2023

Jump to: 2022, 2021, 2020

13 pages, 6705 KiB

Open AccessArticle

Identification of Highly Sensitive Pleural Effusion Protein Biomarkers for Malignant Pleural Mesothelioma by Affinity-Based Quantitative Proteomics

by Nicolai B. Palstrøm, Martin Overgaard, Peter Licht and Hans C. Beck

Cancers 2023, 15(3), 641; https://doi.org/10.3390/cancers15030641 - 19 Jan 2023

Cited by 2 | Viewed by 1627

Abstract

Malignant pleural mesothelioma (MPM) is an asbestos-associated, highly aggressive cancer characterized by late-stage diagnosis and poor prognosis. Gold standards for diagnosis are pleural biopsy and cytology of pleural effusion (PE), both of which are limited by low sensitivity and markedly inter-observer variations. Therefore, [...] Read more.

Malignant pleural mesothelioma (MPM) is an asbestos-associated, highly aggressive cancer characterized by late-stage diagnosis and poor prognosis. Gold standards for diagnosis are pleural biopsy and cytology of pleural effusion (PE), both of which are limited by low sensitivity and markedly inter-observer variations. Therefore, the assessment of PE biomarkers is considered a viable and objective diagnostic tool for MPM diagnosis. We applied a novel affinity-enrichment mass spectrometry-based proteomics method for explorative analysis of pleural effusions from a prospective cohort of 84 patients referred for thoracoscopy due to clinical suspicion of MPM. Protein biomarkers with a high capability to discriminate MPM from non-MPM patients were identified, and a Random Forest algorithm was applied for building classification models. Immunohistology of pleural biopsies confirmed MPM in 40 patients and ruled out MPM in 44 patients. Proteomic analysis of pleural effusions identified panels of proteins with excellent diagnostic properties (90–100% sensitivities, 89–98% specificities, and AUC 0.97–0.99) depending on the specific protein combination. Diagnostic proteins associated with cancer growth included galactin-3 binding protein, testican-2, haptoglobin, Beta ig-h3, and protein AMBP. Moreover, we also confirmed previously reported diagnostic accuracies of the MPM markers fibulin-3 and mesothelin measured by two complementary mass spectrometry-based methods. In conclusion, a novel affinity-enrichment mass spectrometry-based proteomics identified panels of proteins in pleural effusion with extraordinary diagnostic accuracies, which are described here for the first time as biomarkers for MPM. Full article

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2022

Jump to: 2023, 2021, 2020

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 3 | Viewed by 3788

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

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10 pages, 3465 KiB

Open AccessArticle

CTRP1 Knockout Attenuates Tumor Progression in A549 and HCT116 Cancer Cells

by Rackhyun Park, Yea-In Park, Yeonjeong Park, Siyun Lee, Jaeyeon So and Junsoo Park

Cancers 2022, 14(18), 4495; https://doi.org/10.3390/cancers14184495 - 16 Sep 2022

Cited by 3 | Viewed by 1544

Abstract

C1q and TNF-related 1 (C1QTNF1/CTRP1) is an adiponectin-associated protein belonging to the C1q/TNF-related protein family. Recent studies have shown that the C1q and TNF-related protein (CTRP) family is involved in cancer progression; however, the specific role of CTRP1 in tumor progression has not [...] Read more.

C1q and TNF-related 1 (C1QTNF1/CTRP1) is an adiponectin-associated protein belonging to the C1q/TNF-related protein family. Recent studies have shown that the C1q and TNF-related protein (CTRP) family is involved in cancer progression; however, the specific role of CTRP1 in tumor progression has not yet been elucidated. To examine the role of CTRP1 in tumor progression, we generated CTRP1 knockout A549 and HCT116 cell lines, which reduced the expression levels of nuclear factor (NF)-κB-dependent and metastasis-promoting transcripts. We demonstrated that CTRP1 knockout inhibited the cell proliferation and invasion and tumor growth. Finally, database analysis showed that CTRP1 expression was upregulated in metastatic cancers and elevated levels of CTRP1 were associated with poor prognosis. These results suggest that CTRP1 expression contributes to NF-κB signaling and promotes tumor progression. Full article

