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Cancers, Volume 14, Issue 6 (March-2 2022) – 236 articles

Cover Story (view full-size image): Altered cancer metabolism is one of the hallmarks of cancer. Cancer cells have a different metabolism compared to normal cells, and this is associated with alterations in mitochondria function and dynamics. Mitochondria are highly dynamic organelles. Their structure, function, and cellular distribution can reflect metabolic changes, and the role of mitochondria in cancer progression has recently started to attract interest. The tumor microenvironment, in particular the extracellular matrix, plays a critical role in cancer and the interaction between extracellular matrix and the tumor is important for cancer cell growth and invasion. In this review, we discuss the interplay between extracellular matrix and mitochondria and how changes in matrix stiffness and structure can affect mitochondria function and dynamics, which in turn can promote cancer initiation and progression. View this paper
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Article
Selective Targeting of Protein Kinase C (PKC)-θ Nuclear Translocation Reduces Mesenchymal Gene Signatures and Reinvigorates Dysfunctional CD8+ T Cells in Immunotherapy-Resistant and Metastatic Cancers
Cancers 2022, 14(6), 1596; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061596 - 21 Mar 2022
Viewed by 1338
Abstract
Protein kinase C (PKC)-θ is a serine/threonine kinase with both cytoplasmic and nuclear functions. Nuclear chromatin-associated PKC-θ (nPKC-θ) is increasingly recognized to be pathogenic in cancer, whereas its cytoplasmic signaling is restricted to normal T-cell function. Here we show that nPKC-θ is enriched [...] Read more.
Protein kinase C (PKC)-θ is a serine/threonine kinase with both cytoplasmic and nuclear functions. Nuclear chromatin-associated PKC-θ (nPKC-θ) is increasingly recognized to be pathogenic in cancer, whereas its cytoplasmic signaling is restricted to normal T-cell function. Here we show that nPKC-θ is enriched in circulating tumor cells (CTCs) in patients with triple-negative breast cancer (TNBC) brain metastases and immunotherapy-resistant metastatic melanoma and is associated with poor survival in immunotherapy-resistant disease. To target nPKC-θ, we designed a novel PKC-θ peptide inhibitor (nPKC-θi2) that selectively inhibits nPKC-θ nuclear translocation but not PKC-θ signaling in healthy T cells. Targeting nPKC-θ reduced mesenchymal cancer stem cell signatures in immunotherapy-resistant CTCs and TNBC xenografts. PKC-θ was also enriched in the nuclei of CD8+ T cells isolated from stage IV immunotherapy-resistant metastatic cancer patients. We show for the first time that nPKC-θ complexes with ZEB1, a key repressive transcription factor in epithelial-to-mesenchymal transition (EMT), in immunotherapy-resistant dysfunctional PD1+/CD8+ T cells. nPKC-θi2 inhibited the ZEB1/PKC-θ repressive complex to induce cytokine production in CD8+ T cells isolated from patients with immunotherapy-resistant disease. These data establish for the first time that nPKC-θ mediates immunotherapy resistance via its activity in CTCs and dysfunctional CD8+ T cells. Disrupting nPKC-θ but retaining its cytoplasmic function may offer a means to target metastases in combination with chemotherapy or immunotherapy. Full article
(This article belongs to the Special Issue Epigenetics and Cancer Immunotherapy)
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Review
The Role of Surgery in Spinal Intradural Metastases from Renal Cell Carcinoma: A Literature Review
Cancers 2022, 14(6), 1595; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061595 - 21 Mar 2022
Viewed by 580
Abstract
Background: Due to the few reported cases of spinal intradural metastases from renal cell carcinoma (RCC), there is no unanimous consensus on the best treatment strategy, including the role of surgery. Methods: A wide and accurate literature review up to January 2022 has [...] Read more.
Background: Due to the few reported cases of spinal intradural metastases from renal cell carcinoma (RCC), there is no unanimous consensus on the best treatment strategy, including the role of surgery. Methods: A wide and accurate literature review up to January 2022 has disclosed only 51 cases of spinal intradural metastases from RCC. Patients with extramedullary (19) and those with intramedullary (32) localization have been separately considered and compared. Demographics, clinical, pathological, management, and outcome features have been analyzed. Results: Extramedullary lesions more frequently showed the involvement of the lumbar spine, low back pain, and solitary metastasis at diagnosis. Conversely, the intramedullary lesions were most often detected in association with multiple localizations of disease, mainly in the brain. Surgery resulted in improvement of clinical symptoms in both groups. Conclusion: Several factors affect the prognosis of metastatic RCC. The surgical removal of spinal metastases resulted in pain relief and the arresting of neurological deficit progression, improving the quality of life and overall survival of the patient. Considering the relative radioresistant nature of the RCC, the surgical treatment of the metastasis is a valid option even if it is subtotal, with a consequent increased risk of recurrence, and/or a nerve root should be sacrificed. Full article
(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma: From Biology to Treatment)
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Review
Genomics of Plasma Cell Leukemia
Cancers 2022, 14(6), 1594; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061594 - 21 Mar 2022
Viewed by 637
Abstract
Plasma cell leukemia (PCL) is a rare and highly aggressive plasma cell dyscrasia characterized by the presence of clonal circulating plasma cells in peripheral blood. PCL accounts for approximately 2–4% of all multiple myeloma (MM) cases. PCL can be classified in primary PCL [...] Read more.
Plasma cell leukemia (PCL) is a rare and highly aggressive plasma cell dyscrasia characterized by the presence of clonal circulating plasma cells in peripheral blood. PCL accounts for approximately 2–4% of all multiple myeloma (MM) cases. PCL can be classified in primary PCL (pPCL) when it appears de novo and in secondary PCL (sPCL) when it arises from a pre-existing relapsed/refractory MM. Despite the improvement in treatment modalities, the prognosis remains very poor. There is growing evidence that pPCL is a different clinicopathological entity as compared to MM, although the mechanisms underlying its pathogenesis are not fully elucidated. The development of new high-throughput technologies, such as microarrays and new generation sequencing (NGS), has contributed to a better understanding of the peculiar biological and clinical features of this disease. Relevant information is now available on cytogenetic alterations, genetic variants, transcriptome, methylation patterns, and non-coding RNA profiles. Additionally, attempts have been made to integrate genomic alterations with gene expression data. However, given the low frequency of PCL, most of the genetic information comes from retrospective studies with a small number of patients, sometimes leading to inconsistent results. Full article
(This article belongs to the Special Issue Genomics of Rare Hematologic Cancers)
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Article
The Multi-Kinase Inhibitor EC-70124 Is a Promising Candidate for the Treatment of FLT3-ITD-Positive Acute Myeloid Leukemia
Cancers 2022, 14(6), 1593; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061593 - 21 Mar 2022
Cited by 1 | Viewed by 787
Abstract
Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Patients with AML harboring a constitutively active internal tandem duplication mutation (ITDMUT) in the FMS-like kinase tyrosine kinase (FLT3) receptor generally have a poor prognosis. Several tyrosine kinase/FLT3 inhibitors [...] Read more.
Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Patients with AML harboring a constitutively active internal tandem duplication mutation (ITDMUT) in the FMS-like kinase tyrosine kinase (FLT3) receptor generally have a poor prognosis. Several tyrosine kinase/FLT3 inhibitors have been developed and tested clinically, but very few (midostaurin and gilteritinib) have thus far been FDA/EMA-approved for patients with newly diagnosed or relapse/refractory FLT3-ITDMUT AML. Disappointingly, clinical responses are commonly partial or not durable, highlighting the need for new molecules targeting FLT3-ITDMUT AML. Here, we tested EC-70124, a hybrid indolocarbazole analog from the same chemical space as midostaurin with a potent and selective inhibitory effect on FLT3. In vitro, EC-70124 exerted a robust and specific antileukemia activity against FLT3-ITDMUT AML primary cells and cell lines with respect to cytotoxicity, CFU capacity, apoptosis and cell cycle while sparing healthy hematopoietic (stem/progenitor) cells. We also analyzed its efficacy in vivo as monotherapy using two different xenograft models: an aggressive and systemic model based on MOLM-13 cells and a patient-derived xenograft model. Orally disposable EC-70124 exerted a potent inhibitory effect on the growth of FLT3-ITDMUT AML cells, delaying disease progression and debulking the leukemia. Collectively, our findings show that EC-70124 is a promising and safe agent for the treatment of AML with FLT3-ITDMUT. Full article
(This article belongs to the Special Issue New Therapeutic Strategies for Acute Myeloid Leukemia)
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Article
Targeting an MDM2/MYC Axis to Overcome Drug Resistance in Multiple Myeloma
Cancers 2022, 14(6), 1592; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061592 - 21 Mar 2022
Viewed by 1128
Abstract
Background: MDM2 is elevated in multiple myeloma (MM). Although traditionally, MDM2 negatively regulates p53, a growing body of research suggests that MDM2 plays several p53-independent roles in cancer pathogenesis as a regulator of oncogene mRNA stability and translation. Yet, the molecular mechanisms underlying [...] Read more.
Background: MDM2 is elevated in multiple myeloma (MM). Although traditionally, MDM2 negatively regulates p53, a growing body of research suggests that MDM2 plays several p53-independent roles in cancer pathogenesis as a regulator of oncogene mRNA stability and translation. Yet, the molecular mechanisms underlying MDM2 overexpression and its role in drug resistance in MM remain undefined. Methods: Both myeloma cell lines and primary MM samples were employed. Cell viability, cell cycle and apoptosis assays, siRNA transfection, quantitative real-time PCR, immunoblotting, co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), soft agar colony formation and migration assay, pulse-chase assay, UV cross-linking, gel-shift assay, RNA-protein binding assays, MEME-analysis for discovering c-Myc DNA binding motifs studies, reporter gene constructs procedure, gene transfection and reporter assay, MM xenograft mouse model studies, and statistical analysis were applied in this study. Results: We show that MDM2 is associated with poor prognosis. Importantly, its upregulation in primary MM samples and human myeloma cell lines (HMCLs) drives drug resistance. Inhibition of MDM2 by RNAi, or by the MDM2/XIAP dual inhibitor MX69, significantly enhanced the sensitivity of resistant HMCLs and primary MM samples to bortezomib and other anti-myeloma drugs, demonstrating that MDM2 can modulate drug response. MDM2 inhibition resulted in a remarkable suppression of relapsed MM cell growth, colony formation, migration and induction of apoptosis through p53-dependent and -independent pathways. Mechanistically, MDM2 was found to reciprocally regulate c-Myc in MM; MDM2 binds to AREs on c-Myc 3′UTR to increase c-Myc mRNA stability and translation, while MDM2 is a direct transcriptional target of c-Myc. MDM2 inhibition rendered c-Myc mRNA unstable, and reduced c-Myc protein expression in MM cells. Importantly, in vivo delivery of MX69 in combination with bortezomib led to significant regression of tumors and prolonged survival in an MM xenograft model. Conclusion: Our findings provide a rationale for the therapeutic targeting of MDM2/c-Myc axis to improve clinical outcome of patients with refractory/relapsed MM. Full article
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Article
Pterygium and Ocular Surface Squamous Neoplasia: Optical Biopsy Using a Novel Autofluorescence Multispectral Imaging Technique
Cancers 2022, 14(6), 1591; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061591 - 21 Mar 2022
Viewed by 1749
Abstract
In this study, differentiation of pterygium vs. ocular surface squamous neoplasia based on multispectral autofluorescence imaging technique was investigated. Fifty (N = 50) patients with histopathological diagnosis of pterygium (PTG) and/or ocular surface squamous neoplasia (OSSN) were recruited. Fixed unstained biopsy specimens were [...] Read more.
In this study, differentiation of pterygium vs. ocular surface squamous neoplasia based on multispectral autofluorescence imaging technique was investigated. Fifty (N = 50) patients with histopathological diagnosis of pterygium (PTG) and/or ocular surface squamous neoplasia (OSSN) were recruited. Fixed unstained biopsy specimens were imaged by multispectral microscopy. Tissue autofluorescence images were obtained with a custom-built fluorescent microscope with 59 spectral channels, each with specific excitation and emission wavelength ranges, suitable for the most abundant tissue fluorophores such as elastin, flavins, porphyrin, and lipofuscin. Images were analyzed using a new classification framework called fused-classification, designed to minimize interpatient variability, as an established support vector machine learning method. Normal, PTG, and OSSN regions were automatically detected and delineated, with accuracy evaluated against expert assessment by a specialist in OSSN pathology. Signals from spectral channels yielding signals from elastin, flavins, porphyrin, and lipofuscin were significantly different between regions classified as normal, PTG, and OSSN (p < 0.01). Differential diagnosis of PTG/OSSN and normal tissue had accuracy, sensitivity, and specificity of 88 ± 6%, 84 ± 10% and 91 ± 6%, respectively. Our automated diagnostic method generated maps of the reasonably well circumscribed normal/PTG and OSSN interface. PTG and OSSN margins identified by our automated analysis were in close agreement with the margins found in the H&E sections. Such a map can be rapidly generated on a real time basis and potentially used for intraoperative assessment. Full article
(This article belongs to the Topic Biomedical Photonics)
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Article
Immune Landscape and an RBM38-Associated Immune Prognostic Model with Laboratory Verification in Malignant Melanoma
Cancers 2022, 14(6), 1590; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061590 - 21 Mar 2022
Viewed by 615
Abstract
Background: Current studies have revealed that RNA-binding protein RBM38 is closely related to tumor development, while its role in malignant melanoma remains unclear. Therefore, this research aimed to investigate the function of RBM38 in melanoma and the prognosis of the disease. Methods: Functional [...] Read more.
Background: Current studies have revealed that RNA-binding protein RBM38 is closely related to tumor development, while its role in malignant melanoma remains unclear. Therefore, this research aimed to investigate the function of RBM38 in melanoma and the prognosis of the disease. Methods: Functional experiments (CCK-8 assay, cell colony formation, transwell cell migration/invasion experiment, wound healing assay, nude mouse tumor formation, and immunohistochemical analysis) were applied to evaluate the role of RBM38 in malignant melanoma. Immune-associated differentially expressed genes (DEGs) on RBM38 related immune pathways were comprehensively analyzed based on RNA sequencing results. Results: We found that high expression of RBM38 promoted melanoma cell proliferation, invasion, and migration, and RBM38 was associated with immune infiltration. Then, a five-gene (A2M, NAMPT, LIF, EBI3, and ERAP1) model of RBM38-associated immune DEGs was constructed and validated. Our signature showed superior prognosis capacity compared with other melanoma prognostic signatures. Moreover, the risk score of our signature was connected with the infiltration of immune cells, immune-regulatory proteins, and immunophenoscore in melanoma. Conclusions: We constructed an immune prognosis model using RBM38-related immune DEGs that may help evaluate melanoma patient prognosis and immunotherapy modalities. Full article
(This article belongs to the Special Issue Novel Targets and Approaches in Cancer Therapy)
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Article
The Barcelona Predictive Model of Clinically Significant Prostate Cancer
Cancers 2022, 14(6), 1589; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061589 - 21 Mar 2022
Cited by 1 | Viewed by 523
Abstract
A new and externally validated MRI-PM for csPCa was developed in the metropolitan area of Barcelona, and a web-RC designed with the new option of selecting the csPCa probability threshold. The development cohort comprised 1486 men scheduled to undergo a 3-tesla multiparametric MRI [...] Read more.
