Cancers

30 pages, 9240 KiB

Open AccessReview

Challenges in the Early Diagnosis of Oral Cancer, Evidence Gaps and Strategies for Improvement: A Scoping Review of Systematic Reviews

by Miguel Ángel González-Moles, Manuel Aguilar-Ruiz and Pablo Ramos-García

Cancers 2022, 14(19), 4967; https://doi.org/10.3390/cancers14194967 - 10 Oct 2022

Cited by 44 | Viewed by 9507

Abstract

Oral cancer is a growing problem, accounting for 377,713 worldwide new cases per year, and 177,757 deaths annually and representing a 5-year mortality rate close to 50%, which is a considerable mortality that has not decreased substantially in the last 40 years. The [...] Read more.

Oral cancer is a growing problem, accounting for 377,713 worldwide new cases per year, and 177,757 deaths annually and representing a 5-year mortality rate close to 50%, which is a considerable mortality that has not decreased substantially in the last 40 years. The main cause of this high mortality is related to the diagnosis of a high percentage of oral cancers in advanced stages (stages III and IV) in which treatment is complex, mutilating or disabling, and ineffective. The essential cause of a cancer diagnosis at a late stage is the delay in diagnosis, therefore, the achievement of the objective of improving the prognosis of oral cancer involves reducing the delay in its diagnosis. The reasons for the delay in the diagnosis of oral cancer are complex and involve several actors and circumstances—patients, health care providers, and health services. In this paper, we present the results of a scoping review of systematic reviews on the diagnostic delay in oral cancer with the aim to better understand, based on the evidence, and discuss in depth, the reasons for this fact, and to identify evidence gaps and formulate strategies for improvement. Full article

(This article belongs to the Special Issue Oncology: State-of-the-Art Research in Spain)

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11 pages, 2918 KiB

Open AccessArticle

Early Mechanisms of Chemoresistance in Retinoblastoma

by Michelle G. Zhang, Jeffim N. Kuznetsoff, Dawn A. Owens, Ryan A. Gallo, Karthik Kalahasty, Anthony M. Cruz, Stefan Kurtenbach, Zelia M. Correa, Daniel Pelaez and J. William Harbour

Cancers 2022, 14(19), 4966; https://doi.org/10.3390/cancers14194966 - 10 Oct 2022

Cited by 7 | Viewed by 3245

Abstract

Retinoblastoma is the most common eye cancer in children and is fatal if left untreated. Over the past three decades, chemotherapy has become the mainstay of eye-sparing treatment. Nevertheless, chemoresistance continues to represent a major challenge leading to ocular and systemic toxicity, vision [...] Read more.

Retinoblastoma is the most common eye cancer in children and is fatal if left untreated. Over the past three decades, chemotherapy has become the mainstay of eye-sparing treatment. Nevertheless, chemoresistance continues to represent a major challenge leading to ocular and systemic toxicity, vision loss, and treatment failure. Unfortunately, the mechanisms leading to chemoresistance remain incompletely understood. Here, we engineered low-passage human retinoblastoma cells to study the early molecular mechanisms leading to resistance to carboplatin, one of the most widely used agents for treating retinoblastoma. Using single-cell next-generation RNA sequencing (scRNA-seq) and single-cell barcoding technologies, we found that carboplatin induced rapid transcriptomic reprogramming associated with the upregulation of PI3K-AKT pathway targets, including ABC transporters and metabolic regulators. Several of these targets are amenable to pharmacologic inhibition, which may reduce the emergence of chemoresistance. We provide evidence to support this hypothesis using a third-generation inhibitor of the ABCB1 transporter. Full article

(This article belongs to the Special Issue Pediatric Cancer Biology: Basic and Translational Implications)

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20 pages, 1054 KiB

Open AccessPerspective

High Neutrophil-to-Lymphocyte Ratio Facilitates Cancer Growth—Currently Marketed Drugs Tadalafil, Isotretinoin, Colchicine, and Omega-3 to Reduce It: The TICO Regimen

by Richard E. Kast

Cancers 2022, 14(19), 4965; https://doi.org/10.3390/cancers14194965 - 10 Oct 2022

Cited by 5 | Viewed by 3758

Abstract

This paper presents remarkably uniform data showing that higher NLR is a robust prognostic indicator of shorter overall survival across the common metastatic cancers. Myeloid derived suppressor cells, the NLRP3 inflammasome, neutrophil extracellular traps, and absolute neutrophil count tend to all be directly [...] Read more.

This paper presents remarkably uniform data showing that higher NLR is a robust prognostic indicator of shorter overall survival across the common metastatic cancers. Myeloid derived suppressor cells, the NLRP3 inflammasome, neutrophil extracellular traps, and absolute neutrophil count tend to all be directly related to the NLR. They, individually and as an ensemble, contribute to cancer growth and metastasis. The multidrug regimen presented in this paper, TICO, was designed to decrease the NLR with potential to also reduce the other neutrophil related elements favoring malignant growth. TICO is comprised of already marketed generic drugs: the phosphodiesterase 5 inhibitor tadalafil, used to treat inadequate erections; isotretinoin, the retinoid used for acne treatment; colchicine, a standard gout (podagra) treatment; and the common fish oil supplement omega-3 polyunsaturated fatty acids. These individually impose low side effect burdens. The drugs of TICO are old, cheap, well known, and available worldwide. They all have evidence of lowering the NLR or the growth contributing elements related to the NLR when clinically used in general medicine as reviewed in this paper. Full article

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14 pages, 2980 KiB

Open AccessArticle

Development of the Novel Bifunctional Fusion Protein BR102 That Simultaneously Targets PD-L1 and TGF-β for Anticancer Immunotherapy

by Zhen-Hua Wu, Na Li, Zhang-Zhao Gao, Gang Chen, Lei Nie, Ya-Qiong Zhou, Mei-Zhu Jiang, Yao Chen, Juan Chen, Xiao-Fen Mei, Feng Hu and Hai-Bin Wang

Cancers 2022, 14(19), 4964; https://doi.org/10.3390/cancers14194964 - 10 Oct 2022

Cited by 8 | Viewed by 2852

Abstract

Immune checkpoint inhibitors (ICIs) are remarkable breakthroughs in treating various types of cancer, but many patients still do not derive long-term clinical benefits. Increasing evidence shows that TGF-β can promote cancer progression and confer resistance to ICI therapies. Consequently, dual blocking of TGF-β [...] Read more.

Immune checkpoint inhibitors (ICIs) are remarkable breakthroughs in treating various types of cancer, but many patients still do not derive long-term clinical benefits. Increasing evidence shows that TGF-β can promote cancer progression and confer resistance to ICI therapies. Consequently, dual blocking of TGF-β and immune checkpoint may provide an effective approach to enhance the effectiveness of ICI therapies. Here, we reported the development and preclinical characterization of a novel bifunctional anti-PD-L1/TGF-β fusion protein, BR102. BR102 comprises an anti-PD-L1 antibody fused to the extracellular domain (ECD) of human TGF-βRII. BR102 is capable of simultaneously binding to TGF-β and PD-L1. Incorporating TGF-βRII into BR102 does not alter the PD-L1 blocking activity of BR102. In vitro characterization further demonstrated that BR102 could disrupt TGF-β-induced signaling. Moreover, BR102 significantly inhibits tumor growth in vivo and exerts a superior antitumor effect compared to anti-PD-L1. Administration of BR102 to cynomolgus monkeys is well-tolerated, with only minimal to moderate and reversing red cell changes noted. The data demonstrated the efficacy and safety of the novel anti-PD-L1/TGF-β fusion protein and supported the further clinical development of BR102 for anticancer therapy. Full article

(This article belongs to the Special Issue Cell Therapy, Bispecific Antibodies and other Immunotherapies Against Cancer)

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17 pages, 301 KiB

Open AccessReview

Molecular Mechanisms Driving the Formation of Brain Metastases

by Bethany K. Campbell, Zijie Gao, Niall M. Corcoran, Stanley S. Stylli and Christopher M. Hovens

Cancers 2022, 14(19), 4963; https://doi.org/10.3390/cancers14194963 - 10 Oct 2022

Cited by 11 | Viewed by 3122

Abstract

Targeted therapies for cancers have improved primary tumor response rates, but concomitantly, brain metastases (BM) have become the most common brain tumors in adults and are associated with a dismal prognosis of generally less than 6 months, irrespective of the primary cancer type. [...] Read more.