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3 pages, 196 KiB

Open AccessCorrection

Correction: Ciardiello et al. Biomarker-Guided Anti-EGFR Rechallenge Therapy in Metastatic Colorectal Cancer. Cancers 2021, 13, 1941

by Davide Ciardiello, Giulia Martini, Vincenzo Famiglietti, Stefania Napolitano, Vincenzo De Falco, Teresa Troiani, Tiziana Pia Latiano, Javier Ros, Elena Elez Fernandez, Pietro Paolo Vitiello, Evaristo Maiello, Fortunato Ciardiello and Erika Martinelli

Cancers 2022, 14(16), 3900; https://doi.org/10.3390/cancers14163900 - 12 Aug 2022

Cited by 2 | Viewed by 996

Abstract

In the original publication [...] Full article

16 pages, 5992 KiB

Open AccessArticle

Cytoplasmic Clusterin Suppresses Lung Cancer Metastasis by Inhibiting the ROCK1-ERK Axis

by Shaobo Huang, Xu Li, Weiqi Gu, Xiaoyi Li, Jingjing Zhao, Jueheng Wu, Junchao Cai, Xianming Feng and Tianyu Tao

Cancers 2022, 14(10), 2463; https://doi.org/10.3390/cancers14102463 - 17 May 2022

Cited by 4 | Viewed by 2057

Abstract

Clusterin (CLU) is a heterodimeric glycoprotein that has been detected in diverse human tissues and implicated in many cellular processes. Accumulating evidence indicates that the expression of secreted CLU correlates with the progression of cancers. However, the molecular mechanisms underlying its tumor-suppressive roles [...] Read more.

Clusterin (CLU) is a heterodimeric glycoprotein that has been detected in diverse human tissues and implicated in many cellular processes. Accumulating evidence indicates that the expression of secreted CLU correlates with the progression of cancers. However, the molecular mechanisms underlying its tumor-suppressive roles are incompletely uncovered. In this study, we demonstrate that precursor CLU is widely downregulated in lung cancer tissue, in which secretory CLU proteins are slightly decreased. Impressively, overexpressing CLU potently inhibits the migration, invasion and metastasis of lung cancer cells, whereas silencing CLU promotes this behavior; however, it appears that secretory CLU fails to exert similar anti-metastatic effects. Interestingly, the cytoplasmic precursor CLU binds ROCK1 to abrogate the interaction between ROCK1 and ERK and impair ERK activity, leading to the suppression of lung cancer invasiveness. Meanwhile, the expression of CLU was remarkably diminished in lung cancer bone metastasis loci when compared with subcutaneous tumors in the mouse model and hardly detected in the bone metastasis loci of lung cancer patients when compared with the primary. These findings reveal a novel insight into the function and regulation of cytoplasmic CLU in lung cancer, which might be a potential target for the diagnosis and treatment of metastatic lung cancer. Full article

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2021

Jump to: 2023, 2022, 2020

17 pages, 337 KiB

Open AccessReview

Novel Biomarkers and Druggable Targets in Advanced Melanoma

by Pier Francesco Ferrucci and Emilia Cocorocchio

Cancers 2022, 14(1), 81; https://doi.org/10.3390/cancers14010081 - 24 Dec 2021

Cited by 5 | Viewed by 2524

Abstract

Immunotherapy with Ipilimumab or antibodies against programmed death (ligand) 1 (anti-PD1/PDL1), targeted therapies with BRAF-inhibitors (anti-BRAF) and their combinations significantly changed melanoma treatment options in both primary, adjuvant and metastatic setting, allowing for a cure, or at least long-term survival, in most patients. [...] Read more.