A new and externally validated MRI-PM for csPCa was developed in the metropolitan area of Barcelona, and a web-RC designed with the new option of selecting the csPCa probability threshold. The development cohort comprised 1486 men scheduled to undergo a 3-tesla multiparametric MRI (mpMRI) and guided and/or systematic biopsies in one academic institution of Barcelona. The external validation cohort comprised 946 men in whom the same diagnostic approach was carried out as in the development cohort, in two other academic institutions of the same metropolitan area. CsPCa was detected in 36.9% of men in the development cohort and 40.8% in the external validation cohort (p = 0.054). The area under the curve of mpMRI increased from 0.842 to 0.897 in the developed MRI-PM (p < 0.001), and from 0.743 to 0.858 in the external validation cohort (p < 0.001). A selected 15% threshold avoided 40.1% of prostate biopsies and missed 5.4% of the 36.9% csPCa detected in the development cohort. In men with PI-RADS <3, 4.3% would be biopsied and 32.3% of all existing 4.2% of csPCa would be detected. In men with PI-RADS 3, 62% of prostate biopsies would be avoided and 28% of all existing 12.4% of csPCa would be undetected. In men with PI-RADS 4, 4% of prostate biopsies would be avoided and 0.6% of all existing 43.1% of csPCa would be undetected. In men with PI-RADS 5, 0.6% of prostate biopsies would be avoided and none of the existing 42.0% of csPCa would be undetected. The Barcelona MRI-PM presented good performance on the overall population; however, its clinical usefulness varied regarding the PI-RADS category. The selection of csPCa probability thresholds in the designed RC may facilitate external validation and outperformance of MRI-PMs in specific PI-RADS categories. Full article
(This article belongs to the Topic Prostate Cancer: Symptoms, Diagnosis & Treatment)
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Review
Clinical Applications of Short Non-Coding RNA-Based Therapies in the Era of Precision Medicine
Cancers 2022, 14(6), 1588; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061588 - 21 Mar 2022
Cited by 2 | Viewed by 875
Abstract
Traditional targeted therapeutic agents have relied on small synthetic molecules or large proteins, such as monoclonal antibodies. These agents leave a lot of therapeutic targets undruggable because of the lack or inaccessibility of active sites and/or pockets in their three-dimensional structure that can [...] Read more.
Traditional targeted therapeutic agents have relied on small synthetic molecules or large proteins, such as monoclonal antibodies. These agents leave a lot of therapeutic targets undruggable because of the lack or inaccessibility of active sites and/or pockets in their three-dimensional structure that can be chemically engaged. RNA presents an attractive, transformative opportunity to reach any genetic target with therapeutic intent. RNA therapeutic design is amenable to modularity and tunability and is based on a computational blueprint presented by the genetic code. Here, we will focus on short non-coding RNAs (sncRNAs) as a promising therapeutic modality because of their potency and versatility. We review recent progress towards clinical application of small interfering RNAs (siRNAs) for single-target therapy and microRNA (miRNA) activity modulators for multi-target therapy. siRNAs derive their potency from the fact that the underlying RNA interference (RNAi) mechanism is catalytic and reliant on post-transcriptional mRNA degradation. Therapeutic siRNAs can be designed against virtually any mRNA sequence in the transcriptome and specifically target a disease-causing mRNA variant. Two main classes of microRNA activity modulators exist to increase (miRNA mimics) or decrease (anti-miRNA inhibitors) the function of a specific microRNA. Since a single microRNA regulates the expression of multiple target genes, a miRNA activity modulator can have a more profound effect on global gene expression and protein output than siRNAs do. Both types of sncRNA-based drugs have been investigated in clinical trials and some siRNAs have already been granted FDA approval for the treatment of genetic, cardiometabolic, and infectious diseases. Here, we detail clinical results using siRNA and miRNA therapeutics and present an outlook for the potential of these sncRNAs in medicine. Full article
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Review
Considerations and Challenges in the Management of the Older Patients with Gastric Cancer
Cancers 2022, 14(6), 1587; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061587 - 21 Mar 2022
Viewed by 484
Abstract
Gastric cancer is one of the commonest malignancies with high rates of mortality worldwide. Older patients represent a substantial proportion of cases with this diagnosis. However, there are very few ‘elderly-specific’ trials in this setting. In addition, the inclusion rate of such patients [...] Read more.
Gastric cancer is one of the commonest malignancies with high rates of mortality worldwide. Older patients represent a substantial proportion of cases with this diagnosis. However, there are very few ‘elderly-specific’ trials in this setting. In addition, the inclusion rate of such patients in randomised clinical trials is poor, presumably due to concerns about increased toxicity, co-existing comorbidities and impaired performance status. Therapeutic strategies for this patient group are therefore mostly based on retrospective subgroup analysis of randomised clinical trials. Review of currently available evidence suggests that older gastric cancer patients who are fit for trial inclusion may benefit from surgical intervention and peri-operative systemic chemotherapy strategies. For patients with metastatic disease, management has been revolutionized by the use of anti-HER2 directed therapies as well as immune checkpoint inhibitors with or without chemotherapy. Early data suggest that fit older patients may also benefit from these therapeutic interventions. However, once again there may be limitations in extrapolating these data to everyday clinical practice with older patients being less likely to have a good performance status and an intact immune system. Therefore, determining the functional age and not just the chronological age of a patient prior to initiating therapy becomes very important. The functional decline including reduced organ function that may occur in older patients makes the integration of some form of geriatric assessment in routine clinical practice very relevant. Full article
Article
Prometastatic Effect of ATX Derived from Alveolar Type II Pneumocytes and B16-F10 Melanoma Cells
Cancers 2022, 14(6), 1586; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061586 - 21 Mar 2022
Viewed by 679
Abstract
Although metastases are the principal cause of cancer-related deaths, the molecular aspects of the role of stromal cells in the establishment of the metastatic niche remain poorly understood. One of the most prevalent sites for cancer metastasis is the lungs. According to recent [...] Read more.