Targeted therapies for cancers have improved primary tumor response rates, but concomitantly, brain metastases (BM) have become the most common brain tumors in adults and are associated with a dismal prognosis of generally less than 6 months, irrespective of the primary cancer type. They most commonly occur in patients with primary breast, lung, or melanoma histologies; however, they also appear in patients with other primary cancers including, but not limited to, prostate cancer, colorectal cancer, and renal cell carcinoma. Historically, molecular biomarkers have normally been identified from primary tumor resections. However, clinically informative genomic alterations can occur during BM development and these potentially actionable alterations are not always detected in the primary tumor leading to missed opportunities for effective targeted therapy. The molecular mechanisms that facilitate and drive metastasis to the brain are poorly understood. Identifying the differences between the brain and other extracranial sties of metastasis, and between primary tumors and BM, is essential to improving our understanding of BM development and ultimately patient management and survival. In this review, we present the current data on the genomic landscape of BM from various primary cancers which metastasize to the brain and outline potential mechanisms which may play a role in promoting the formation of the distant metastases in the brain. Full article

(This article belongs to the Section Molecular Cancer Biology)

16 pages, 338 KiB

Open AccessArticle

Paternal Occupational Exposure to Heavy Metals and Welding Fumes and Testicular Germ Cell Tumours in Sons in France

by Shukrullah Ahmadi, Margot Guth, Astrid Coste, Liacine Bouaoun, Aurélie Danjou, Marie Lefevre, Brigitte Dananché, Delphine Praud, Martie Van Tongeren, Louis Bujan, Olivia Pérol, Joachim Schüz, Barbara Charbotel, Béatrice Fervers, Ann Olsson and the TESTIS Study Group

Cancers 2022, 14(19), 4962; https://doi.org/10.3390/cancers14194962 - 10 Oct 2022

Cited by 4 | Viewed by 2586

Abstract

Testicular cancer is the most common cancer in young men. Its causes are largely unknown, although prenatal occupational and environmental exposures have been suggested. We investigated paternal occupational exposure to heavy metals and welding fumes and the risk of testicular germ cell tumors [...] Read more.

Testicular cancer is the most common cancer in young men. Its causes are largely unknown, although prenatal occupational and environmental exposures have been suggested. We investigated paternal occupational exposure to heavy metals and welding fumes and the risk of testicular germ cell tumors (TGCT) in their offspring. A total of 454 cases and 670 controls were included from a French nationwide case–control study. The INTEROCC job exposure matrix was used to assign occupational exposures (cadmium, chromium, iron, nickel, lead, and welding fumes) to the fathers’ jobs. Odds ratios (ORs) for TGCT were estimated using conditional logistic regression models for frequency-matched sets. Three complementary analytical approaches were used: (1) single-agent analysis, (2) analysis by groups, and (3) principal component analysis (PCA). The proportion of paternal exposure to different heavy metals and welding fumes ranged from 0.7% (cadmium) to 11.3% (lead). Based on PCA, three principal components explained 93.5% of the cumulative variance. No associations were found between heavy metals or welding fumes and TGCT. In this study, paternal occupational exposure to heavy metals or welding fumes was not associated with TGCT development in their sons. Full article

(This article belongs to the Special Issue Occupational Cancers)

18 pages, 3538 KiB

Open AccessArticle

Gene Regulatory Network Characterization of Gastric Cancer’s Histological Subtypes: Distinctive Biological and Clinically Relevant Master Regulators

by Sabino Russi, Luigi Marano, Simona Laurino, Giovanni Calice, Dario Scala, Graziella Marino, Alessandro Sgambato, Pellegrino Mazzone, Ludovico Carbone, Giuliana Napolitano, Franco Roviello, Geppino Falco and Pietro Zoppoli

Cancers 2022, 14(19), 4961; https://doi.org/10.3390/cancers14194961 - 10 Oct 2022

Cited by 5 | Viewed by 2761

Abstract

Gastric cancer (GC) molecular heterogeneity represents a major determinant for clinical outcomes, and although new molecular classifications have been introduced, they are not easy to translate from bench to bedside. We explored the data from GC public databases by performing differential gene expression [...] Read more.

Gastric cancer (GC) molecular heterogeneity represents a major determinant for clinical outcomes, and although new molecular classifications have been introduced, they are not easy to translate from bench to bedside. We explored the data from GC public databases by performing differential gene expression analysis (DEGs) and gene network reconstruction to identify master regulators (MRs), as well as a gene set analysis (GSA) to reveal their biological features. Moreover, we evaluated the association of MRs with clinicopathological parameters. According to the GSA, the Diffuse group was characterized by an epithelial-mesenchymal transition (EMT) and inflammatory response, while the Intestinal group was associated with a cell cycle and drug resistance pathways. In particular, the regulons of Diffuse MRs, such as Vgll3 and Ciita, overlapped with the EMT and interferon-gamma response, while the regulons Top2a and Foxm1 were shared with the cell cycle pathways in the Intestinal group. We also found a strict association between MR activity and several clinicopathological features, such as survival. Our approach led to the identification of genes and pathways differentially regulated in the Intestinal and Diffuse GC histotypes, highlighting biologically interesting MRs and subnetworks associated with clinical features and prognosis, suggesting putative actionable candidates. Full article

(This article belongs to the Topic Big Data in Healthcare, Bioinformatics and Precision Medicine)

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25 pages, 2529 KiB

Open AccessReview

Advances in Preclinical/Clinical Glioblastoma Treatment: Can Nanoparticles Be of Help?

by Daniel Ruiz-Molina, Xiaoman Mao, Paula Alfonso-Triguero, Julia Lorenzo, Jordi Bruna, Victor J. Yuste, Ana Paula Candiota and Fernando Novio

Cancers 2022, 14(19), 4960; https://doi.org/10.3390/cancers14194960 - 10 Oct 2022

Cited by 13 | Viewed by 2564

Abstract

Glioblastoma multiforme (GB) is the most aggressive and frequent primary malignant tumor in the central nervous system (CNS), with unsatisfactory and challenging treatment nowadays. Current standard of care includes surgical resection followed by chemotherapy and radiotherapy. However, these treatments do not much improve [...] Read more.

Glioblastoma multiforme (GB) is the most aggressive and frequent primary malignant tumor in the central nervous system (CNS), with unsatisfactory and challenging treatment nowadays. Current standard of care includes surgical resection followed by chemotherapy and radiotherapy. However, these treatments do not much improve the overall survival of GB patients, which is still below two years (the 5-year survival rate is below 7%). Despite various approaches having been followed to increase the release of anticancer drugs into the brain, few of them demonstrated a significant success, as the blood brain barrier (BBB) still restricts its uptake, thus limiting the therapeutic options. Therefore, enormous efforts are being devoted to the development of novel nanomedicines with the ability to cross the BBB and specifically target the cancer cells. In this context, the use of nanoparticles represents a promising non-invasive route, allowing to evade BBB and reducing systemic concentration of drugs and, hence, side effects. In this review, we revise with a critical view the different families of nanoparticles and approaches followed so far with this aim. Full article

(This article belongs to the Section Cancer Therapy)

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22 pages, 6176 KiB

Open AccessReview

The Good, the Bad and the New about Uric Acid in Cancer

by Simone Allegrini, Mercedes Garcia-Gil, Rossana Pesi, Marcella Camici and Maria Grazia Tozzi

Cancers 2022, 14(19), 4959; https://doi.org/10.3390/cancers14194959 - 10 Oct 2022

Cited by 34 | Viewed by 9825

Abstract

Uric acid is the final product of purine catabolism in man and apes. The serum concentration of uric acid is sex-, age- and diet-dependent and is maintained close to its maximal solubility, indicating that it plays some important role. Indeed, it has been [...] Read more.