Immunotherapy with Ipilimumab or antibodies against programmed death (ligand) 1 (anti-PD1/PDL1), targeted therapies with BRAF-inhibitors (anti-BRAF) and their combinations significantly changed melanoma treatment options in both primary, adjuvant and metastatic setting, allowing for a cure, or at least long-term survival, in most patients. However, up to 50% of those with advance or metastatic disease still have no significant benefit from such innovative therapies, and clinicians are not able to discriminate in advance neither who is going to respond and for how long nor who is going to develop collateral effects and which ones. However, druggable targets, as well as affordable and reliable biomarkers are needed to personalize resources at a single-patient level. In this manuscript, different molecules, genes, cells, pathways and even combinatorial algorithms or scores are included in four biomarker chapters (molecular, immunological, peripheral and gut microbiota) and reviewed in order to evaluate their role in indicating a patient’s possible response to treatment or development of toxicities. Full article

24 pages, 1915 KiB

Open AccessArticle

Hsp70 in Liquid Biopsies—A Tumor-Specific Biomarker for Detection and Response Monitoring in Cancer

by Caroline Werner, Stefan Stangl, Lukas Salvermoser, Melissa Schwab, Maxim Shevtsov, Alexia Xanthopoulos, Fei Wang, Ali Bashiri Dezfouli, Dennis Thölke, Christian Ostheimer, Daniel Medenwald, Martin Windberg, Matthias Bache, Martin Schlapschy, Arne Skerra and Gabriele Multhoff

Cancers 2021, 13(15), 3706; https://doi.org/10.3390/cancers13153706 - 23 Jul 2021

Cited by 18 | Viewed by 3247

Abstract

In contrast to normal cells, tumor cells of multiple entities overexpress the Heat shock protein 70 (Hsp70) not only in the cytosol, but also present it on their plasma membrane in a tumor-specific manner. Furthermore, membrane Hsp70-positive tumor cells actively release Hsp70 in [...] Read more.

In contrast to normal cells, tumor cells of multiple entities overexpress the Heat shock protein 70 (Hsp70) not only in the cytosol, but also present it on their plasma membrane in a tumor-specific manner. Furthermore, membrane Hsp70-positive tumor cells actively release Hsp70 in small extracellular vesicles with biophysical characteristics of exosomes. Due to conformational changes of Hsp70 in a lipid environment, most commercially available antibodies fail to detect membrane-bound and vesicular Hsp70. To fill this gap and to assess the role of vesicular Hsp70 in circulation as a potential tumor biomarker, we established the novel complete (comp)Hsp70 sandwich ELISA, using two monoclonal antibodies (mAbs), that is able to recognize both free and lipid-associated Hsp70 on the cell surface of viable tumor cells and on small extracellular vesicles. The epitopes of the mAbs cmHsp70.1 (aa 451–461) and cmHsp70.2 (aa 614–623) that are conserved among different species reside in the substrate-binding domain of Hsp70 with measured affinities of 0.42 nM and 0.44 nM, respectively. Validation of the compHsp70 ELISA revealed a high intra- and inter-assay precision, linearity in a concentration range of 1.56 to 25 ng/mL, high recovery rates of spiked liposomal Hsp70 (>84%), comparable values between human serum and plasma samples and no interference by food intake or age of the donors. Hsp70 concentrations in the circulation of patients with glioblastoma, squamous cell or adeno non-small cell lung carcinoma (NSCLC) at diagnosis were significantly higher than those of healthy donors. Hsp70 concentrations dropped concomitantly with a decrease in viable tumor mass upon irradiation of patients with approximately 20 Gy (range 18–22.5 Gy) and after completion of radiotherapy (60–70 Gy). In summary, the compHsp70 ELISA presented herein provides a sensitive and reliable tool for measuring free and vesicular Hsp70 in liquid biopsies of tumor patients, levels of which can be used as a tumor-specific biomarker, for risk assessment (i.e., differentiation of grade III vs. IV adeno NSCLC) and monitoring of therapeutic outcomes. Full article

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20 pages, 54485 KiB

Open AccessArticle

Canopy Homolog 2 as a Novel Molecular Target in Hepatocarcinogenesis

by Anna Kakehashi, Shugo Suzuki, Masayuki Shiota, Nina Raymo, Min Gi, Taro Tachibana, Vasily Stefanov and Hideki Wanibuchi

Cancers 2021, 13(14), 3613; https://doi.org/10.3390/cancers13143613 - 19 Jul 2021

Cited by 5 | Viewed by 2430

Abstract

In the present study, the role of a novel protein involved in neurite development and endoplasmic reticulum (ER) stress, canopy homolog 2 (CNPY2), was investigated in mouse and human hepatocarcinogenesis. Firstly, a sensitive quantitative and qualitative detection of protein expression using QSTAR Elite [...] Read more.

