ovarian cancer (AEOC) patients who underwent cytoreductive surgery. Methods: The Embase, Medline, Web of Science, Cochrane Library, and Google Scholar databases were searched for articles from the database [...] Read more.

Purpose: To evaluate the clinical outcomes of enlarged cardiophrenic lymph node (CPLN) in advanced-stage epithelial ovarian cancer (AEOC) patients who underwent cytoreductive surgery. Methods: The Embase, Medline, Web of Science, Cochrane Library, and Google Scholar databases were searched for articles from the database inception to June 2021. Meta-analysis was conducted to determine the prognostic impact of surgical outcome, postoperative complication, and survival using random-effects models. Results: A total of 15 studies involving 727 patients with CPLN adenopathy and 981 patients without CPLN adenopathy were included. The mean size of preoperative CPLN was 9.1± 3.75 mm. Overall, 82 percent of the resected CPLN were histologically confirmed pathologic nodes. Surgical outcomes and perioperative complications did not differ between both groups. The median OS time was 42.7 months (95% CI 10.8–74.6) vs. 47.3 months (95% CI 23.2–71.2), in patients with and without CPLN adenopathy, respectively. At 5 years, patients with CPLN adenopathy had a significantly increased risk of disease recurrence (HR 2.14, 95% CI 1.82–2.52, p < 0.001) and dying from the disease (HR 1.74, 95% CI 1.06–2.86, p = 0.029), compared with those without CPLN adenopathy. CPLN adenopathy was significantly associated with ascites (OR 3.30, 95% CI 1.90–5.72, p < 0.001), pleural metastasis (OR 2.58, 95% CI 1.37–4.82, p = 0.003), abdominal adenopathy (OR 2.30, 95% CI 1.53–3.46, p < 0.001) and extra-abdominal metastasis (OR 2.30, 95% CI 1.61–6.67, p = 0.001). Conclusions: Enlarged CPLN in preoperative imaging is highly associated with metastatic involvement. Patients with CPLN adenopathy had a lower survival rate, compared with patients without CPLN adenopathy. Further randomized controlled trials should be conducted to definitively demonstrate whether CPLN resection at the time of cytoreductive surgery is beneficial. Full article

(This article belongs to the Special Issue Advances in Gynecological Oncology: From Pathogenesis to Therapy)

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12 pages, 1476 KiB

Open AccessArticle

Characteristics of Nephroblastoma/Nephroblastomatosis in Children with a Clinically Reported Underlying Malformation or Cancer Predisposition Syndrome

by Nils Welter, Angelo Wagner, Rhoikos Furtwängler, Patrick Melchior, Leo Kager, Christian Vokuhl, Jens-Peter Schenk, Clemens Magnus Meier, Stefan Siemer, Manfred Gessler and Norbert Graf

Cancers 2021, 13(19), 5016; https://doi.org/10.3390/cancers13195016 - 7 Oct 2021

Cited by 11 | Viewed by 3219 | Correction

Abstract

(1) Background: about 10% of Wilms Tumor (WT) patients have a malformation or cancer predisposition syndrome (CPS) with causative germline genetic or epigenetic variants. Knowledge on CPS is essential for genetic counselling. (2) Methods: this retrospective analysis focused on 2927 consecutive patients with [...] Read more.