Uric acid is the final product of purine catabolism in man and apes. The serum concentration of uric acid is sex-, age- and diet-dependent and is maintained close to its maximal solubility, indicating that it plays some important role. Indeed, it has been demonstrated that, at physiological concentrations, uric acid is a powerful antioxidant, while at high intracellular concentrations, it is a pro-oxidant molecule. In this review, we describe the possible causes of uric acid accumulation or depletion and some of the metabolic and regulatory pathways it may impact. Particular attention has been given to fructose, which, because of the complex correlation between carbohydrate and nucleotide metabolism, causes uric acid accumulation. We also present recent results on the positive and negative effects played by uric acid in cancer and some new findings and hypotheses about the implication of this metabolite in a variety of signaling pathways, which can play a role in the pathogenesis of diseases such as metabolic syndrome, diabetes, and inflammation, thus favoring the development of cancer. The loss of uricase in Homo sapiens and great apes, although exposing these species to the potentially adverse effects of uric acid, appears to be associated with evolutionary advantages. Full article

(This article belongs to the Special Issue Molecular Links between Cancer and Metabolic Diseases: New Perspectives and Therapeutic Strategies for Cancer Prevention and Treatment by Targeting Nutritional Patterns and Metabolic Alterations)

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18 pages, 4448 KiB

Open AccessArticle

TNTdetect.AI: A Deep Learning Model for Automated Detection and Counting of Tunneling Nanotubes in Microscopy Images

by Yasin Ceran, Hamza Ergüder, Katherine Ladner, Sophie Korenfeld, Karina Deniz, Sanyukta Padmanabhan, Phillip Wong, Murat Baday, Thomas Pengo, Emil Lou and Chirag B. Patel

Cancers 2022, 14(19), 4958; https://doi.org/10.3390/cancers14194958 - 10 Oct 2022

Cited by 5 | Viewed by 3766

Abstract

Background: Tunneling nanotubes (TNTs) are cellular structures connecting cell membranes and mediating intercellular communication. TNTs are manually identified and counted by a trained investigator; however, this process is time-intensive. We therefore sought to develop an automated approach for quantitative analysis of TNTs. Methods: [...] Read more.

Background: Tunneling nanotubes (TNTs) are cellular structures connecting cell membranes and mediating intercellular communication. TNTs are manually identified and counted by a trained investigator; however, this process is time-intensive. We therefore sought to develop an automated approach for quantitative analysis of TNTs. Methods: We used a convolutional neural network (U-Net) deep learning model to segment phase contrast microscopy images of both cancer and non-cancer cells. Our method was composed of preprocessing and model development. We developed a new preprocessing method to label TNTs on a pixel-wise basis. Two sequential models were employed to detect TNTs. First, we identified the regions of images with TNTs by implementing a classification algorithm. Second, we fed parts of the image classified as TNT-containing into a modified U-Net model to estimate TNTs on a pixel-wise basis. Results: The algorithm detected 49.9% of human expert-identified TNTs, counted TNTs, and calculated the number of TNTs per cell, or TNT-to-cell ratio (TCR); it detected TNTs that were not originally detected by the experts. The model had 0.41 precision, 0.26 recall, and 0.32 f-1 score on a test dataset. The predicted and true TCRs were not significantly different across the training and test datasets (p = 0.78). Conclusions: Our automated approach labeled and detected TNTs and cells imaged in culture, resulting in comparable TCRs to those determined by human experts. Future studies will aim to improve on the accuracy, precision, and recall of the algorithm. Full article

(This article belongs to the Special Issue The Role of Tunneling Nanotubes in Intercellular Communication and Pathophysiology of Cancer)

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14 pages, 3660 KiB

Open AccessArticle

CellCallEXT: Analysis of Ligand–Receptor and Transcription Factor Activities in Cell–Cell Communication of Tumor Immune Microenvironment

by Shouguo Gao, Xingmin Feng, Zhijie Wu, Sachiko Kajigaya and Neal S. Young

Cancers 2022, 14(19), 4957; https://doi.org/10.3390/cancers14194957 - 10 Oct 2022

Cited by 3 | Viewed by 2553

Abstract

(1) Background: Single-cell RNA sequencing (scRNA-seq) data are useful for decoding cell–cell communication. CellCall is a tool that is used to infer inter- and intracellular communication pathways by integrating paired ligand–receptor (L–R) and transcription factor (TF) activities from steady-state data and thus cannot [...] Read more.

(1) Background: Single-cell RNA sequencing (scRNA-seq) data are useful for decoding cell–cell communication. CellCall is a tool that is used to infer inter- and intracellular communication pathways by integrating paired ligand–receptor (L–R) and transcription factor (TF) activities from steady-state data and thus cannot directly handle two-condition comparisons. For tumor and healthy status, it can only individually analyze cells from tumor or healthy tissue and examine L–R pairs only identified in either tumor or healthy controls, but not both together. Furthermore, CellCall is highly affected by gene expression specificity in tissues. (2) Methods: CellCallEXT is an extension of CellCall that deconvolutes intercellular communication and related internal regulatory signals based on scRNA-seq. Information on Reactome was retrieved and integrated with prior knowledge of L–R–TF signaling and gene regulation datasets of CellCall. (3) Results: CellCallEXT was successfully applied to examine tumors and immune cell microenvironments and to identify the altered L–R pairs and downstream gene regulatory networks among immune cells. Application of CellCallEXT to scRNA-seq data from patients with deficiency of adenosine deaminase 2 demonstrated its ability to impute dysfunctional intercellular communication and related transcriptional factor activities. (4) Conclusions: CellCallEXT provides a practical tool to examine intercellular communication in disease based on scRNA-seq data. Full article

(This article belongs to the Special Issue Advance in Computational Methods in Cancer Research)

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13 pages, 4620 KiB

Open AccessArticle

Dose-Escalated Salvage Radiotherapy for Macroscopic Local Recurrence of Prostate Cancer in the Prostate-Specific Membrane Antigen Positron Emission Tomography Era

by Jörg Tamihardja, Leonie Zehner, Philipp E. Hartrampf, Sinan Cirsi, Sonja Wegener, Andreas K. Buck, Michael Flentje and Bülent Polat

Cancers 2022, 14(19), 4956; https://doi.org/10.3390/cancers14194956 - 10 Oct 2022

Cited by 4 | Viewed by 1948

Abstract

Background: The purpose of this study was to access the oncological outcome of prostate-specific membrane antigen positron emission tomography (PSMA PET/CT)-guided salvage radiotherapy (SRT) for localized macroscopic prostate cancer recurrence. Methods: Between February 2010 and June 2021, 367 patients received SRT after radical [...] Read more.