In the present study, the role of a novel protein involved in neurite development and endoplasmic reticulum (ER) stress, canopy homolog 2 (CNPY2), was investigated in mouse and human hepatocarcinogenesis. Firstly, a sensitive quantitative and qualitative detection of protein expression using QSTAR Elite LC-Ms/Ms was performed for the analysis of lysates of microdissected hepatocellular altered foci (AF), adenomas (HCAs), carcinomas (HCCs) and peri-tumoral livers from C57Bl/6J mice treated with diethylnitrosamine (DEN) and then maintained for 27 or 38 weeks on basal diet. Significant overexpression of 18.5 kDa CNPY2 processed form was demonstrated in AF, HCAs and HCCs, while low expression was observed in the livers of DEN-treated and control mice. Furthermore, CNPY2 elevation in AF and tumors was coordinated with accumulation of numerous cytoskeletal proteins, including cytokeratins 8 and 18, actin, non-muscle myosin and septin 9 and those involved in ER and mitochondrial stresses such as calreticulin, prohibitins 1 and 2 and YME1-like-1. Knockdown of CNPY2 in Huh7 and HepG2 human liver cancer cells resulted in significant suppression of cell survival and invasive potential, inhibition of cyclin D1, induction of p21^Waf1/Cip1 and suppression of the apoptosis inhibitor Bcl2. In contrast, transfection of a mouse CNPY2 (mCNPY2-Ds-Red) vector plasmid in Huh7 and HepG2 cancer cells, with subsequent accumulation of CNPY2 in the ER, resulted in significant increase in cancer cells survival. Clinicopathological analysis in 90 HCV-positive HCC patients, revealed significant association of CNPY2 overexpression with poor overall (p = 0.041) survival. Furthermore, CNPY2 increase was associated with vessel invasion (p = 0.038), poor histological differentiation (p = 0.035) and advanced clinical stage (p = 0.016). In conclusion, CNPY2 is a promising molecular target elevated early in hepatocarcinogenesis and prognostic marker for human HCV-associated HCC. CNPY2 is involved in the processes of ER stress, cell cycle progression, proliferation, survival and invasion of liver tumor cells. Full article

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17 pages, 2211 KiB

Open AccessArticle

TBC1D9: An Important Modulator of Tumorigenesis in Breast Cancer

by Charu Kothari, Alisson Clemenceau, Geneviève Ouellette, Kaoutar Ennour-Idrissi, Annick Michaud, René C.-Gaudreault, Caroline Diorio and Francine Durocher

Cancers 2021, 13(14), 3557; https://doi.org/10.3390/cancers13143557 - 16 Jul 2021

Cited by 8 | Viewed by 3112

Abstract

Triple-negative breast cancer (TNBC) is a major concern among the different subtypes of breast cancer (BC) due to the lack of effective treatment. In a previous study by our group aimed at understanding the difference between TNBC and non-TNBC tumors, we identified the [...] Read more.

Triple-negative breast cancer (TNBC) is a major concern among the different subtypes of breast cancer (BC) due to the lack of effective treatment. In a previous study by our group aimed at understanding the difference between TNBC and non-TNBC tumors, we identified the gene TBC1 domain family member 9 (TBC1D9), the expression of which was lower in TNBC as compared to non-TNBC tumors. In the present study, analysis of TBC1D9 expression in TNBC (n = 58) and non-TNBC (n = 25) patient tumor samples validated that TBC1D9 expression can differentiate TNBC (low) from non-TNBC (high) samples and that expression of TBC1D9 was inversely correlated with grade and proliferative index. Moreover, we found that downregulation of the TBC1D9 gene decreases the proliferation marginally in non-TNBC and was associated with increased migratory and tumorigenic potential in both TNBC and luminal BC cell lines. This increase was mediated by the upregulation of ARL8A, ARL8B, PLK1, HIF1α, STAT3, and SPP1 expression in TBC1D9 knockdown cells. Our results suggest that TBC1D9 expression might limit tumor aggressiveness and that it has a differential expression in TNBC vs. non-TNBC tumors. Full article