(1) Background: about 10% of Wilms Tumor (WT) patients have a malformation or cancer predisposition syndrome (CPS) with causative germline genetic or epigenetic variants. Knowledge on CPS is essential for genetic counselling. (2) Methods: this retrospective analysis focused on 2927 consecutive patients with WTs registered between 1989 and 2017 in the SIOP/GPOH studies. (3) Results: Genitourinary malformations (GU, N = 66, 2.3%), Beckwith-Wiedemann spectrum (BWS, N = 32, 1.1%), isolated hemihypertrophy (IHH, N = 29, 1.0%), Denys-Drash syndrome (DDS, N = 24, 0.8%) and WAGR syndrome (N = 20, 0.7%) were reported most frequently. Compared to others, these patients were younger at WT diagnosis (median age 24.5 months vs. 39.0 months), had smaller tumors (349.4 mL vs. 487.5 mL), less often metastasis (8.2% vs. 18%), but more often nephroblastomatosis (12.9% vs. 1.9%). WT with IHH was associated with blastemal WT and DDS with stromal subtype. Bilateral WTs were common in WAGR (30%), DDS (29%) and BWS (31%). Chemotherapy induced reduction in tumor volume was poor in DDS (0.4% increase) and favorable in BWS (86.9% reduction). The event-free survival (EFS) of patients with BWS was significantly (p = 0.002) worse than in others. (4) Conclusions: CPS should be considered in WTs with specific clinical features resulting in referral to a geneticist. Their outcome was not always favorable. Full article

(This article belongs to the Special Issue Pediatric Cancers)

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Graphical abstract

19 pages, 1200 KiB

Open AccessSystematic Review

Patient-Reported Financial Distress in Cancer: A Systematic Review of Risk Factors in Universal Healthcare Systems

by Sophie Pauge, Bastian Surmann, Katja Mehlis, Andrea Zueger, Luise Richter, Natalja Menold, Wolfgang Greiner and Eva C. Winkler

Cancers 2021, 13(19), 5015; https://doi.org/10.3390/cancers13195015 - 7 Oct 2021

Cited by 21 | Viewed by 5289

Abstract

Financial toxicity is a side effect of cancer that results from the perceived financial distress an individual may experience in the course of the disease. The purpose of this paper is to analyse underlying factors related to subjective financial distress in high-income countries [...] Read more.

Financial toxicity is a side effect of cancer that results from the perceived financial distress an individual may experience in the course of the disease. The purpose of this paper is to analyse underlying factors related to subjective financial distress in high-income countries with universal healthcare coverage. A systematic literature review was conducted to identify qualitative and quantitative studies of cancer patient-reported subjective financial distress by performing a search in the databases of PubMed, PsycINFO and CINAHL up to December 2020. A qualitative synthesis was performed linking the time-dependent occurrence of risk factors to derived categories of risk factors. Out of 4321 identified records, 30 quantitative and 16 qualitative studies were eligible. Classification of risk factors resulted in eight categories with a total of 34 subcategories. Subjective financial distress is primarily determined by pre-diagnosis sociodemographic- factors as well as financial and work factors that might change during the course of the disease. The design of healthcare and social security systems shapes the country-specific degree of subjective financial distress. Further research should focus on evolving multidisciplinary intervention schemes and multidimensional instruments for subjective financial distress to account for identified risk factors in universal healthcare systems more precisely. Full article

(This article belongs to the Special Issue Systematic Reviews of Patient-Reported Outcomes in Patients with Cancer)

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18 pages, 2281 KiB

Open AccessArticle

EZH2 Inhibition as New Epigenetic Treatment Option for Pancreatic Neuroendocrine Neoplasms (PanNENs)

by Simon Leonhard April-Monn, Valentina Andreasi, Marco Schiavo Lena, Martin Carl Sadowski, Corina Kim-Fuchs, Michelle Claudine Buri, Avanee Ketkar, Renaud Maire, Annunziata Di Domenico, Jörg Schrader, Francesca Muffatti, Claudio Doglioni, Stefano Partelli, Massimo Falconi, Aurel Perren and Ilaria Marinoni

Cancers 2021, 13(19), 5014; https://doi.org/10.3390/cancers13195014 - 7 Oct 2021

Cited by 9 | Viewed by 3663

Abstract

Pancreatic neuroendocrine neoplasms are epigenetically driven tumors, but therapies against underlying epigenetic drivers are currently not available in the clinical practice. We aimed to investigate EZH2 (Enhancer of Zest homolog) expression in PanNEN and the impact of EZH2 inhibition in three different PanNEN [...] Read more.