Background: The purpose of this study was to access the oncological outcome of prostate-specific membrane antigen positron emission tomography (PSMA PET/CT)-guided salvage radiotherapy (SRT) for localized macroscopic prostate cancer recurrence. Methods: Between February 2010 and June 2021, 367 patients received SRT after radical prostatectomy. Out of the 367 screened patients, 111 patients were staged by PSMA PET/CT before SRT. A total of 59 out of these 111 (53.2%) patients were treated for PSMA PET-positive macroscopic prostatic fossa recurrence. Dose-escalated SRT was applied with a simultaneous integrated boost at a median prescribed dose of 69.3 Gy (IQR 69.3–72.6 Gy). The oncological outcome was investigated using Kaplan-Meier and Cox regression analyses. The genitourinary (GU)/gastrointestinal (GI) toxicity evaluation utilized Common Toxicity Criteria for Adverse Events (version 5.0). Results: The median follow-up was 38.2 months. The three-year biochemical progression-free survival rate was 89.1% (95% CI: 81.1–97.8%) and the three-year metastasis-free survival rate reached 96.2% (95% CI: 91.2–100.0%). The cumulative three-year late grade 3 GU toxicity rate was 3.4%. No late grade 3 GI toxicity occurred. Conclusions: Dose-escalated PSMA PET/CT-guided salvage radiotherapy for macroscopic prostatic fossa recurrence resulted in favorable survival and toxicity rates. Full article

(This article belongs to the Special Issue Current Use of PSMA in Prostate Cancer Treatment)

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16 pages, 4081 KiB

Open AccessReview

Mechanosensitive Ion Channel PIEZO1 Signaling in the Hall-Marks of Cancer: Structure and Functions

by Fuqiang Zhao, Lei Zhang, Mankun Wei, Wei Duan, Shourong Wu and Vivi Kasim

Cancers 2022, 14(19), 4955; https://doi.org/10.3390/cancers14194955 - 10 Oct 2022

Cited by 11 | Viewed by 4930

Abstract

Tumor cells alter their characteristics and behaviors during tumorigenesis. These characteristics, known as hallmarks of cancer, are crucial for supporting their rapid growth, need for energy, and adaptation to tumor microenvironment. Tumorigenesis is also accompanied by alteration in mechanical properties. Cells in tumor [...] Read more.

Tumor cells alter their characteristics and behaviors during tumorigenesis. These characteristics, known as hallmarks of cancer, are crucial for supporting their rapid growth, need for energy, and adaptation to tumor microenvironment. Tumorigenesis is also accompanied by alteration in mechanical properties. Cells in tumor tissue sense mechanical signals from the tumor microenvironment, which consequently drive the acquisition of hallmarks of cancer, including sustained proliferative signaling, evading growth suppressors, apoptosis resistance, sustained angiogenesis, metastasis, and immune evasion. Piezo-type mechanosensitive ion channel component 1 (Piezo1) is a mechanically sensitive ion channel protein that can be activated mechanically and is closely related to various diseases. Recent studies showed that Piezo1 mediates tumor development through multiple mechanisms, and its overexpression is associated with poor prognosis. Therefore, the discovery of Piezo1, which links-up physical factors with biological properties, provides a new insight for elucidating the mechanism of tumor progression under a mechanical microenvironment, and suggests its potential application as a tumor marker and therapeutic target. In this review, we summarize current knowledge regarding the role of Piezo1 in regulating cancer hallmarks and the underlying molecular mechanisms. Furthermore, we discuss the potential of Piezo1 as an antitumor therapeutic target and the limitations that need to be overcome. Full article

(This article belongs to the Collection Novel Biomarkers and Molecular Targets in Cancer)

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18 pages, 729 KiB

Open AccessReview

Prognostic Value of Circulating Tumor DNA (ctDNA) in Oncogene-Driven NSCLC: Current Knowledge and Future Perspectives

by Eleni Zografos, Foteinos-Ioannis Dimitrakopoulos and Angelos Koutras

Cancers 2022, 14(19), 4954; https://doi.org/10.3390/cancers14194954 - 10 Oct 2022

Cited by 6 | Viewed by 3158

Abstract

As we enter an unprecedented era of personalized medicine, molecular targeted therapies have the potential to induce improved survival outcome in patients with non-small cell lung cancer (NSCLC). However, a significant percentage of oncogene-driven NSCLC patients will relapse even after definitive treatment, whereas [...] Read more.

As we enter an unprecedented era of personalized medicine, molecular targeted therapies have the potential to induce improved survival outcome in patients with non-small cell lung cancer (NSCLC). However, a significant percentage of oncogene-driven NSCLC patients will relapse even after definitive treatment, whereas chronic and durable response to targeted therapies is a less common event in advanced-stage lung cancer. This phenomenon could be attributed to minimal residual disease (MRD), defined as a population of disseminated tumor cells that survive during the course or after treatment, eventually leading to recurrence and limiting patient survival. Circulating tumor DNA (ctDNA) is a powerful biomarker for MRD detection and monitoring and is a non-invasive approach of treating cancer, and especially NSCLC, based on a real-time assessment of the tumor genomic landscape. In this review, we present the key findings of studies that have used ctDNA with regard to its prognostic value and in respect to the most common druggable driver mutations of genes in NSCLC, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), rearranged during transfection (RET), Kirsten rat sarcoma virus (KRAS), B-Raf proto-oncogene (BRAF), and mesenchymal epithelial transition factor receptor (MET). Full article

(This article belongs to the Section Cancer Biomarkers)

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12 pages, 2538 KiB

Open AccessArticle

Clinical Trends in Management of Locally Advanced ESCC: Real-World Evidence from a Large Single-Center Cohort Study

by Yeong Jeong Jeon, Junsang Yoo, Jong Ho Cho and Young Mog Shim

Cancers 2022, 14(19), 4953; https://doi.org/10.3390/cancers14194953 - 10 Oct 2022

Viewed by 1916

Abstract

Neoadjuvant chemoradiation followed by surgery (NCRT+S) has been widely applied to patients with locally advanced esophageal squamous cell carcinoma (ESCC); however, treatment trends and their survival outcomes in a real-world clinical setting are poorly understood. This study aimed to analyze real-world evidence to [...] Read more.

Neoadjuvant chemoradiation followed by surgery (NCRT+S) has been widely applied to patients with locally advanced esophageal squamous cell carcinoma (ESCC); however, treatment trends and their survival outcomes in a real-world clinical setting are poorly understood. This study aimed to analyze real-world evidence to understand treatment patterns and outcomes for patients with ESCC. We analyzed the treatment pattern and 5-year overall survival (5yOS) by synthesizing the individuals’ general characteristics, cancer information, and treatment records extracted from the Clinical Data Warehouse from 1994 to 2018. Of a total of 2151 patients, most patients received upfront surgery and 5yOS was 36.8% (31.4–43.1%). From 2003 to 2012, the use of NCRT increased, and 5yOS was improved to 42.2% (38.8–45.7%). Notably, after 2013, the proportion of NCRT+S markedly increased up to >50% of patients: 5yOS was much improved to 56.3% (53.2–59.6%). With regard to treatment, patients with NCRT+S had the most favorable 5yOS of 58.1% (53–63.7%), although that for patients with upfront surgery was 48.6% (45.9–51.5%, p < 0.001). Moreover, patients who received adjuvant therapy after surgery had better OS than those with surgery alone (58.4% (52.7–64.7%) vs. 47.3% (44.1–50.7%), p < 0.001). This analysis of real-world data demonstrated a significantly improved survival outcome for locally advanced ESCC over time since NCRT prior to surgery had been routinely applied. We revealed that NCRT+S was the most effective treatment for locally advanced ESCC and that adjuvant chemotherapy may be an encouraging therapeutic option for patients with positive nodes after upfront surgery. Full article

(This article belongs to the Special Issue Research Progress in Esophageal Squamous Cell Carcinoma)

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20 pages, 4078 KiB

Open AccessArticle

Targeting E2F Sensitizes Prostate Cancer Cells to Drug-Induced Replication Stress by Promoting Unscheduled CDK1 Activity

by Mohaddase Hamidi, Ainhoa Eriz, Jone Mitxelena, Larraitz Fernandez-Ares, Igor Aurrekoetxea, Patricia Aspichueta, Ainhoa Iglesias-Ara and Ana M. Zubiaga

Cancers 2022, 14(19), 4952; https://doi.org/10.3390/cancers14194952 - 10 Oct 2022

Cited by 4 | Viewed by 2915

Abstract

E2F1/E2F2 expression correlates with malignancy in prostate cancer (PCa), but its functional significance remains unresolved. To define the mechanisms governed by E2F in PCa, we analyzed the contribution of E2F target genes to the control of genome integrity, and the impact of modulating [...] Read more.