Although metastases are the principal cause of cancer-related deaths, the molecular aspects of the role of stromal cells in the establishment of the metastatic niche remain poorly understood. One of the most prevalent sites for cancer metastasis is the lungs. According to recent research, lung stromal cells such as bronchial epithelial cells and resident macrophages secrete autotaxin (ATX), an enzyme with lysophospholipase D activity that promotes cancer progression. In fact, several studies have shown that many cell types in the lung stroma could provide a rich source of ATX in diseases. In the present study, we sought to determine whether ATX derived from alveolar type II epithelial (ATII) pneumocytes could modulate the progression of lung metastasis, which has not been evaluated previously. To accomplish this, we used the B16-F10 syngeneic melanoma model, which readily metastasizes to the lungs when injected intravenously. Because B16-F10 cells express high levels of ATX, we used the CRISPR-Cas9 technology to knock out the ATX gene in B16-F10 cells, eliminating the contribution of tumor-derived ATX in lung metastasis. Next, we used the inducible Cre/loxP system (Sftpc-CreERT2/Enpp2fl/fl) to generate conditional knockout (KO) mice in which ATX is specifically deleted in ATII cells (i.e., Sftpc-KO). Injection of ATX-KO B16-F10 cells into Sftpc-KO or Sftpc-WT control littermates allowed us to investigate the specific contribution of ATII-derived ATX in lung metastasis. We found that targeted KO of ATX in ATII cells significantly reduced the metastatic burden of ATX-KO B16-F10 cells by 30% (unpaired t-test, p = 0.028) compared to Sftpc-WT control mice, suggesting that ATX derived from ATII cells could affect the metastatic progression. We detected upregulated levels of cytokines such as IFNγ (unpaired t-test, p < 0.0001) and TNFα (unpaired t-test, p = 0.0003), which could favor the increase in infiltrating CD8+ T cells observed in the tumor regions of Sftpc-KO mice. Taken together, our results highlight the contribution of host ATII cells as a stromal source of ATX in the progression of melanoma lung metastasis. Full article
(This article belongs to the Collection Metastatic Progression of Human Melanoma)
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Review
The Role of ROS as a Double-Edged Sword in (In)Fertility: The Impact of Cancer Treatment
Cancers 2022, 14(6), 1585; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061585 - 21 Mar 2022
Cited by 1 | Viewed by 640
Abstract
Tumor cells are highly resistant to oxidative stress resulting from the imbalance between high reactive oxygen species (ROS) production and insufficient antioxidant defenses. However, when intracellular levels of ROS rise beyond a certain threshold, largely above cancer cells’ capacity to reduce it, they [...] Read more.
Tumor cells are highly resistant to oxidative stress resulting from the imbalance between high reactive oxygen species (ROS) production and insufficient antioxidant defenses. However, when intracellular levels of ROS rise beyond a certain threshold, largely above cancer cells’ capacity to reduce it, they may ultimately lead to apoptosis or necrosis. This is, in fact, one of the molecular mechanisms of anticancer drugs, as most chemotherapeutic treatments alter redox homeostasis by further elevation of intracellular ROS levels or inhibition of antioxidant pathways. In traditional chemotherapy, it is widely accepted that most therapeutic effects are due to ROS-mediated cell damage, but in targeted therapies, ROS-mediated effects are mostly unknown and data are still emerging. The increasing effectiveness of anticancer treatments has raised new challenges, especially in the field of reproduction. With cancer patients’ life expectancy increasing, many aiming to become parents will be confronted with the adverse effects of treatments. Consequently, concerns about the impact of anticancer therapies on reproductive capacity are of particular interest. In this review, we begin with a short introduction on anticancer therapies, then address ROS physiological/pathophysiological roles in both male and female reproductive systems, and finish with ROS-mediated adverse effects of anticancer treatments in reproduction. Full article
(This article belongs to the Section Cancer Therapy)
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Article
APOBEC SBS13 Mutational Signature—A Novel Predictor of Radioactive Iodine Refractory Papillary Thyroid Carcinoma
Cancers 2022, 14(6), 1584; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061584 - 21 Mar 2022
Cited by 2 | Viewed by 690
Abstract
Standard surgery followed by radioactive iodine (131I, RAI) therapy are not curative for 5–20% of papillary thyroid carcinoma (PTC) patients with RAI refractory disease. Early predictors indicating therapeutic response to RAI therapy in PTC are yet to be elucidated. Whole-exome sequencing [...] Read more.
Standard surgery followed by radioactive iodine (131I, RAI) therapy are not curative for 5–20% of papillary thyroid carcinoma (PTC) patients with RAI refractory disease. Early predictors indicating therapeutic response to RAI therapy in PTC are yet to be elucidated. Whole-exome sequencing was performed (at median depth 198x) on 66 RAI-refractory and 92 RAI-avid PTCs with patient-matched germline. RAI-refractory tumors were significantly associated with distinct aggressive clinicopathological features, including positive surgical margins (p = 0.016) and the presence of lymph node metastases at primary diagnosis (p = 0.012); higher nonsilent tumor mutation burden (p = 0.011); TERT promoter (TERTp) mutation (p < 0.0001); and the enrichment of the APOBEC-related single-base substitution (SBS) COSMIC mutational signatures 2 (p = 0.030) and 13 (p < 0.001). Notably, SBS13 (odds ratio [OR] 30.4, 95% confidence intervals [CI] 1.43–647.22) and TERTp mutation (OR 41.3, 95% CI 4.35–391.60) were revealed to be independent predictors of RAI refractoriness in PTC (p = 0.029 and 0.001, respectively). Although SBS13 and TERTp mutations alone highly predicted RAI refractoriness, when combined, they significantly increased the likelihood of predicting RAI refractoriness in PTC. This study highlights the APOBEC SBS13 mutational signature as a novel independent predictor of RAI refractoriness in a distinct subgroup of PTC. Full article
(This article belongs to the Special Issue Advances in Thyroid Carcinoma)
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Article
Immunophenotypic Analysis of Acute Megakaryoblastic Leukemia: A EuroFlow Study
Cancers 2022, 14(6), 1583; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061583 - 21 Mar 2022
Viewed by 624
Abstract
Acute megakaryoblastic leukemia (AMKL) is a rare and heterogeneous subtype of acute myeloid leukemia (AML). We evaluated the immunophenotypic profile of 72 AMKL and 114 non-AMKL AML patients using the EuroFlow AML panel. Univariate and multivariate/multidimensional analyses were performed to identify most relevant [...] Read more.
Acute megakaryoblastic leukemia (AMKL) is a rare and heterogeneous subtype of acute myeloid leukemia (AML). We evaluated the immunophenotypic profile of 72 AMKL and 114 non-AMKL AML patients using the EuroFlow AML panel. Univariate and multivariate/multidimensional analyses were performed to identify most relevant markers contributing to the diagnosis of AMKL. AMKL patients were subdivided into transient abnormal myelopoiesis (TAM), myeloid leukemia associated with Down syndrome (ML-DS), AML—not otherwise specified with megakaryocytic differentiation (NOS-AMKL), and AMKL—other patients (AML patients with other WHO classification but with flowcytometric features of megakaryocytic differentiation). Flowcytometric analysis showed good discrimination between AMKL and non-AMKL patients based on differential expression of, in particular, CD42a.CD61, CD41, CD42b, HLADR, CD15 and CD13. Combining CD42a.CD61 (positive) and CD13 (negative) resulted in a sensitivity of 71% and a specificity of 99%. Within AMKL patients, TAM and ML-DS patients showed higher frequencies of immature CD34+/CD117+ leukemic cells as compared to NOS-AMKL and AMKL-Other patients. In addition, ML-DS patients showed a significantly higher expression of CD33, CD11b, CD38 and CD7 as compared to the other three subgroups, allowing for good distinction of these patients. Overall, our data show that the EuroFlow AML panel allows for straightforward diagnosis of AMKL and that ML-DS is associated with a unique immunophenotypic profile. Full article
(This article belongs to the Special Issue Leukemia and Lymphoma Immunophenotyping)
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Systematic Review
The Impact of Cognitive Impairment on Treatment Toxicity, Treatment Completion, and Survival among Older Adults Receiving Chemotherapy: A Systematic Review
Cancers 2022, 14(6), 1582; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061582 - 21 Mar 2022
Viewed by 517
Abstract
Cognitive impairment (CI) is common among older adults with cancer, but its effect on cancer outcomes is not known. This systematic review sought to identify research investigating clinical endpoints (toxicity risk, treatment completion, and survival) of chemotherapy treatment in those with baseline CI. [...] Read more.