Pancreatic neuroendocrine neoplasms are epigenetically driven tumors, but therapies against underlying epigenetic drivers are currently not available in the clinical practice. We aimed to investigate EZH2 (Enhancer of Zest homolog) expression in PanNEN and the impact of EZH2 inhibition in three different PanNEN preclinical models. EZH2 expression in PanNEN patient samples (n = 172) was assessed by immunohistochemistry and correlated with clinico-pathological data. Viability of PanNEN cell lines treated with EZH2 inhibitor (GSK126) was determined in vitro. Lentiviral transduction of shRNA targeting EZH2 was performed in QGP1 cells, and cell proliferation was measured. Rip1TAG2 mice underwent GSK126 treatment for three weeks starting from week 10 of age. Primary cells isolated from PanNEN patients (n = 6) were cultivated in 3D as islet-like tumoroids and monitored for 10 consecutive days upon GSK126 treatment. Viability was measured continuously for the whole duration of the treatment. We found that high EZH2 expression correlated with higher tumor grade (p < 0.001), presence of distant metastases (p < 0.001), and shorter disease-free survival (p < 0.001) in PanNEN patients. Inhibition of EZH2 in vitro in PanNEN cell lines and in patient-derived islet-like tumoroids reduced cell viability and impaired cell proliferation, while inhibition of EZH2 in vivo in Rip1TAG2 mice reduced tumor burden. Our results show that EZH2 is highly expressed in high-grade PanNENs, and during disease progression it may contribute to aberrations in the epigenetic cellular landscape. Targeting EZH2 may represent a valuable epigenetic treatment option for patients with PanNEN. Full article

(This article belongs to the Special Issue Translational Research on Neuroendocrine Tumors and Experimental Tumor Therapy)

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16 pages, 14304 KiB

Open AccessArticle

Reversal of Bortezomib-Induced Neurotoxicity by Suvecaltamide, a Selective T-Type Ca-Channel Modulator, in Preclinical Models

by Cristina Meregalli, Yuri Maricich, Guido Cavaletti, Annalisa Canta, Valentina A. Carozzi, Alessia Chiorazzi, Evan Newbold, Paola Marmiroli, Cecilia Ceresa, Arthur Diani, Spyros Papapetropoulos and Margaret S. Lee

Cancers 2021, 13(19), 5013; https://doi.org/10.3390/cancers13195013 - 7 Oct 2021

Cited by 11 | Viewed by 2397

Abstract

This study evaluated suvecaltamide, a selective T-type calcium channel modulator, on chemotherapy-induced peripheral neurotoxicity (CIPN) and anti-cancer activity associated with bortezomib (BTZ). Rats received BTZ (0.2 mg/kg thrice weekly) for 4 weeks, then BTZ alone (n = 8) or BTZ+suvecaltamide (3, 10, [...] Read more.

This study evaluated suvecaltamide, a selective T-type calcium channel modulator, on chemotherapy-induced peripheral neurotoxicity (CIPN) and anti-cancer activity associated with bortezomib (BTZ). Rats received BTZ (0.2 mg/kg thrice weekly) for 4 weeks, then BTZ alone (n = 8) or BTZ+suvecaltamide (3, 10, or 30 mg/kg once daily; each n = 12) for 4 weeks. Nerve conduction velocity (NCV), mechanical threshold, β-tubulin polymerization, and intraepidermal nerve fiber (IENF) density were assessed. Proteasome inhibition was evaluated in peripheral blood mononuclear cells. Cytotoxicity was assessed in human multiple myeloma cell lines (MCLs) exposed to BTZ alone (IC₅₀ concentration), BTZ+suvecaltamide (10, 30, 100, 300, or 1000 nM), suvecaltamide alone, or vehicle. Tumor volume was estimated in athymic nude mice bearing MCL xenografts receiving vehicle, BTZ alone (1 mg/kg twice weekly), or BTZ+suvecaltamide (30 mg/kg once daily) for 28 days, or no treatment (each n = 8). After 4 weeks, suvecaltamide 10 or 30 mg/kg reversed BTZ-induced reduction in NCV, and suvecaltamide 30 mg/kg reversed BTZ-induced reduction in IENF density. Proteasome inhibition and cytotoxicity were similar between BTZ alone and BTZ+suvecaltamide. BTZ alone and BTZ+suvecaltamide reduced tumor volume versus the control (day 18), and BTZ+suvecaltamide reduced tumor volume versus BTZ alone (day 28). Suvecaltamide reversed CIPN without affecting BTZ anti-cancer activity in preclinical models. Full article