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18 pages, 3918 KiB

Open AccessArticle

The Ability of Metabolomics to Discriminate Non-Small-Cell Lung Cancer Subtypes Depends on the Stage of the Disease and the Type of Material Studied

by Tomasz Kowalczyk, Joanna Kisluk, Karolina Pietrowska, Joanna Godzien, Miroslaw Kozlowski, Joanna Reszeć, Ewa Sierko, Wojciech Naumnik, Robert Mróz, Marcin Moniuszko, Adam Kretowski, Jacek Niklinski and Michal Ciborowski

Cancers 2021, 13(13), 3314; https://doi.org/10.3390/cancers13133314 - 01 Jul 2021

Cited by 14 | Viewed by 3744

Abstract

Identification of the NSCLC subtype at an early stage is still quite sophisticated. Metabolomics analysis of tissue and plasma of NSCLC patients may indicate new, and yet unknown, metabolic pathways active in the NSCLC. Our research characterized the metabolomics profile of tissue and [...] Read more.

Identification of the NSCLC subtype at an early stage is still quite sophisticated. Metabolomics analysis of tissue and plasma of NSCLC patients may indicate new, and yet unknown, metabolic pathways active in the NSCLC. Our research characterized the metabolomics profile of tissue and plasma of patients with early and advanced NSCLC stage. Samples were subjected to thorough metabolomics analyses using liquid chromatography-mass spectrometry (LC-MS) technique. Tissue and/or plasma samples from 137 NSCLC patients were analyzed. Based on the early stage tissue analysis, more than 200 metabolites differentiating adenocarcinoma (ADC) and squamous cell lung carcinoma (SCC) subtypes as well as normal tissue, were identified. Most of the identified metabolites were amino acids, fatty acids, carnitines, lysoglycerophospholipids, sphingomyelins, plasmalogens and glycerophospholipids. Moreover, metabolites related to N-acyl ethanolamine (NAE) biosynthesis, namely glycerophospho (N-acyl) ethanolamines (GP-NAE), which discriminated early-stage SCC from ADC, have also been identified. On the other hand, the analysis of plasma of chronic obstructive pulmonary disease (COPD) and NSCLC patients allowed exclusion of the metabolites related to the inflammatory state in lungs and the identification of compounds (lysoglycerophospholipids, glycerophospholipids and sphingomyelins) truly characteristic to cancer. Our results, among already known, showed novel, thus far not described, metabolites discriminating NSCLC subtypes, especially in the early stage of cancer. Moreover, the presented results also indicated the activity of new metabolic pathways in NSCLC. Further investigations on the role of NAE biosynthesis pathways in the early stage of NSCLC may reveal new prognostic and diagnostic targets. Full article

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11 pages, 2913 KiB

Open AccessArticle

Clinically Advanced Pheochromocytomas and Paragangliomas: A Comprehensive Genomic Profiling Study

by Gennady Bratslavsky, Ethan S. Sokol, Michael Daneshvar, Andrea Necchi, Oleg Shapiro, Joseph Jacob, Nick Liu, Tom S. Sanford, Ruben Pinkhasov, Hanan Goldberg, Jonathan K. Killian, Shakti Ramkissoon, Eric A. Severson, Richard S. P. Huang, Natalie Danziger, Mehdi Mollapour, Jeffrey S. Ross and Karel Pacak

Cancers 2021, 13(13), 3312; https://doi.org/10.3390/cancers13133312 - 01 Jul 2021

Cited by 8 | Viewed by 2506

Abstract

Patients with clinically advanced paragangliomas (CA-Para) and pheochromocytomas (CA-Pheo) have limited surgical or systemic treatments. We used comprehensive genomic profiling (CGP) to compare genomic alterations (GA) in CA-Para and CA-Pheo to identify potential therapeutic targets. Eighty-three CA-Para and 45 CA-Pheo underwent hybrid-capture-based CGP [...] Read more.