Cognitive impairment (CI) is common among older adults with cancer, but its effect on cancer outcomes is not known. This systematic review sought to identify research investigating clinical endpoints (toxicity risk, treatment completion, and survival) of chemotherapy treatment in those with baseline CI. A systematic search of five databases (inception to March 2021) was conducted. Eligible studies included randomized trials, prospective studies, and retrospective studies in which the sample or a subgroup were older adults (aged ≥ 65) screened positive for CI prior to receiving chemotherapy. Risk of bias assessment was performed using the Quality in Prognosis Studies (QUIPS) tool. Twenty-three articles were included. Sample sizes ranged from n = 31 to 703. There was heterogeneity of cancer sites, screening tools and cut-offs used to ascertain CI, and proportion of patients with CI within study samples. Severity of CI and corresponding proportion of each level within study samples were unclear in all but one study. Among studies investigating CI in a qualified multivariable model, statistically significant findings were found in 4/6 studies on survival and in 1/1 study on nonhematological toxicity. The lack of robust evidence indicates a need for further research on the role of CI in predicting survival, treatment completion, and toxicity among older adults receiving chemotherapy, and the potential implications that could shape treatment decisions. Full article
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Editorial
Vulvar Cancer: Facing a Rare Disease
Cancers 2022, 14(6), 1581; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061581 - 20 Mar 2022
Viewed by 663
Abstract
“We must never be afraid to go too far, for truth lies beyond [...] Full article
(This article belongs to the Special Issue Recent Advances in Vulvar Cancer)
Review
Addressing the Elephant in the Immunotherapy Room: Effector T-Cell Priming versus Depletion of Regulatory T-Cells by Anti-CTLA-4 Therapy
Cancers 2022, 14(6), 1580; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061580 - 20 Mar 2022
Cited by 1 | Viewed by 1323
Abstract
Cytotoxic T-lymphocyte Associated Protein 4 (CTLA-4) is an immune checkpoint molecule highly expressed on regulatory T-cells (Tregs) that can inhibit the activation of effector T-cells. Anti-CTLA-4 therapy can confer long-lasting clinical benefits in cancer patients as a single agent or in combination with [...] Read more.
Cytotoxic T-lymphocyte Associated Protein 4 (CTLA-4) is an immune checkpoint molecule highly expressed on regulatory T-cells (Tregs) that can inhibit the activation of effector T-cells. Anti-CTLA-4 therapy can confer long-lasting clinical benefits in cancer patients as a single agent or in combination with other immunotherapy agents. However, patient response rates to anti-CTLA-4 are relatively low, and a high percentage of patients experience severe immune-related adverse events. Clinical use of anti-CTLA-4 has regained interest in recent years; however, the mechanism(s) of anti-CTLA-4 is not well understood. Although activating T-cells is regarded as the primary anti-tumor mechanism of anti-CTLA-4 therapies, mounting evidence in the literature suggests targeting intra-tumoral Tregs as the primary mechanism of action of these agents. Tregs in the tumor microenvironment can suppress the host anti-tumor immune responses through several cell contact-dependent and -independent mechanisms. Anti-CTLA-4 therapy can enhance the priming of T-cells by blockading CD80/86-CTLA-4 interactions or depleting Tregs through antibody-dependent cellular cytotoxicity and phagocytosis. This review will discuss proposed fundamental mechanisms of anti-CTLA-4 therapy, novel uses of anti-CTLA-4 in cancer treatment and approaches to improve the therapeutic efficacy of anti-CTLA-4. Full article
(This article belongs to the Section Cancer Immunology and Immunotherapy)
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Article
MRI Response Assessment in Glioblastoma Patients Treated with Dendritic-Cell-Based Immunotherapy
Cancers 2022, 14(6), 1579; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061579 - 20 Mar 2022
Viewed by 682
Abstract
Introduction: In this post hoc analysis we compared various response-assessment criteria in newly diagnosed glioblastoma (GB) patients treated with tumor lysate-charged autologous dendritic cells (Audencel) and determined the differences in prediction of progression-free survival (PFS) and overall survival (OS). Methods: 76 patients enrolled [...] Read more.
Introduction: In this post hoc analysis we compared various response-assessment criteria in newly diagnosed glioblastoma (GB) patients treated with tumor lysate-charged autologous dendritic cells (Audencel) and determined the differences in prediction of progression-free survival (PFS) and overall survival (OS). Methods: 76 patients enrolled in a multicenter phase II trial receiving standard of care (SOC, n = 40) or SOC + Audencel vaccine (n = 36) were included. MRI scans were evaluated using MacDonald, RANO, Vol-RANO, mRANO, Vol-mRANO and iRANO criteria. Tumor volumes (T1 contrast-enhancing as well as T2/FLAIR volumes) were calculated by semiautomatic segmentation. The Kruskal-Wallis-test was used to detect differences in PFS among the assessment criteria; for correlation analysis the Spearman test was used. Results: There was a significant difference in median PFS between mRANO (8.6 months) and Vol-mRANO (8.6 months) compared to MacDonald (4.0 months), RANO (4.2 months) and Vol-RANO (5.4 months). For the vaccination arm, median PFS by iRANO was 6.2 months. There was no difference in PFS between SOC and SOC + Audencel. The best correlation between PFS/OS was detected for mRANO (r = 0.65) and Vol-mRANO (r = 0.69, each p < 0.001). A total of 16/76 patients developed a pure T2/FLAIR progressing disease, and 4/36 patients treated with Audencel developed pseudoprogression. Conclusion: When comparing different response-assessment criteria in GB patients treated with dendritic cell-based immunotherapy, the best correlation between PFS and OS was observed for mRANO and Vol-mRANO. Interestingly, iRANO was not superior for predicting OS in patients treated with Audencel. Full article
(This article belongs to the Special Issue Biomarker in Glioblastoma)
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Review
Circadian and Immunity Cycle Talk in Cancer Destination: From Biological Aspects to In Silico Analysis
Cancers 2022, 14(6), 1578; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061578 - 20 Mar 2022
Viewed by 938
Abstract
Cancer is the leading cause of death and a major problem to increasing life expectancy worldwide. In recent years, various approaches such as surgery, chemotherapy, radiation, targeted therapies, and the newest pillar, immunotherapy, have been developed to treat cancer. Among key factors impacting [...] Read more.