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18 pages, 4536 KiB

Open AccessArticle

Aberrant Expression of and Cell Death Induction by Engagement of the MHC-II Chaperone CD74 in Anaplastic Large Cell Lymphoma (ALCL)

by Kathrin D. Wurster, Mariantonia Costanza, Stephan Kreher, Selina Glaser, Björn Lamprecht, Nikolai Schleussner, Ioannis Anagnostopoulos, Michael Hummel, Korinna Jöhrens, Harald Stein, Arturo Molina, Arjan Diepstra, Bernd Gillissen, Karl Köchert, Reiner Siebert, Olaf Merkel, Lukas Kenner, Martin Janz and Stephan Mathas

Cancers 2021, 13(19), 5012; https://doi.org/10.3390/cancers13195012 - 7 Oct 2021

Cited by 3 | Viewed by 2751

Abstract

In 50–60% of cases, systemic anaplastic large cell lymphoma (ALCL) is characterized by the t(2;5)(p23;q35) or one of its variants, considered to be causative for anaplastic lymphoma kinase (ALK)-positive (ALK⁺) ALCL. Key pathogenic events in ALK-negative (ALK⁻) ALCL are [...] Read more.

In 50–60% of cases, systemic anaplastic large cell lymphoma (ALCL) is characterized by the t(2;5)(p23;q35) or one of its variants, considered to be causative for anaplastic lymphoma kinase (ALK)-positive (ALK⁺) ALCL. Key pathogenic events in ALK-negative (ALK⁻) ALCL are less well defined. We have previously shown that deregulation of oncogenic genes surrounding the chromosomal breakpoints on 2p and 5q is a unifying feature of both ALK⁺ and ALK⁻ ALCL and predisposes for occurrence of t(2;5). Here, we report that the invariant chain of the MHC-II complex CD74 or li, which is encoded on 5q32, can act as signaling molecule, and whose expression in lymphoid cells is usually restricted to B cells, is aberrantly expressed in T cell-derived ALCL. Accordingly, ALCL shows an altered DNA methylation pattern of the CD74 locus compared to benign T cells. Functionally, CD74 ligation induces cell death of ALCL cells. Furthermore, CD74 engagement enhances the cytotoxic effects of conventional chemotherapeutics in ALCL cell lines, as well as the action of the ALK-inhibitor crizotinib in ALK⁺ ALCL or of CD95 death-receptor signaling in ALK⁻ ALCL. Additionally, a subset of ALCL cases expresses the proto-oncogene MET, which can form signaling complexes together with CD74. Finally, we demonstrate that the CD74-targeting antibody-drug conjugate STRO-001 efficiently and specifically kills CD74-positive ALCL cell lines in vitro. Taken together, these findings enabled us to demonstrate aberrant CD74-expression in ALCL cells, which might serve as tool for the development of new treatment strategies for this lymphoma entity. Full article

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25 pages, 4784 KiB

Open AccessReview

Artificial Intelligence in Brain Tumour Surgery—An Emerging Paradigm

by Simon Williams, Hugo Layard Horsfall, Jonathan P. Funnell, John G. Hanrahan, Danyal Z. Khan, William Muirhead, Danail Stoyanov and Hani J. Marcus

Cancers 2021, 13(19), 5010; https://doi.org/10.3390/cancers13195010 - 7 Oct 2021

Cited by 36 | Viewed by 8602

Abstract

Artificial intelligence (AI) platforms have the potential to cause a paradigm shift in brain tumour surgery. Brain tumour surgery augmented with AI can result in safer and more effective treatment. In this review article, we explore the current and future role of AI [...] Read more.