Patients with clinically advanced paragangliomas (CA-Para) and pheochromocytomas (CA-Pheo) have limited surgical or systemic treatments. We used comprehensive genomic profiling (CGP) to compare genomic alterations (GA) in CA-Para and CA-Pheo to identify potential therapeutic targets. Eighty-three CA-Para and 45 CA-Pheo underwent hybrid-capture-based CGP using a targeted panel of 324 genes. Tumor mutational burden (TMB) and microsatellite instability (MSI) were determined. The GA/tumor frequencies were low for both tumor types (1.9 GA/tumor for CA-Para, 2.3 GA/tumor for CA-Pheo). The most frequent potentially targetable GA in CA-Para were in FGFR1 (7%, primarily amplifications), NF1, PTEN, NF2, and CDK4 (all 2%) and for CA-Pheo in RET (9%, primarily fusions), NF1 (11%) and FGFR1 (7%). Germline mutations in known cancer predisposition genes were predicted in 13 (30%) of CA-Pheo and 38 (45%) of CA-Para cases, predominantly involving SDHA/B genes. Both CA-Para and CA-Para had low median TMB, low PD-L1 expression levels and none had MSI high status. While similar GA frequency is seen in both CA-Para and CA-Para, germline GA were seen more frequently in CA-Para. Low PD-L1 expression levels and no MSI high status argue against strong potential for novel immune checkpoint inhibitors. However, several important potential therapeutic targets in both CA-Para and CA-Para are identified using CGP. Full article

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24 pages, 6364 KiB

Open AccessArticle

Protein Aggregation Patterns Inform about Breast Cancer Response to Antiestrogens and Reveal the RNA Ligase RTCB as Mediator of Acquired Tamoxifen Resistance

by Inês Direito, Liliana Monteiro, Tânia Melo, Daniela Figueira, João Lobo, Vera Enes, Gabriela Moura, Rui Henrique, Manuel A. S. Santos, Carmen Jerónimo, Francisco Amado, Margarida Fardilha and Luisa A. Helguero

Cancers 2021, 13(13), 3195; https://doi.org/10.3390/cancers13133195 - 26 Jun 2021

Cited by 12 | Viewed by 4718

Abstract

The protein quality control network, including autophagy, the proteasome and the unfolded protein response (UPR), is triggered by stress and is overactive in acquired antiestrogen therapy resistance. We show for the first time that the aggresome load correlates with apoptosis and is increased [...] Read more.

The protein quality control network, including autophagy, the proteasome and the unfolded protein response (UPR), is triggered by stress and is overactive in acquired antiestrogen therapy resistance. We show for the first time that the aggresome load correlates with apoptosis and is increased in antiestrogen-sensitive cells compared to endocrine-resistant variants. LC-MS/MS analysis of the aggregated proteins obtained after 4OH-tamoxifen and Fulvestrant treatment identified proteins with essential function in protein quality control in antiestrogen-sensitive cells, but not in resistant variants. These include the UPR modulators RTCB and PDIA6, as well as many proteasome proteins such as PSMC2 and PSMD11. RTCB is a tRNA and XBP1 ligase and its aggregation induced by antiestrogens correlated with impaired XBP1s expression in sensitive cells. Knock down of RTCB was sufficient to restore sensitivity to tamoxifen in endocrine-resistant cells and increased the formation of aggresomes, leading to apoptotic cell death. Analysis of primary human breast cancer samples and their metastases appearing after endocrine treatment showed that RTCB is only localized to aggresomes in the primary tumors, while total aggresomes, including aggregated RTCB, were significantly reduced in the metastases. Therefore, different protein aggregation patterns may indicate loss of function of essential proteins resulting in enhanced protein aggregation that can be used to identify antiestrogen-resistant breast cancer cells and improve the response to antiestrogenic therapy. Full article

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23 pages, 2963 KiB

Open AccessArticle

Tracking the Antibody Immunome in Sporadic Colorectal Cancer by Using Antigen Self-Assembled Protein Arrays

by María González-González, José María Sayagués, Luis Muñoz-Bellvís, Carlos Eduardo Pedreira, Marcello L. R. de Campos, Jacinto García, José Antonio Alcázar, Patrick F. Braz, Breno L. Galves, Luis Miguel González, Oscar Bengoechea, María del Mar Abad, Juan Jesús Cruz, Lorena Bellido, Emilio Fonseca, Paula Díez, Pablo Juanes-Velasco, Alicia Landeira-Viñuela, Quentin Lecrevisse, Enrique Montalvillo, Rafael Góngora, Oscar Blanco, José Manuel Sánchez-Santos, Joshua LaBaer, Alberto Orfao and Manuel Fuentes Show full author list Hide full author list

Cancers 2021, 13(11), 2718; https://doi.org/10.3390/cancers13112718 - 31 May 2021

Cited by 9 | Viewed by 3218

Abstract

Sporadic Colorectal Cancer (sCRC) is the third leading cause of cancer death in the Western world, and the sCRC patients presenting with synchronic metastasis have the poorest prognosis. Genetic alterations accumulated in sCRC tumor cells translate into mutated proteins and/or abnormal protein expression [...] Read more.