Cancer is the leading cause of death and a major problem to increasing life expectancy worldwide. In recent years, various approaches such as surgery, chemotherapy, radiation, targeted therapies, and the newest pillar, immunotherapy, have been developed to treat cancer. Among key factors impacting the effectiveness of treatment, the administration of drugs based on the circadian rhythm in a person and within individuals can significantly elevate drug efficacy, reduce adverse effects, and prevent drug resistance. Circadian clocks also affect various physiological processes such as the sleep cycle, body temperature cycle, digestive and cardiovascular processes, and endocrine and immune systems. In recent years, to achieve precision patterns for drug administration using computational methods, the interaction of the effects of drugs and their cellular pathways has been considered more seriously. Integrated data-derived pathological images and genomics, transcriptomics, and proteomics analyses have provided an understanding of the molecular basis of cancer and dramatically revealed interactions between circadian and immunity cycles. Here, we describe crosstalk between the circadian cycle signaling pathway and immunity cycle in cancer and discuss how tumor microenvironment affects the influence on treatment process based on individuals’ genetic differences. Moreover, we highlight recent advances in computational modeling that pave the way for personalized immune chronotherapy. Full article
(This article belongs to the Special Issue Quantitative Approaches to Cancer Immunotherapy)
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Review
At the Intersection of Cardiology and Oncology: TGFβ as a Clinically Translatable Therapy for TNBC Treatment and as a Major Regulator of Post-Chemotherapy Cardiomyopathy
Cancers 2022, 14(6), 1577; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061577 - 19 Mar 2022
Viewed by 708
Abstract
Triple-negative breast cancer (TNBC) is a subtype of breast cancer that accounts for the majority of breast cancer-related deaths due to the lack of specific targets for effective treatments. While there is immense focus on the development of novel therapies for TNBC treatment, [...] Read more.
Triple-negative breast cancer (TNBC) is a subtype of breast cancer that accounts for the majority of breast cancer-related deaths due to the lack of specific targets for effective treatments. While there is immense focus on the development of novel therapies for TNBC treatment, a persistent and critical issue is the rate of heart failure and cardiomyopathy, which is a leading cause of mortality and morbidity amongst cancer survivors. In this review, we highlight mechanisms of post-chemotherapeutic cardiotoxicity exposure, evaluate how this is assessed clinically and highlight the transforming growth factor-beta family (TGF-β) pathway and its significance as a mediator of cardiomyopathy. We also highlight recent findings demonstrating TGF-β inhibition as a potent method to prevent cardiac remodeling, fibrosis and cardiomyopathy. We describe how dysregulation of the TGF-β pathway is associated with negative patient outcomes across 32 types of cancer, including TNBC. We then highlight how TGF-β modulation may be a potent method to target mesenchymal (CD44+/CD24) and epithelial (ALDHhigh) cancer stem cell (CSC) populations in TNBC models. CSCs are associated with tumorigenesis, metastasis, relapse, resistance and diminished patient prognosis; however, due to plasticity and differential regulation, these populations remain difficult to target and continue to present a major barrier to successful therapy. TGF-β inhibition represents an intersection of two fields: cardiology and oncology. Through the inhibition of cardiomyopathy, cardiac damage and heart failure may be prevented, and through CSC targeting, patient prognoses may be improved. Together, both approaches, if successfully implemented, would target the two greatest causes of cancer-related morbidity in patients and potentially lead to a breakthrough therapy. Full article
(This article belongs to the Special Issue Signalling Pathways of Cancer Stem Cells)
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Article
Expression of Membranous CD155 Is Associated with Aggressive Phenotypes and a Poor Prognosis in Patients with Bladder Cancer
Cancers 2022, 14(6), 1576; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061576 - 19 Mar 2022
Viewed by 621
Abstract
Objective: To investigate the relationship between clinicopathological findings and membranous CD155 (mCD155) or cytoplasmic CD155 (cCD155) expression in bladder cancer (BC). Methods: We retrospectively analyzed 103 patients with BC who underwent radical cystectomy between 1990 to 2015 at Kitasato University Hospital. Immunohistochemical staining [...] Read more.
Objective: To investigate the relationship between clinicopathological findings and membranous CD155 (mCD155) or cytoplasmic CD155 (cCD155) expression in bladder cancer (BC). Methods: We retrospectively analyzed 103 patients with BC who underwent radical cystectomy between 1990 to 2015 at Kitasato University Hospital. Immunohistochemical staining was performed to evaluate CD155 expression in tumor cells. Cases with > 10% expression on the membrane or cytoplasm of tumor cells were positive. The Fisher′s exact test was used for categorical variables and the Kaplan–Meier method was used for survival outcomes. Univariate and multivariate Cox regression hazard models were used to evaluate the survival risk factors. Results: Cases that were mCD155-positive were associated with high-grade tumors (p = 0.02), nodal status (p < 0.01), and pT stage (p = 0.04). No association with any clinicopathological factor was observed in the cCD155 cases. Kaplan–Meier analysis showed that mCD155-positive cases had shorter periods of recurrence-free survival (p = 0.015) and cancer-specific survival (p = 0.005). Only nodal status was an independent predictor for both cancer-specific survival and recurrence-free survival in multivariate analysis (p = 0.02 and p < 0.01, respectively). Conclusion: mCD155 expression may be a marker of an aggressive phenotype and a poor prognosis in patients with BC. Full article
(This article belongs to the Special Issue Insights into Urologic Cancer)
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Article
Identification of New Vulnerabilities in Conjunctival Melanoma Using Image-Based High Content Drug Screening
Cancers 2022, 14(6), 1575; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061575 - 19 Mar 2022
Viewed by 696
Abstract
Recent evidence suggests that numerous similarities exist between the genomic landscapes of both conjunctival and cutaneous melanoma. Since alterations of several components of the MAP kinases, PI3K/mTOR, and cell cycle pathways have been reported in conjunctival melanoma, we decided to assess the sensitivity [...] Read more.
Recent evidence suggests that numerous similarities exist between the genomic landscapes of both conjunctival and cutaneous melanoma. Since alterations of several components of the MAP kinases, PI3K/mTOR, and cell cycle pathways have been reported in conjunctival melanoma, we decided to assess the sensitivity of conjunctival melanoma to targeted inhibition mostly of kinase inhibitors. A high content drug screening assay based on automated fluorescence microscopy was performed in three conjunctival melanoma cell lines with different genomic backgrounds with 489 kinase inhibitors and 53 other inhibitors. IC50 and apoptosis induction were respectively assessed for 53 and 48 compounds. The genomic background influenced the response to MAK and PI3K/mTOR inhibition, more specifically cell lines with BRAF V600E mutations were more sensitive to BRAF/MEK inhibition, while CRMM2 bearing the NRASQ61L mutation was more sensitive to PI3k/mTOR inhibition. All cell lines demonstrated sensitivity to cell cycle inhibition, being more pronounced in CRMM2, especially with polo-like inhibitors. Our data also revealed new vulnerabilities to Hsp90 and Src inhibition. This study demonstrates that the genomic background partially influences the response to targeted therapy and uncovers a large panel of potential vulnerabilities in conjunctival melanoma that may expand available options for the management of this tumor. Full article
(This article belongs to the Special Issue Systemic Therapies in Melanoma)
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Article
Effect of Osimertinib on CTCs and ctDNA in EGFR Mutant Non-Small Cell Lung Cancer Patients: The Prognostic Relevance of Liquid Biopsy
Cancers 2022, 14(6), 1574; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061574 - 19 Mar 2022
Viewed by 638
Abstract
Introduction: Liquid biopsy is a useful tool for monitoring treatment outcome in solid tumors, including lung cancer. The relevance of monitoring CTCs and plasma ctDNA as predictors of clinical outcome was assessed in EGFR-mutant NSCLC patients treated with osimertinib. Methods: Forty-seven EGFR-mutant NSCLC [...] Read more.