E2F1/E2F2 expression correlates with malignancy in prostate cancer (PCa), but its functional significance remains unresolved. To define the mechanisms governed by E2F in PCa, we analyzed the contribution of E2F target genes to the control of genome integrity, and the impact of modulating E2F activity on PCa progression. We show that silencing or inhibiting E2F1/E2F2 induces DNA damage during S phase and potentiates 5-FU-induced replication stress and cellular toxicity. Inhibition of E2F downregulates the expression of E2F targets involved in nucleotide biosynthesis (TK1, DCK, TYMS), whose expression is upregulated by 5-FU. However, their enzymatic products failed to rescue DNA damage of E2F1/E2F2 knockdown cells, suggesting additional mechanisms for E2F function. Interestingly, targeting E2F1/E2F2 in PCa cells reduced WEE1 expression and resulted in premature CDK1 activation during S phase. Inhibition of CDK1/CDK2 prevented DNA damage induced by E2F loss, suggesting that E2F1/E2F2 safeguard genome integrity by restraining CDK1/CDK2 activity. Importantly, combined inhibition of E2F and ATR boosted replication stress and dramatically reduced tumorigenic capacity of PCa cells in xenografts. Collectively, inhibition of E2F in combination with drugs targeting nucleotide biosynthesis or DNA repair is a promising strategy to provoke catastrophic levels of replication stress that could be applied to PCa treatment. Full article

(This article belongs to the Special Issue Genomic Instability in Tumor Evolution and Therapy Response)

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16 pages, 2776 KiB

Open AccessArticle

A Multi-Centre Study to Risk Stratify Colorectal Polyp Surveillance Patients Utilising Volatile Organic Compounds and Faecal Immunochemical Test

by Subashini Chandrapalan, Farah Khasawneh, Baljit Singh, Stephen Lewis, James Turvill, Krishna Persaud and Ramesh P. Arasaradnam

Cancers 2022, 14(19), 4951; https://doi.org/10.3390/cancers14194951 - 9 Oct 2022

Cited by 2 | Viewed by 2295

Abstract

(1) Background: The service capacity for colonoscopy remains constrained, and while efforts are being made to recover elective services, polyp surveillance remains a challenge. (2) Methods: This is a multi-centre study recruiting patients already on polyp surveillance. Stool and urine samples were collected [...] Read more.

(1) Background: The service capacity for colonoscopy remains constrained, and while efforts are being made to recover elective services, polyp surveillance remains a challenge. (2) Methods: This is a multi-centre study recruiting patients already on polyp surveillance. Stool and urine samples were collected for the faecal immunochemical test (FIT) and volatile organic compounds (VOC) analysis, and all participants then underwent surveillance colonoscopy. (3) Results: The sensitivity and specificity of VOC for the detection of a high-risk finding ((≥2 premalignant polyps including ≥1 advanced polyp or ≥5 premalignant polyps) were 0.94 (95% CI, 0.88 to 0.98) and 0.69 (95% CI, 0.64 to 0.75) respectively. For FIT, the sensitivity was (≥10 µg of haemoglobin (Hb) / g faeces) 0.54 (95% CI, 0.43 to 0.65) and the specificity was 0.79 (95% CI, 0.73 to 0.84). The probability reduction for having a high-risk finding following both negative VOC and FIT will be 24% if both tests are applied sequentially. (4) Conclusion: The diagnostic performance of VOC is superior to FIT for the detection of a high-risk finding. The performance further improves when VOC is applied together with FIT sequentially (VOC first and then FIT). VOC alone or the combination of VOC and FIT can be used as a triage tool for patients awaiting colonoscopy within a polyp surveillance population, especially in resource-constrained healthcare systems. Full article

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13 pages, 3156 KiB

Open AccessArticle

CircKIF4A Is a Prognostic Factor and Modulator of Natural Killer/T-Cell Lymphoma Progression

by Rongfang He, Wei Wen, Bibo Fu, Renjie Zhu, Guanjun Chen, Shenrui Bai, Xi Cao and Hua Wang

Cancers 2022, 14(19), 4950; https://doi.org/10.3390/cancers14194950 - 9 Oct 2022

Cited by 3 | Viewed by 2141

Abstract

Background: Natural killer/T-cell lymphoma (NKTL) is difficult to treat. Circular RNAs (circ RNAs) have been implicated in tumorigenesis. However, the function of circKIF4A in NKTL has not been investigated. Methods: QPCR analysis was used to compare circKIF4A levels in NKTL cell lines versus [...] Read more.

Background: Natural killer/T-cell lymphoma (NKTL) is difficult to treat. Circular RNAs (circ RNAs) have been implicated in tumorigenesis. However, the function of circKIF4A in NKTL has not been investigated. Methods: QPCR analysis was used to compare circKIF4A levels in NKTL cell lines versus normal cell lines. Kaplan–Meier survival analysis was used to assess the effect of circKIF4A on the prognosis of NKTL. The correlation between clinicopathological features and circKIF4A expression was examined using cox regression analysis. Luciferase reporter, RNA immunoprecipitation and immunohistochemistry assays were also used to investigate the mechanisms of circKIF4A in NKTL. Results: Our analyses revealed that circKIF4A is significantly upregulated in NKTL cell lines and that its upregulation correlates with the poor prognosis of NKTL. The silencing of circKIF4A significantly suppressed glucose uptake and lactate production in NKTL cells. Moreover, we showed that circKIF4A, PDK1, and BCL11A bind miR-1231 and that circKIF4A regulates PDK1 and BCL11A expressions by sponging miR-1231. Conclusions: During NKTL progression, circKIF4A regulated PDK1 and BCL11A levels by sponging miR-1231. Our data indicated that circKIF4A is oncogenic in NKTL and that it is a predictor of poor prognosis of NKTL. Full article

(This article belongs to the Special Issue Advances in Cancer Therapeutics)

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13 pages, 4687 KiB

Open AccessArticle

Evaluation of the Cellular Dissociation Grading, Based on Tumor Budding and Cell Nest Size, in Squamous Cell Carcinoma of the Penis

by Hayel Derani, Anne-Sophie Becker, Oliver Hakenberg and Andreas Erbersdobler

Cancers 2022, 14(19), 4949; https://doi.org/10.3390/cancers14194949 - 9 Oct 2022

Cited by 2 | Viewed by 1980

Abstract

The “Cellular Dissociation Grade” (CDG) is based on tumor cell budding and cell nest size. Many studies have examined the CDG in squamous cell carcinomas of other organs such as the lungs, oral cavity, pharynx, larynx, cervix and esophagus. In this study, the [...] Read more.

The “Cellular Dissociation Grade” (CDG) is based on tumor cell budding and cell nest size. Many studies have examined the CDG in squamous cell carcinomas of other organs such as the lungs, oral cavity, pharynx, larynx, cervix and esophagus. In this study, the CDG was examined in 109 cases of invasive penile squamous cell carcinoma that were treated at the University Medicine Rostock between 2014 and 2022. Furthermore, its correlation with the pathologic status of regional lymph nodes (pN) as the main prognostic factor was verified. Finally, cellular dissociation grading was compared with classic WHO grading. The results showed that pN in penile squamous cell carcinoma showed a highly significant association with the CDG and no statistically significant association with WHO grading. These results support the notion that cellular dissociation grading is an important prognostic factor for squamous cell carcinoma. Full article

(This article belongs to the Special Issue Penile Carcinoma)

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10 pages, 741 KiB

Open AccessArticle

Time Trend and Association of Early-Onset Colorectal Cancer with Diverticular Disease in the United States: 2010–2021

by Lindsey Wang, Rong Xu, David C. Kaelber and Nathan A. Berger

Cancers 2022, 14(19), 4948; https://doi.org/10.3390/cancers14194948 - 9 Oct 2022

Cited by 11 | Viewed by 2935

Abstract

Purpose: To examine time trends of incidence rates of EOCRC from 2010 to 2021 among patients with and without diverticular disease and to examine whether diverticular disease is associated with increased risk of EOCRC. Methods: This is a retrospective cohort study of 46,179,351 [...] Read more.