Artificial intelligence (AI) platforms have the potential to cause a paradigm shift in brain tumour surgery. Brain tumour surgery augmented with AI can result in safer and more effective treatment. In this review article, we explore the current and future role of AI in patients undergoing brain tumour surgery, including aiding diagnosis, optimising the surgical plan, providing support during the operation, and better predicting the prognosis. Finally, we discuss barriers to the successful clinical implementation, the ethical concerns, and we provide our perspective on how the field could be advanced. Full article

(This article belongs to the Collection Artificial Intelligence in Oncology)

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17 pages, 6665 KiB

Open AccessReview

Estrogens and the Schrödinger’s Cat in the Ovarian Tumor Microenvironment

by Marija Gjorgoska and Tea Lanišnik Rižner

Cancers 2021, 13(19), 5011; https://doi.org/10.3390/cancers13195011 - 6 Oct 2021

Cited by 5 | Viewed by 4334

Abstract

Ovarian cancer is a heterogeneous disease affecting the aging ovary, in concert with a complex network of cells and signals, together representing the ovarian tumor microenvironment. As in the “Schrödinger’s cat” thought experiment, the context-dependent constituents of the—by the time of diagnosis—well-established tumor [...] Read more.

Ovarian cancer is a heterogeneous disease affecting the aging ovary, in concert with a complex network of cells and signals, together representing the ovarian tumor microenvironment. As in the “Schrödinger’s cat” thought experiment, the context-dependent constituents of the—by the time of diagnosis—well-established tumor microenvironment may display a tumor-protective and -destructive role. Systemic and locally synthesized estrogens contribute to the formation of a pro-tumoral microenvironment that enables the sustained tumor growth, invasion and metastasis. Here we focus on the estrogen biosynthetic and metabolic pathways in ovarian cancer and elaborate their actions on phenotypically plastic, estrogen-responsive, aging immune cells of the tumor microenvironment, altogether highlighting the multicomponent-connectedness and complexity of cancer, and contributing to a broader understanding of the ovarian cancer biology. Full article

(This article belongs to the Special Issue Immune Microenviroment in Gynecologic Malignancies)

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Graphical abstract

18 pages, 4440 KiB

Open AccessArticle

Drug-Induced Resistance and Phenotypic Switch in Triple-Negative Breast Cancer Can Be Controlled via Resolution and Targeting of Individualized Signaling Signatures

by Swetha Vasudevan, Ibukun A. Adejumobi, Heba Alkhatib, Sangita Roy Chowdhury, Shira Stefansky, Ariel M. Rubinstein and Nataly Kravchenko-Balasha

Cancers 2021, 13(19), 5009; https://doi.org/10.3390/cancers13195009 - 6 Oct 2021

Cited by 16 | Viewed by 2996

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subgroup of breast cancers which is treated mainly with chemotherapy and radiotherapy. Epidermal growth factor receptor (EGFR) was considered to be frequently expressed in TNBC, and therefore was suggested as a therapeutic target. However, clinical trials [...] Read more.

Triple-negative breast cancer (TNBC) is an aggressive subgroup of breast cancers which is treated mainly with chemotherapy and radiotherapy. Epidermal growth factor receptor (EGFR) was considered to be frequently expressed in TNBC, and therefore was suggested as a therapeutic target. However, clinical trials of EGFR inhibitors have failed. In this study, we examine the relationship between the patient-specific TNBC network structures and possible mechanisms of resistance to anti-EGFR therapy. Using an information-theoretical analysis of 747 breast tumors from the TCGA dataset, we resolved individualized protein network structures, namely patient-specific signaling signatures (PaSSS) for each tumor. Each PaSSS was characterized by a set of 1–4 altered protein–protein subnetworks. Thirty-one percent of TNBC PaSSSs were found to harbor EGFR as a part of the network and were predicted to benefit from anti-EGFR therapy as long as it is combined with anti-estrogen receptor (ER) therapy. Using a series of single-cell experiments, followed by in vivo support, we show that drug combinations which are not tailored accurately to each PaSSS may generate evolutionary pressure in malignancies leading to an expansion of the previously undetected or untargeted subpopulations, such as ER+ populations. This corresponds to the PaSSS-based predictions suggesting to incorporate anti-ER drugs in certain anti-TNBC treatments. These findings highlight the need to tailor anti-TNBC targeted therapy to each PaSSS to prevent diverse evolutions of TNBC tumors and drug resistance development. Full article