Introduction: Liquid biopsy is a useful tool for monitoring treatment outcome in solid tumors, including lung cancer. The relevance of monitoring CTCs and plasma ctDNA as predictors of clinical outcome was assessed in EGFR-mutant NSCLC patients treated with osimertinib. Methods: Forty-seven EGFR-mutant NSCLC patients who had progressed on prior first- or second-generation EGFR inhibitors were enrolled in the study and treated with osimertinib, irrespective of the presence of the T790M mutation in the primary tumor or the plasma. Peripheral blood was collected at baseline (n = 47), post-Cycle 1 (n = 47), and at the end of treatment (EOT; n = 39). CTCs were evaluated in 32 patients at the same time points (n = 32, n = 27, and n = 21, respectively) and phenotypic characterization was performed using triple immunofluorescence staining (CK/VIM/CD45). Results: Osimertinib resulted in an ORR of 34% (2 CR) and a DCR of 76.6%. The median PFS and OS values were 7.5 (range, 0.8–52.8) and 15.1 (range, 2.1–52.8) months, respectively. ctDNA was detected in 61.7%, 27.7%, and 61.5% of patients at baseline, post-Cycle 1, and EOT, respectively. CTCs (CK+/CD45-) were detected in 68.8%, 48.1%, and 61.9% of patients at the three time points, respectively. CTCs expressing both epithelial and mesenchymal markers (CK+/VIM+/CD45-) were detected in 56.3% and 29.6% of patients at baseline and post-Cycle 1, respectively. The detection of ctDNA at baseline and post-Cycle 1 was associated with shorter PFS and OS, whereas the ctDNA clearance post-Cycle 1 resulted in a significantly longer PFS and OS. Multivariate analysis revealed that male sex and the detection of ctDNA at baseline were independent predictors of shorter PFS (HR: 2.6, 95% C.I.: 1.2–5.5, p = 0.015 and HR: 3.0, 95% C.I.: 1.3–6.9; p = 0.009, respectively). Conclusions: The decrease in both CTCs and ctDNA occurring early during osimertinib treatment is predictive of better outcome, implying that liquid biopsy monitoring may be a valuable tool for the assessment of treatment efficacy. Full article
(This article belongs to the Special Issue Liquid Biopsy in Cancer)
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Article
A Gene Co-Expression Network-Based Drug Repositioning Approach Identifies Candidates for Treatment of Hepatocellular Carcinoma
Cancers 2022, 14(6), 1573; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061573 - 19 Mar 2022
Cited by 1 | Viewed by 847
Abstract
Hepatocellular carcinoma (HCC) is a malignant liver cancer that continues to increase deaths worldwide owing to limited therapies and treatments. Computational drug repurposing is a promising strategy to discover potential indications of existing drugs. In this study, we present a systematic drug repositioning [...] Read more.
Hepatocellular carcinoma (HCC) is a malignant liver cancer that continues to increase deaths worldwide owing to limited therapies and treatments. Computational drug repurposing is a promising strategy to discover potential indications of existing drugs. In this study, we present a systematic drug repositioning method based on comprehensive integration of molecular signatures in liver cancer tissue and cell lines. First, we identify robust prognostic genes and two gene co-expression modules enriched in unfavorable prognostic genes based on two independent HCC cohorts, which showed great consistency in functional and network topology. Then, we screen 10 genes as potential target genes for HCC on the bias of network topology analysis in these two modules. Further, we perform a drug repositioning method by integrating the shRNA and drug perturbation of liver cancer cell lines and identifying potential drugs for every target gene. Finally, we evaluate the effects of the candidate drugs through an in vitro model and observe that two identified drugs inhibited the protein levels of their corresponding target genes and cell migration, also showing great binding affinity in protein docking analysis. Our study demonstrates the usefulness and efficiency of network-based drug repositioning approach to discover potential drugs for cancer treatment and precision medicine approach. Full article
(This article belongs to the Special Issue Drug Repurposing for Cancer Therapy)
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Article
Identification of a Steroid Hormone-Associated Gene Signature Predicting the Prognosis of Prostate Cancer through an Integrative Bioinformatics Analysis
Cancers 2022, 14(6), 1565; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061565 - 19 Mar 2022
Viewed by 802
Abstract
The importance of anti-androgen therapy for prostate cancer (PC) has been well recognized. However, the mechanisms underlying prostate cancer resistance to anti-androgens are not completely understood. Therefore, identifying pharmacological targets in driving the development of castration-resistant PC is necessary. In the present study, [...] Read more.
The importance of anti-androgen therapy for prostate cancer (PC) has been well recognized. However, the mechanisms underlying prostate cancer resistance to anti-androgens are not completely understood. Therefore, identifying pharmacological targets in driving the development of castration-resistant PC is necessary. In the present study, we sought to identify core genes in regulating steroid hormone pathways and associating them with the disease progression of PC. The selection of steroid hormone-associated genes was identified from functional databases, including gene ontology, KEGG, and Reactome. The gene expression profiles and relevant clinical information of patients with PC were obtained from TCGA and used to examine the genes associated with steroid hormone. The machine-learning algorithm was performed for key feature selection and signature construction. With the integrative bioinformatics analysis, an eight-gene signature, including CA2, CYP2E1, HSD17B, SSTR3, SULT1E1, TUBB3, UCN, and UGT2B7 was established. Patients with higher expression of this gene signature had worse progression-free interval in both univariate and multivariate cox models adjusted for clinical variables. The expression of the gene signatures also showed the aggressiveness consistently in two external cohorts, PCS and PAM50. Our findings demonstrated a validated eight-gene signature could successfully predict PC prognosis and regulate the steroid hormone pathway. Full article
(This article belongs to the Special Issue Cytokine and Steroid Hormone Signaling in Prostate Cancer)
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Article
Intraoperative Near-Infrared Fluorescence Imaging with Indocyanine Green for Identification of Gastrointestinal Stromal Tumors (GISTs), a Feasibility Study
Cancers 2022, 14(6), 1572; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061572 - 18 Mar 2022
Viewed by 626
Abstract
Background: Optimal intraoperative tumor identification of gastrointestinal stromal tumors (GISTs) is important for the quality of surgical resections. This study aims to assess the potential of near-infrared fluorescence (NIRF) imaging with indocyanine green (ICG) to improve intraoperative tumor identification. Methods: Ten GIST patients, [...] Read more.
Background: Optimal intraoperative tumor identification of gastrointestinal stromal tumors (GISTs) is important for the quality of surgical resections. This study aims to assess the potential of near-infrared fluorescence (NIRF) imaging with indocyanine green (ICG) to improve intraoperative tumor identification. Methods: Ten GIST patients, planned to undergo resection, were included. During surgery, 10 mg of ICG was intravenously administered, and NIRF imaging was performed at 5, 10, and 15 min after the injection. The tumor fluorescence intensity was visually assessed, and tumor-to-background ratios (TBRs) were calculated for exophytic lesions. Results: Eleven GIST lesions were imaged. The fluorescence intensity of the tumor was visually synchronous and similar to the background in five lesions. In one lesion, the tumor fluorescence was more intense than in the surrounding tissue. Almost no fluorescence was observed in both the tumor and healthy peritoneal tissue in two patients with GIST lesions adjacent to the liver. In three GISTs without exophytic growth, no fluorescence of the tumor was observed. The median TBRs at 5, 10, and 15 min were 1.0 (0.4–1.2), 1.0 (0.5–1.9), and 0.9 (0.7–1.2), respectively. Conclusion: GISTs typically show similar fluorescence intensity to the surrounding tissue in NIRF imaging after intraoperative ICG administration. Therefore, intraoperatively administered ICG is currently not applicable for adequate tumor identification, and further research should focus on the development of tumor-specific fluorescent tracers for GISTs. Full article
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Review
PI3K Inhibitors for the Treatment of Chronic Lymphocytic Leukemia: Current Status and Future Perspectives
Cancers 2022, 14(6), 1571; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061571 - 18 Mar 2022
Viewed by 951
Abstract
Phosphoinositide 3-kinases (PI3Ks) signaling regulates key cellular processes, such as growth, survival and apoptosis. Among the three classes of PI3K, class I is the most important for the development, differentiation and activation of B and T cells. Four isoforms are distinguished within class [...] Read more.