Sporadic Colorectal Cancer (sCRC) is the third leading cause of cancer death in the Western world, and the sCRC patients presenting with synchronic metastasis have the poorest prognosis. Genetic alterations accumulated in sCRC tumor cells translate into mutated proteins and/or abnormal protein expression levels, which contribute to the development of sCRC. Then, the tumor-associated proteins (TAAs) might induce the production of auto-antibodies (aAb) via humoral immune response. Here, Nucleic Acid Programmable Protein Arrays (NAPPArray) are employed to identify aAb in plasma samples from a set of 50 sCRC patients compared to seven healthy donors. Our goal was to establish a systematic workflow based on NAPPArray to define differential aAb profiles between healthy individuals and sCRC patients as well as between non-metastatic (n = 38) and metastatic (n = 12) sCRC, in order to gain insight into the role of the humoral immune system in controlling the development and progression of sCRC. Our results showed aAb profile based on 141 TAA including TAAs associated with biological cellular processes altered in genesis and progress of sCRC (e.g., FSCN1, VTI2 and RPS28) that discriminated healthy donors vs. sCRC patients. In addition, the potential capacity of discrimination (between non-metastatic vs. metastatic sCRC) of 7 TAAs (USP5, ML4, MARCKSL1, CKMT1B, HMOX2, VTI2, TP53) have been analyzed individually in an independent cohort of sCRC patients, where two of them (VTI2 and TP53) were validated (AUC ~75%). In turn, these findings provided novel insights into the immunome of sCRC, in combination with transcriptomics profiles and protein antigenicity characterizations, wich might lead to the identification of novel sCRC biomarkers that might be of clinical utility for early diagnosis of the tumor. These results explore the immunomic analysis as potent source for biomarkers with diagnostic and prognostic value in CRC. Additional prospective studies in larger series of patients are required to confirm the clinical utility of these novel sCRC immunomic biomarkers. Full article

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16 pages, 1228 KiB

Open AccessReview

Challenging, Accurate and Feasible: CAF-1 as a Tumour Proliferation Marker of Diagnostic and Prognostic Value

by Alexandros G. Sykaras, Alexandros Pergaris and Stamatios Theocharis

Cancers 2021, 13(11), 2575; https://doi.org/10.3390/cancers13112575 - 24 May 2021

Cited by 11 | Viewed by 3197

Abstract

The discovery of novel biomarkers of diagnostic, prognostic, and therapeutic value is a major challenge of current cancer research. The assessment of tumour cell proliferative capacity is pivotal for grading and clinical decision-making, highlighting the importance of proliferation markers as diagnostic and prognostic [...] Read more.

The discovery of novel biomarkers of diagnostic, prognostic, and therapeutic value is a major challenge of current cancer research. The assessment of tumour cell proliferative capacity is pivotal for grading and clinical decision-making, highlighting the importance of proliferation markers as diagnostic and prognostic tools. Currently, the immunohistochemical analysis of Ki-67 expression levels is routinely used in clinical settings to assess tumour proliferation. Inasmuch as the function of Ki-67 is not fully understood and its evaluation lacks standardization, there is interest in chromatin regulator proteins as alternative proliferation markers of clinical value. Here, we review recent evidence demonstrating that chromatin assembly factor 1 (CAF-1), a histone chaperone selectively expressed in cycling cells, is a proliferation marker of clinical value. CAF-1 expression, when evaluated by immunocytochemistry in breast cancer cytology smears and immunohistochemistry in cancer biopsies from several tissues, strongly correlates with the expression of Ki-67 and other proliferation markers. Notably, CAF-1 expression is upregulated in almost all cancers, and CAF-1 overexpression is significantly associated, in most cancer types, with high histological tumour grade, advanced stage, recurrence, metastasis, and decreased patient survival. These findings suggest that CAF-1 is a robust, reproducible, and feasible proliferation marker of prognostic importance. CAF-1 may represent an attractive alternative or complementary to Ki-67 for cancer stratification and clinical guidance. Full article