(This article belongs to the Special Issue Understanding the Evolutionary Dynamics and Ecology of Cancer in Treatment Resistance)

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19 pages, 4695 KiB

Open AccessArticle

BOLD Coupling between Lesioned and Healthy Brain Is Associated with Glioma Patients’ Recovery

by Rafael Romero-Garcia, Michael G. Hart, Richard A. I. Bethlehem, Ayan Mandal, Moataz Assem, Benedicto Crespo-Facorro, Juan Manuel Gorriz, G. A. Amos Burke, Stephen J. Price, Thomas Santarius, Yaara Erez and John Suckling

Cancers 2021, 13(19), 5008; https://doi.org/10.3390/cancers13195008 - 6 Oct 2021

Cited by 7 | Viewed by 3536

Abstract

Predicting functional outcomes after surgery and early adjuvant treatment is difficult due to the complex, extended, interlocking brain networks that underpin cognition. The aim of this study was to test glioma functional interactions with the rest of the brain, thereby identifying the risk [...] Read more.

Predicting functional outcomes after surgery and early adjuvant treatment is difficult due to the complex, extended, interlocking brain networks that underpin cognition. The aim of this study was to test glioma functional interactions with the rest of the brain, thereby identifying the risk factors of cognitive recovery or deterioration. Seventeen patients with diffuse non-enhancing glioma (aged 22–56 years) were longitudinally MRI scanned and cognitively assessed before and after surgery and during a 12-month recovery period (55 MRI scans in total after exclusions). We initially found, and then replicated in an independent dataset, that the spatial correlation pattern between regional and global BOLD signals (also known as global signal topography) was associated with tumour occurrence. We then estimated the coupling between the BOLD signal from within the tumour and the signal extracted from different brain tissues. We observed that the normative global signal topography is reorganised in glioma patients during the recovery period. Moreover, we found that the BOLD signal within the tumour and lesioned brain was coupled with the global signal and that this coupling was associated with cognitive recovery. Nevertheless, patients did not show any apparent disruption of functional connectivity within canonical functional networks. Understanding how tumour infiltration and coupling are related to patients’ recovery represents a major step forward in prognostic development. Full article

(This article belongs to the Special Issue Perioperative Imaging and Mapping Methods in Glioma Patients)

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13 pages, 11381 KiB

Open AccessArticle

Level of Combined Estrogen and Progesterone Receptor Expression Determines the Eligibility for Adjuvant Endocrine Therapy in Breast Cancer Patients

by Jee Hyun Ahn, Soon Bo Choi, Jung Min Park, Jee Ye Kim, Hyung Seok Park, Seung Il Kim, Byeong-Woo Park and Seho Park

Cancers 2021, 13(19), 5007; https://doi.org/10.3390/cancers13195007 - 6 Oct 2021

Cited by 2 | Viewed by 2471

Abstract

Hormone receptor (HR)-positive breast cancer has a heterogeneous pattern according to the level of receptor expression. Patients whose breast cancers express low levels of estrogen receptor (ER) or progesterone receptor (PgR) may be eligible for adjuvant endocrine therapy, but limited data are available [...] Read more.