Phosphoinositide 3-kinases (PI3Ks) signaling regulates key cellular processes, such as growth, survival and apoptosis. Among the three classes of PI3K, class I is the most important for the development, differentiation and activation of B and T cells. Four isoforms are distinguished within class I (PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ). PI3Kδ expression is limited mainly to the B cells and their precursors, and blocking PI3K has been found to promote apoptosis of chronic lymphocytic leukemia (CLL) cells. Idelalisib, a selective PI3Kδ inhibitor, was the first-in-class PI3Ki introduced into CLL treatment. It showed efficacy in patients with del(17p)/TP53 mutation, unmutated IGHV status and refractory/relapsed disease. However, its side effects, such as autoimmune-mediated pneumonitis and colitis, infections and skin changes, limited its widespread use. The dual PI3Kδ/γ inhibitor duvelisib is approved for use in CLL patients but with similar toxicities to idelalisib. Umbralisib, a highly selective inhibitor of PI3Kδ and casein kinase-1ε (CK1ε), was found to be efficient and safe in monotherapy and in combination regimens in phase 3 trials in patients with CLL. Novel PI3Kis are under evaluation in early phase clinical trials. In this paper we present the mechanism of action, efficacy and toxicities of PI3Ki approved in the treatment of CLL and developed in clinical trials. Full article
(This article belongs to the Special Issue Therapeutic Targets in Chronic Lymphocytic Leukemia)
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Article
Aptamer Targets Triple-Negative Breast Cancer through Specific Binding to Surface CD49c
Cancers 2022, 14(6), 1570; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061570 - 18 Mar 2022
Viewed by 760
Abstract
Although targeted cancer therapy can induce higher therapeutic efficacy and cause fewer side effects in patients, the lack of targetable biomarkers on triple-negative breast cancer (TNBC) cells limits the development of targeted therapies by antibody technology. Therefore, we investigated an alternative approach to [...] Read more.
Although targeted cancer therapy can induce higher therapeutic efficacy and cause fewer side effects in patients, the lack of targetable biomarkers on triple-negative breast cancer (TNBC) cells limits the development of targeted therapies by antibody technology. Therefore, we investigated an alternative approach to target TNBC by using the PDGC21T aptamer, which selectively binds to poorly differentiated carcinoma cells and tumor tissues, although the cellular target is still unknown. We found that synthetic aptamer probes specifically bound cultured TNBC cells in vitro and selectively targeted TNBC xenografts in vivo. Subsequently, to identify the target molecule on TNBC cells, we performed aptamer-mediated immunoprecipitation in lysed cell membranes followed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Sequencing analysis revealed a highly conserved peptide sequence consistent with the cell surface protein CD49c (integrin α3). For target validation, we stained cultured TNBC and non-TNBC cells with an aptamer probe or a CD49c antibody and found similar cell staining patterns. Finally, competition cell-binding assays using both aptamer and anti-CD49c antibody revealed that CD49c is the biomarker targeted by the PDGC21T aptamer on TNBC cells. Our findings provide a molecular foundation for the development of targeted TNBC therapy using the PDGC21T aptamer as a targeting ligand. Full article
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Review
The New Treatment Methods for Non-Hodgkin Lymphoma in Pediatric Patients
Cancers 2022, 14(6), 1569; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061569 - 18 Mar 2022
Cited by 1 | Viewed by 757
Abstract
One of the most common cancer malignancies is non-Hodgkin lymphoma, whose incidence is nearly 3% of all 36 cancers combined. It is the fourth highest cancer occurrence in children and accounts for 7% of cancers in patients under 20 years of age. Today, [...] Read more.
One of the most common cancer malignancies is non-Hodgkin lymphoma, whose incidence is nearly 3% of all 36 cancers combined. It is the fourth highest cancer occurrence in children and accounts for 7% of cancers in patients under 20 years of age. Today, the survivability of individuals diagnosed with non-Hodgkin lymphoma varies by about 70%. Chemotherapy, radiation, stem cell transplantation, and immunotherapy have been the main methods of treatment, which have improved outcomes for many oncological patients. However, there is still the need for creation of novel medications for those who are treatment resistant. Additionally, more effective drugs are necessary. This review gathers the latest findings on non-Hodgkin lymphoma treatment options for pediatric patients. Attention will be focused on the most prominent therapies such as monoclonal antibodies, antibody–drug conjugates, chimeric antigen receptor T cell therapy and others. Full article
(This article belongs to the Special Issue Non-Hodgkin Lymphoma in Children)
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Article
Tumor Treating Fields Concomitant with Sorafenib in Advanced Hepatocellular Cancer: Results of the HEPANOVA Phase II Study
Cancers 2022, 14(6), 1568; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061568 - 18 Mar 2022
Cited by 1 | Viewed by 918
Abstract
Advanced hepatocellular carcinoma (HCC) is an aggressive disease associated with poor prognosis. Tumor Treating Fields (TTFields) therapy is a non-invasive, loco-regional treatment approved for glioblastoma and malignant pleural mesothelioma. HCC preclinical and abdominal simulation data, together with clinical results in other solid tumors, [...] Read more.
Advanced hepatocellular carcinoma (HCC) is an aggressive disease associated with poor prognosis. Tumor Treating Fields (TTFields) therapy is a non-invasive, loco-regional treatment approved for glioblastoma and malignant pleural mesothelioma. HCC preclinical and abdominal simulation data, together with clinical results in other solid tumors, provide a rationale for investigating TTFields with sorafenib in this patient population. HEPANOVA was a phase II, single arm, historical control study in adults with advanced HCC (NCT03606590). Patients received TTFields (150 kHz) for ≥18 h/day concomitant with sorafenib (400 mg BID). Imaging assessments occurred every 12 weeks until disease progression. The primary endpoint was the overall response rate (ORR). Safety was also evaluated. Patients (n = 27 enrolled; n = 21 evaluable) had a poor prognosis; >50% were Child–Turcotte–Pugh class B and >20% had a baseline Eastern Clinical Oncology Group performance status (ECOG PS) of 2. The ORR was higher, but not statistically significant, for TTFields/sorafenib vs. historical controls: 9.5% vs. 4.5% (p = 0.24), respectively; all responses were partial. Among patients (n = 11) with ≥12 weeks of TTFields/sorafenib, ORR was 18%. Common adverse events (AEs) were diarrhea (n = 15/27, 56%) and asthenia (n = 11/27, 40%). Overall, 19/27 (70%) patients had TTFields-related skin AEs; none were serious. TTFields/sorafenib improved response rates vs. historical controls in patients with advanced HCC, with no new safety concerns or related systemic toxicity. Full article
(This article belongs to the Collection Novel Therapies for Hepatocellular Carcinoma)
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