Purpose: To examine time trends of incidence rates of EOCRC from 2010 to 2021 among patients with and without diverticular disease and to examine whether diverticular disease is associated with increased risk of EOCRC. Methods: This is a retrospective cohort study of 46,179,351 young adults aged 20–49, including 298,117 with diverticular disease. We examined yearly incidence rate of first diagnosis of EOCRC from 2010 through 2021 among patients with and without diverticular disease. The 5-year risk of EOCRC among patients with pre-existing diverticular disease was compared to propensity-matched patients without diverticular disease and EOCRC and odds ratio (OR) and 95% confidence interval (CI) were calculated. Results: The yearly incidence rate of new diagnosis of EOCRC (measured as new cases per 100,000 people per year) in young adults with pre-existing diverticular disease increased from 100 in 2010 to 402 in 2021, 4–6 times higher than in those without diverticular disease (24 in 2010 to 77 in 2021) (p < 0.001). Patients with diverticular disease were at higher risk for EOCRC than those without (OR: 1.76, 95% CI: 1.40–2.32). Conclusion: The incidence of EOCRC continuously increased from 2010 through 2021 in patients with and without diverticular disease and was 4–6 times higher among patients with diverticular disease. Patients with pre-existing diverticular disease were at a significantly increased risk for EOCRC. Full article

(This article belongs to the Special Issue Early Onset Colorectal Cancer: Epidemiology and Etiology)

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14 pages, 3021 KiB

Open AccessArticle

Combination of a Novel Fusion Protein CD3εζ28 and Bispecific T Cell Engager Enhances the Persistance and Anti-Cancer Effects of T Cells

by Feng Yu, Yang Gao, Yan Wu, Anran Dai, Xiaoyan Wang, Xiangzhi Zhang, Guodong Liu, Qinggang Xu and Dongfeng Chen

Cancers 2022, 14(19), 4947; https://doi.org/10.3390/cancers14194947 - 9 Oct 2022

Cited by 2 | Viewed by 2296

Abstract

Bi-specific T cell engager (BiTE), an artificial bi-functional fusion protein, has shown promising therapeutic potential in preclinical and clinical studies. However, T cells cannot be sufficiently activated by BiTE, most likely due to lacking co-stimulatory signal. We reasoned that incorporating co-stimulatory signal might [...] Read more.

Bi-specific T cell engager (BiTE), an artificial bi-functional fusion protein, has shown promising therapeutic potential in preclinical and clinical studies. However, T cells cannot be sufficiently activated by BiTE, most likely due to lacking co-stimulatory signal. We reasoned that incorporating co-stimulatory signal might have the potential to enhance the T cell activation mediated by BiTE. We, therefore, designed a chimeric fusion protein, named as CD3εζ28, which consists of the CD3ε extracellular region, the CD28 costimulatory signal and the intracellular region of CD3ζ in tandem. T cells genetically modified to express both CD3εζ28 and GFP (T-CD3εζ28-GFP) were generated by retroviral transduction. The results from in vitro experiments showed that T-CD3εζCD28-GFP cells had superior cytotoxic effects on tumor cells in presence of BiTE compared with control T cells, as evidenced by IL-2 and IFN-γ production, T cell proliferation and sequential killing assay. In vivo, T-CD3εζCD28-GFP cells showed superior anti-tumor effects in Hela-BiTE. EGFRvIII xenograft tumor model, as evaluated by tumor growth rate and T cell persistence in comparison with control T cells. In order to further confirm these findings, we generated T cells modified to express both CD3εζCD28 on cell surface and BiTE.CD19 by autocrine manner (T-CD3εζCD28-BiTE.19). The superior anti-tumor effects of T-CD3εζCD28-BiTE.19 cells could also be evidenced by the similar in vitro and in vivo experiments; thus, incorporating co-stimulatory signal may be an effective approach to improve the effector function of T cells mediated by BiTE. Full article

(This article belongs to the Special Issue Advances in Cancer Immunotherapy)

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27 pages, 5692 KiB

Open AccessArticle

Acid Adaptation Promotes TRPC1 Plasma Membrane Localization Leading to Pancreatic Ductal Adenocarcinoma Cell Proliferation and Migration through Ca²⁺ Entry and Interaction with PI3K/CaM

by Julie Schnipper, Sana Kouba, Frédéric Hague, Alban Girault, Marie-Sophie Telliez, Stéphanie Guénin, Ahmed Ahidouch, Stine Falsig Pedersen and Halima Ouadid-Ahidouch

Cancers 2022, 14(19), 4946; https://doi.org/10.3390/cancers14194946 - 9 Oct 2022

Cited by 3 | Viewed by 2006

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a low overall survival rate of less than 10% and limited therapeutic options. Fluctuations in tumor microenvironment pH are a hallmark of PDAC development and progression. Many ion channels are bona [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a low overall survival rate of less than 10% and limited therapeutic options. Fluctuations in tumor microenvironment pH are a hallmark of PDAC development and progression. Many ion channels are bona fide cellular sensors of changes in pH. Yet, the interplay between the acidic tumor microenvironment and ion channel regulation in PDAC is poorly understood. In this study, we show that acid adaption increases PANC-1 cell migration but attenuates proliferation and spheroid growth, which are restored upon recovery. Moreover, acid adaptation and recovery conditions favor the plasma membrane localization of the pH-sensitive calcium (Ca²⁺) channel transient receptor potential C1 (TRPC1), TRPC1-mediated Ca²⁺ influx, channel interaction with the PI3K p85α subunit and calmodulin (CaM), and AKT and ERK1/2 activation. Knockdown (KD) of TRPC1 suppresses cell migration, proliferation, and spheroid growth, notably in acid-recovered cells. KD of TRPC1 causes the accumulation of cells in G0/G1 and G2/M phases, along with reduced expression of CDK6, −2, and −1, and cyclin A, and increased expression of p21^CIP1. TRPC1 silencing decreases the basal Ca²⁺ influx in acid-adapted and -recovered cells, but not in normal pH conditions, and Ca²⁺ chelation reduces cell migration and proliferation solely in acid adaptation and recovery conditions. In conclusion, acid adaptation and recovery reinforce the involvement of TRPC1 in migration, proliferation, and cell cycle progression by permitting Ca²⁺ entry and forming a complex with the PI3K p85α subunit and CaM. Full article

(This article belongs to the Special Issue Regulation, Role and Targeting of Calcium Signaling Pathways in Cancer)

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29 pages, 6253 KiB

Open AccessReview

Recent Advances in Bacteria-Based Cancer Treatment

by Xianyuan Wei, Meng Du, Zhiyi Chen and Zhen Yuan

Cancers 2022, 14(19), 4945; https://doi.org/10.3390/cancers14194945 - 9 Oct 2022

Cited by 17 | Viewed by 5247

Abstract

Owing to its unique mechanism of abundant pathogen-associated molecular patterns in antitumor immune responses, bacteria-based cancer immunotherapy has recently attracted wide attention. Compared to traditional cancer treatments such as surgery, chemotherapy, radiotherapy, and phototherapy, bacteria-based cancer immunotherapy exhibits the versatile capabilities for suppressing [...] Read more.