Hormone receptor (HR)-positive breast cancer has a heterogeneous pattern according to the level of receptor expression. Patients whose breast cancers express low levels of estrogen receptor (ER) or progesterone receptor (PgR) may be eligible for adjuvant endocrine therapy, but limited data are available to support this notion. We aimed to determine whether HR expression level is related to prognosis. Tumors from 6042 patients with breast cancer were retrospectively analyzed for combined HR levels of ER and PgR. Low expression was defined as ER 1–10% and PgR 1–20%. Four HR groups were identified by combining ER and PgR expression levels. Patients whose tumors expressed high levels of a single receptor showed the worst survival outcomes, and their risk continuously increased even after the 10-year follow-up. Endocrine therapy had a significant benefit for patients whose tumors expressed high HR levels and a favorable tendency for patients with tumors expressing low HR levels. We established the possible benefit of endocrine therapy for patients whose breast tumors expressed low HR levels. Thus, HR level was a prognostic factor and might be a determinant of extended therapy, especially for patients with high expression of a single receptor. Full article

(This article belongs to the Collection The Biomarkers for the Diagnosis and Prognosis in Cancer)

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20 pages, 34028 KiB

Open AccessArticle

Novel 3D µtissues Mimicking the Fibrotic Stroma in Pancreatic Cancer to Study Cellular Interactions and Stroma-Modulating Therapeutics

by Kunal P. Pednekar, Marcel A. Heinrich, Joop van Baarlen and Jai Prakash

Cancers 2021, 13(19), 5006; https://doi.org/10.3390/cancers13195006 - 6 Oct 2021

Cited by 8 | Viewed by 3450

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor type with low patient survival due to the low efficacy of current treatment options. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) create a dense fibrotic environment around the tumor cells, preventing therapies from [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor type with low patient survival due to the low efficacy of current treatment options. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) create a dense fibrotic environment around the tumor cells, preventing therapies from reaching their target. Novel 3D in vitro models are needed that mimic this fibrotic barrier for the development of therapies in a biologically relevant environment. Here, novel PDAC microtissues (µtissues) consisting of pancreatic cancer cell core surrounded by a CAF-laden collagen gel are presented, that is based on the cells own contractility to form a hard-to-penetrate barrier. The contraction of CAFs is demonstrated facilitating the embedding of tumor cells in the center of the µtissue as observed in patients. The µtissues displayed a PDAC-relevant gene expression by comparing their gene profile with transcriptomic patient data. Furthermore, the CAF-dependent proliferation of cancer cells is presented, as well as the suitability of the µtissues to serve as a platform for the screening of CAF-modulating therapies in combination with other (nano)therapies. It is envisioned that these PDAC µtissues can serve as a high-throughput platform for studying cellular interactions in PDAC and for evaluating different treatment strategies in the future. Full article

(This article belongs to the Special Issue Organotypic 3D In Vitro Tumor Models: Bioengineering and Applications)

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10 pages, 1879 KiB

Open AccessArticle

Enhanced Delivery of Thermoresponsive Polymer-Based Medicine into Tumors by Using Heat Produced from Gold Nanorods Irradiated with Near-Infrared Light

by Kohei Sano, Yumi Ishida, Toshie Tanaka, Tatsuya Mizukami, Tomono Nagayama, Yoshie Haratake, Masayuki Munekane, Toshihide Yamasaki and Takahiro Mukai

Cancers 2021, 13(19), 5005; https://doi.org/10.3390/cancers13195005 - 6 Oct 2021

Cited by 4 | Viewed by 1970

Abstract

The aim of this study was to establish a drug delivery system (DDS) for marked therapy of tumors using a thermoresponsive polymer, polyoxazoline (POZ). The effectiveness of the following was investigated: (i) the delivery of gold nanorods (GNRs) to tumor tissues, (ii) heat [...] Read more.