Owing to its unique mechanism of abundant pathogen-associated molecular patterns in antitumor immune responses, bacteria-based cancer immunotherapy has recently attracted wide attention. Compared to traditional cancer treatments such as surgery, chemotherapy, radiotherapy, and phototherapy, bacteria-based cancer immunotherapy exhibits the versatile capabilities for suppressing cancer thanks to its preferentially accumulating and proliferating within tumors. In particular, bacteria have demonstrated their anticancer effect through the toxins, and other active components from the cell membrane, cell wall, and dormant spores. More importantly, the design of engineering bacteria with detoxification and specificity is essential for the efficacy of bacteria-based cancer therapeutics. Meanwhile, bacteria can deliver the cytokines, antibody, and other anticancer theranostic nanoparticles to tumor microenvironments by regulating the expression of the bacterial genes or chemical and physical loading. In this review, we illustrate that naïve bacteria and their components can serve as robust theranostic agents for cancer eradication. In addition, we summarize the recent advances in efficient antitumor treatments by genetically engineering bacteria and bacteria-based nanoparticles. Further, possible future perspectives in bacteria-based cancer immunotherapy are also inspected. Full article

(This article belongs to the Special Issue Tumor Immunology and Immunotherapy Resistance)

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12 pages, 1987 KiB

Open AccessArticle

A Single Center Analysis of Thymic Neuroendocrine Tumors

by Yirui Zhai, Qiang Zeng, Nan Bi, Zongmei Zhou, Zefen Xiao, Zhouguang Hui, Dongfu Chen, Luhua Wang, Jianyang Wang, Wenyang Liu, Lei Deng, Jima Lv, Wenqing Wang, Yang Luo, Junling Li, Xin Wang, Tao Zhang, Yushun Gao and Qinfu Feng

Cancers 2022, 14(19), 4944; https://doi.org/10.3390/cancers14194944 - 9 Oct 2022

Cited by 2 | Viewed by 2164

Abstract

Purpose: Thymic neuroendocrine tumors (TNETs) are a collection of slow-progressing neoplasms located in the anterior mediastinum. Relatively few previously published studies have focused on thymic carcinomas. This study investigated the basic clinical characteristics, treatment, and prognosis of TNETs. Methods: Patients were enrolled in [...] Read more.

Purpose: Thymic neuroendocrine tumors (TNETs) are a collection of slow-progressing neoplasms located in the anterior mediastinum. Relatively few previously published studies have focused on thymic carcinomas. This study investigated the basic clinical characteristics, treatment, and prognosis of TNETs. Methods: Patients were enrolled in the study from January 2003 to December 2017 who had been diagnosed with TNETs through pathological screening and treated at our institution. Demographic data from each patient, the Masaoka stage, histology and size of the tumor, tumor invasion characteristics, and therapeutic strategies were gathered. The Kaplan–Meier method was used to assess patient survival. In addition, the log-rank test was used to carry out univariate analyses. Results: Twenty-six patients were eligible for inclusion in the study. The median age of the patients was 46.5 (25–69) years. The tumor median maximum diameter was 7.9 cm (from 3 to 19 cm). Twenty-four patients were treated surgically. Nineteen patients completed radiation therapy, and sixteen patients underwent chemotherapy. A median follow-up time of 54.95 months was observed. The survival rate for three years was 75.0% and 70.6% for five years. The corresponding progression-free survival rates for three and five years were 55.7% and 37.7%, respectively. The local, regional recurrence-free survival (LRFS) rates were 87.2% and 81.7%, and the distant metastasis-free survival (DMFS) rates were 55.7% and 37.7%, at three and five years, respectively. Local recurrence (six patients) and bone metastasis (six patients) were observed as the most frequent failures. Conclusion: TNET was observed to be an aggressive but rare malignant lesion. While the predominant treatment was complete resection, chemotherapy and radiotherapy were also required due to the high recurrence rate. Full article

(This article belongs to the Special Issue Thymoma and Thymic Carcinoma: Therapy and Outcomes)

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14 pages, 2891 KiB

Open AccessArticle

A Potential Fatty Acid Metabolism-Related Gene Signature for Prognosis in Clear Cell Renal Cell Carcinoma

by He Zhang, Di Zhang and Xiaopeng Hu

Cancers 2022, 14(19), 4943; https://doi.org/10.3390/cancers14194943 - 9 Oct 2022

Cited by 3 | Viewed by 2344

Abstract

This study aims to explore the role of abnormal fatty acid metabolism (FAM) in ccRCC and construct a novel fatty acid metabolism-related gene signature (FAMGS) for prognosis. Three independent ccRCC cohorts, including The Cancer Genome Atlas, E-MTAB-1980 and our clinical cohort (including RNA-seq, [...] Read more.

This study aims to explore the role of abnormal fatty acid metabolism (FAM) in ccRCC and construct a novel fatty acid metabolism-related gene signature (FAMGS) for prognosis. Three independent ccRCC cohorts, including The Cancer Genome Atlas, E-MTAB-1980 and our clinical cohort (including RNA-seq, microarray and RT-qPCR data), were applied as training and two independent validation cohorts. Firstly, FAM levels were found to be significantly decreased in ccRCC and correlated with degrees of malignancy, confirming the pivotal role of FAM in ccRCC. Applying the least absolute shrinkage and selection operator cox regression, we established a novel FAMGS for overall survival (OS). The FAMGS divided patients into low or high-risk groups in the training cohort and were successfully validated in both the EMTAB and our clinical validation cohorts. Additionally, the FAMGS serves as an independent risk factor for OS of ccRCC. Results of the immune cell abundance identifier (ImmuCellAI) algorithm and gene set variation analysis (GSVA) revealed that patients in the high-risk group have comprehensively impaired metabolism, including lipids, amino acids and tricarboxylic acid cycle-related pathways and a more immunosuppressive tumor microenvironment. In conclusion, our study constructed and validated a novel FAMGS, which may improve the risk stratification optimization and personalized management of ccRCC. Full article

(This article belongs to the Special Issue Advances and Updates in Prognostic and Predictive Biomarkers of Urologic Malignancy)

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18 pages, 1304 KiB

Open AccessReview

Roles of Chromatin Remodelling and Molecular Heterogeneity in Therapy Resistance in Glioblastoma

by Huey-Miin Chen, Ana Nikolic, Divya Singhal and Marco Gallo

Cancers 2022, 14(19), 4942; https://doi.org/10.3390/cancers14194942 - 9 Oct 2022

Cited by 4 | Viewed by 2585

Abstract

Cancer stem cells (CSCs) represent a therapy-resistant reservoir in glioblastoma (GBM). It is now becoming clear that epigenetic and chromatin remodelling programs link the stemlike behaviour of CSCs to their treatment resistance. New evidence indicates that the epigenome of GBM cells is shaped [...] Read more.

Cancer stem cells (CSCs) represent a therapy-resistant reservoir in glioblastoma (GBM). It is now becoming clear that epigenetic and chromatin remodelling programs link the stemlike behaviour of CSCs to their treatment resistance. New evidence indicates that the epigenome of GBM cells is shaped by intrinsic and extrinsic factors, including their genetic makeup, their interactions and communication with other neoplastic and non-neoplastic cells, including immune cells, and their metabolic niche. In this review, we explore how all these factors contribute to epigenomic heterogeneity in a tumour and the selection of therapy-resistant cells. Lastly, we discuss current and emerging experimental platforms aimed at precisely understanding the epigenetic mechanisms of therapy resistance that ultimately lead to tumour relapse. Given the growing arsenal of drugs that target epigenetic enzymes, our review addresses promising preclinical and clinical applications of epidrugs to treat GBM, and possible mechanisms of resistance that need to be overcome. Full article

(This article belongs to the Special Issue Mechanisms of Therapeutic Resistance in Glioblastoma)

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17 pages, 699 KiB

Open AccessReview

Novel Therapies for Unmet Clinical Needs in Myelodysplastic Syndromes

by Giulio Cassanello, Raffaella Pasquale, Wilma Barcellini and Bruno Fattizzo

Cancers 2022, 14(19), 4941; https://doi.org/10.3390/cancers14194941 - 9 Oct 2022

Cited by 10 | Viewed by 2588

Abstract

Myelodysplastic syndromes (MDS) are a very heterogeneous disease, with extremely variable clinical features and outcomes. Current management relies on risk stratification based on IPSS and IPSS-R, which categorizes patients into low (LR-) and high-risk (HR-) MDS. Therapeutic strategies in LR-MDS patients mainly consist [...] Read more.