The aim of this study was to establish a drug delivery system (DDS) for marked therapy of tumors using a thermoresponsive polymer, polyoxazoline (POZ). The effectiveness of the following was investigated: (i) the delivery of gold nanorods (GNRs) to tumor tissues, (ii) heat production of GNR upon irradiation with near-infrared (NIR) light, and (iii) high accumulation of an intravenously injected radiolabeled POZ as a drug carrier in tumors by sensing heat produced by GNRs. When the GNR solution was irradiated with NIR light (808 nm), the solution temperature was increased both in a GNR-concentration-dependent manner and in a light-dose-dependent manner. POZ, with a lower critical solution temperature of 38 °C, was aggregated depending on the heat produced by the GNR irradiated by NIR light. When it was intratumorally pre-injected into colon26-tumor-bearing mice, followed by NIR light irradiation (GNR+/Light+ group), the tumor surface temperature increased to approximately 42 °C within 5 min. Fifteen minutes after irradiation with NIR light, indium-111 (¹¹¹In)-labeled POZ was intravenously injected into tumor-bearing mice, and the radioactivity distribution was evaluated. The accumulation of POZ in the tumor was significantly (approximately 4-fold) higher than that in the control groups (GNR+/without NIR light irradiation (Light–), without injection of GNR (GNR–)/Light+, and GNR–/Light– groups). Furthermore, an in vivo confocal fluorescence microscopy study, using fluorescence-labeled POZ, revealed that uptake of POZ by the tumor could be attributed to the heat produced by GNR. In conclusion, we successfully established a novel DDS in which POZ could be efficiently delivered into tumors by using the heat produced by GNR irradiated with NIR light. Full article

(This article belongs to the Special Issue Radioprobes and Other Bioconjugates for Cancer Theranostics)

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20 pages, 41659 KiB

Open AccessArticle

The RXR Agonist MSU42011 Is Effective for the Treatment of Preclinical HER2+ Breast Cancer and Kras-Driven Lung Cancer

by Ana S. Leal, Jessica A. Moerland, Di Zhang, Sarah Carapellucci, Beth Lockwood, Teresa Krieger-Burke, Bilal Aleiwi, Edmund Ellsworth and Karen T. Liby

Cancers 2021, 13(19), 5004; https://doi.org/10.3390/cancers13195004 - 6 Oct 2021

Cited by 10 | Viewed by 3026

Abstract

(1) Background: Notwithstanding numerous therapeutic advances, 176,000 deaths from breast and lung cancers will occur in the United States in 2021 alone. The tumor microenvironment and its modulation by drugs have gained increasing attention and relevance, especially with the introduction of immunotherapy as [...] Read more.

(1) Background: Notwithstanding numerous therapeutic advances, 176,000 deaths from breast and lung cancers will occur in the United States in 2021 alone. The tumor microenvironment and its modulation by drugs have gained increasing attention and relevance, especially with the introduction of immunotherapy as a standard of care in clinical practice. Retinoid X receptors (RXRs) are members of the nuclear receptor superfamily and upon ligand binding, function as transcription factors to modulate multiple cell functions. Bexarotene, the only FDA-approved RXR agonist, is still used to treat cutaneous T-cell lymphoma. (2) Methods: To test the immunomodulatory and anti-tumor effects of MSU42011, a new RXR agonist, we used two different immunocompetent murine models (MMTV-Neu mice, a HER2 positive model of breast cancer and the A/J mouse model, in which vinyl carbamate is used to initiate lung tumorigenesis) and an immunodeficient xenograft lung cancer model. (3) Results: Treatment of established tumors in immunocompetent models of HER2-positive breast cancer and Kras-driven lung cancer with MSU42011 significantly decreased the tumor burden and increased the ratio of CD8/CD4, CD25 T cells, which correlates with enhanced anti-tumor efficacy. Moreover, the combination of MSU42011 and immunotherapy (anti-PDL1 and anti-PD1 antibodies) significantly (p < 0.05) reduced tumor size vs. individual treatments. However, MSU42011 was ineffective in an athymic human A549 lung cancer xenograft model, supporting an immunomodulatory mechanism of action. (4) Conclusions: Collectively, these data suggest that the RXR agonist MSU42011 can be used to modulate the tumor microenvironment in breast and lung cancer. Full article

(This article belongs to the Section Cancer Therapy)

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Cancers, Volume 13, Issue 19 (October-1 2021) – 300 articles

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