Myelodysplastic syndromes (MDS) are a very heterogeneous disease, with extremely variable clinical features and outcomes. Current management relies on risk stratification based on IPSS and IPSS-R, which categorizes patients into low (LR-) and high-risk (HR-) MDS. Therapeutic strategies in LR-MDS patients mainly consist of erythropoiesis stimulating agents (ESAs), transfusion support, and luspatercept or lenalidomide for selected patients. Current unmet needs include the limited options available after treatment failure, and the consequent transfusion burden with several hospital admissions and poor quality of life. Therapeutic approaches in HR-MDS patients are aimed at changing the natural course of the disease and hypometylating agents (HMA) are the first choice. The only potentially curative treatment is allogeneic stem cell transplant (allo-HCT), restricted to a minority of young and fit candidates. Patients unfit for or those that relapse after the abovementioned options harbor an adverse prognosis, with limited overall survival and frequent leukemic evolution. Recent advances in genetic mutations and intracellular pathways that are relevant for MDS pathogenesis are improving disease risk stratification and highlighting therapeutic targets addressed by novel agents. Several drugs are under evaluation for LR and HR patients, which differ by their mechanism of action, reported efficacy, and phase of development. This review analyzes the current unmet clinical needs for MDS patients and provides a critical overview of the novel agents under development in this setting. Full article

(This article belongs to the Section Cancer Therapy)

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20 pages, 7305 KiB

Open AccessArticle

LINC01526 Promotes Proliferation and Metastasis of Gastric Cancer by Interacting with TARBP2 to Induce GNG7 mRNA Decay

by Jin-Yong Zhou, Jin-Yan Liu, Yu Tao, Chen Chen and Shen-Lin Liu

Cancers 2022, 14(19), 4940; https://doi.org/10.3390/cancers14194940 - 9 Oct 2022

Cited by 5 | Viewed by 1914

Abstract

Gastric cancer is the most common malignancy of the human digestive system. Long noncoding RNAs (lncRNAs) influence the occurrence and development of gastric cancer in multiple ways. However, the function and mechanism of LINC01526 in gastric cancer remain unknown. Herein, we investigated the [...] Read more.

Gastric cancer is the most common malignancy of the human digestive system. Long noncoding RNAs (lncRNAs) influence the occurrence and development of gastric cancer in multiple ways. However, the function and mechanism of LINC01526 in gastric cancer remain unknown. Herein, we investigated the function of LINC01526 with respect to the malignant progression of gastric cancer. We found that LINC01526 was upregulated in gastric cancer cells and tissues. The function experiments in vitro and the Xenograft mouse model in vivo proved that LINC01526 could promote gastric cancer cell proliferation and migration. Furthermore, LINC01526 interacted with TAR (HIV-1) RNA-binding protein 2 (TARBP2) and decreased the mRNA stability of G protein gamma 7 (GNG7) through TARBP2. Finally, the rescue assay showed that downregulating GNG7 partially rescued the cell proliferation inhibited by LINC01526 or TARBP2 silencing. In summary, LINC01526 promoted gastric cancer progression by interacting with TARBP2, which subsequently degraded GNG7 mRNA. This study not only explores the role of LINC01526 in gastric cancer, but also provides a laboratory basis for its use as a new biomarker for diagnosis and therapeutic targets. Full article

(This article belongs to the Special Issue Signaling Pathway in Gastrointestinal Cancer)

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19 pages, 6638 KiB

Open AccessArticle

Identifying Tissue- and Cohort-Specific RNA Regulatory Modules in Cancer Cells Using Multitask Learning

by Milad Mokhtaridoost, Philipp G. Maass and Mehmet Gönen

Cancers 2022, 14(19), 4939; https://doi.org/10.3390/cancers14194939 - 9 Oct 2022

Cited by 1 | Viewed by 2203

Abstract

MicroRNA (miRNA) alterations significantly impact the formation and progression of human cancers. miRNAs interact with messenger RNAs (mRNAs) to facilitate degradation or translational repression. Thus, identifying miRNA–mRNA regulatory modules in cohorts of primary tumor tissues are fundamental for understanding the biology of tumor [...] Read more.

MicroRNA (miRNA) alterations significantly impact the formation and progression of human cancers. miRNAs interact with messenger RNAs (mRNAs) to facilitate degradation or translational repression. Thus, identifying miRNA–mRNA regulatory modules in cohorts of primary tumor tissues are fundamental for understanding the biology of tumor heterogeneity and precise diagnosis and treatment. We established a multitask learning sparse regularized factor regression (MSRFR) method to determine key tissue- and cohort-specific miRNA–mRNA regulatory modules from expression profiles of tumors. MSRFR simultaneously models the sparse relationship between miRNAs and mRNAs and extracts tissue- and cohort-specific miRNA–mRNA regulatory modules separately. We tested the model’s ability to determine cohort-specific regulatory modules of multiple cancer cohorts from the same tissue and their underlying tissue-specific regulatory modules by extracting similarities between cancer cohorts (i.e., blood, kidney, and lung). We also detected tissue-specific and cohort-specific signatures in the corresponding regulatory modules by comparing our findings from various other tissues. We show that MSRFR effectively determines cancer-related miRNAs in cohort-specific regulatory modules, distinguishes tissue- and cohort-specific regulatory modules from each other, and extracts tissue-specific information from different cohorts of disease-related tissue. Our findings indicate that the MSRFR model can support current efforts in precision medicine to define tumor-specific miRNA–mRNA signatures. Full article

(This article belongs to the Collection miRNAs: New Insights in Tumor Biology)

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21 pages, 3141 KiB

Open AccessArticle

The Prognostic Value of Postoperative Radiotherapy for Thymoma and Thymic Carcinoma: A Propensity-Matched Study Based on SEER Database

by Chi Zhang, Qin Wang, Liwen Hu, Zhuangzhuang Cong, Yong Qiang, Fei Xu, Zheng Zhang, Chao Luo, Bingmei Qiu, Xiaokun Li and Yi Shen

Cancers 2022, 14(19), 4938; https://doi.org/10.3390/cancers14194938 - 8 Oct 2022

Cited by 7 | Viewed by 2379

Abstract

(1) Objectives: The effect of postoperative radiotherapy (PORT) for thymoma and thymic carcinoma remains controversial. This study aimed to investigate the prognostic value of PORT for thymoma and thymic carcinoma in a population-based registry. (2) Methods: This retrospective study used the Surveillance, Epidemiology, [...] Read more.

(1) Objectives: The effect of postoperative radiotherapy (PORT) for thymoma and thymic carcinoma remains controversial. This study aimed to investigate the prognostic value of PORT for thymoma and thymic carcinoma in a population-based registry. (2) Methods: This retrospective study used the Surveillance, Epidemiology, and End Results (SEER) database to identify patients diagnosed with thymoma and thymic carcinoma between 2010 and 2019. Propensity score matching was performed to adjust statistical influences between the PORT and non-PORT groups. (3) Results: A total of 2558 patients with thymoma (n = 2138) or thymic carcinoma (n = 420) were included. In the multivariate analysis, PORT was an independent prognostic factor for OS (overall survival; p < 0.001) and CSS (cancer-specific survival; p = 0.001) in thymoma and an independent prognostic factor for OS in thymic carcinoma (p = 0.018). Subgroup analyses revealed that PORT was beneficial to OS and CSS in patients with Masaoka-Koga stage IIB-IV thymoma (OS: IIB, p < 0.001; III-IV, p = 0.005; CSS: IIB, p = 0.015; III-IV, p = 0.002) and stage IIB thymic carcinoma (OS: p = 0.012; CSS: p = 0.029). (4) Conclusion: This propensity-matched analysis identified the prognostic value of PORT in thymoma and thymic carcinoma based on the SEER database. For patients with stage IIB-IV thymoma and stage IIB thymic carcinoma, PORT was associated with improved OS and CSS. A more positive attitude towards the use of PORT for nonlocalized thymoma and thymic carcinoma may be appropriate. Full article

(This article belongs to the Special Issue Thymoma and Thymic Carcinoma: Therapy and Outcomes)

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