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14 pages, 5684 KiB

Open AccessReview

Cathepsin K: A Novel Diagnostic and Predictive Biomarker for Renal Tumors

by Anna Caliò, Matteo Brunelli, Stefano Gobbo, Pedram Argani, Enrico Munari, George Netto and Guido Martignoni

Cancers 2021, 13(10), 2441; https://doi.org/10.3390/cancers13102441 - 18 May 2021

Cited by 19 | Viewed by 3971

Abstract

Cathepsin K is a papain-like cysteine protease with high matrix-degrading activity. Among several cathepsins, cathepsin K is the most potent mammalian collagenase, mainly expressed by osteoclasts. This review summarizes most of the recent findings of cathepsin K expression, highlighting its role in renal [...] Read more.

Cathepsin K is a papain-like cysteine protease with high matrix-degrading activity. Among several cathepsins, cathepsin K is the most potent mammalian collagenase, mainly expressed by osteoclasts. This review summarizes most of the recent findings of cathepsin K expression, highlighting its role in renal tumors for diagnostic purposes and as a potential molecular target. Indeed, cathepsin K is a recognized diagnostic tool for the identification of TFE3/TFEB-rearranged renal cell carcinoma, TFEB-amplified renal cell carcinoma, and pure epithelioid PEComa/epithelioid angiomyolipoma. More recently, its expression has been observed in a subgroup of eosinophilic renal neoplasms molecularly characterized by TSC/mTOR gene mutations. Interestingly, both TSC mutations or TFE3 rearrangement have been reported in pure epithelioid PEComa/epithelioid angiomyolipoma. Therefore, cathepsin K seems to be a downstream marker of TFE3/TFEB rearrangement, TFEB amplification, and mTOR pathway activation. Given the established role of mTOR inhibitors as a pharmacological option in renal cancers, cathepsin K could be of use as a predictive marker of therapy response and as a potential target. In the future, uropathologists may implement the use of cathepsin K to establish a diagnosis among renal tumors with clear cells, papillary architecture, and oncocytic features. Full article

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42 pages, 748 KiB

Open AccessReview

Liquid Biopsy in Hepatocellular Carcinoma: Where Are We Now?

by Filippo Pelizzaro, Romilda Cardin, Barbara Penzo, Elisa Pinto, Alessandro Vitale, Umberto Cillo, Francesco Paolo Russo and Fabio Farinati

Cancers 2021, 13(9), 2274; https://doi.org/10.3390/cancers13092274 - 10 May 2021

Cited by 20 | Viewed by 3380

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide. Diagnostic, prognostic, and predictive biomarkers are urgently needed in order to improve patient survival. Indeed, the most widely used biomarkers, such as alpha-fetoprotein (AFP), have limited accuracy as both [...] Read more.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide. Diagnostic, prognostic, and predictive biomarkers are urgently needed in order to improve patient survival. Indeed, the most widely used biomarkers, such as alpha-fetoprotein (AFP), have limited accuracy as both diagnostic and prognostic tests. Liver biopsy provides an insight on the biology of the tumor, but it is an invasive procedure, not routinely used, and not representative of the whole neoplasia due to the demonstrated intra-tumoral heterogeneity. In recent years, liquid biopsy, defined as the molecular analysis of cancer by-products, released by the tumor in the bloodstream, emerged as an appealing source of new biomarkers. Several studies focused on evaluating extracellular vesicles, circulating tumor cells, cell-free DNA and non-coding RNA as novel reliable biomarkers. In this review, we aimed to provide a comprehensive overview on the most relevant available evidence on novel circulating biomarkers for early diagnosis, prognostic stratification, and therapeutic monitoring. Liquid biopsy seems to be a very promising instrument and, in the near future, some of these new non-invasive tools will probably change the clinical management of HCC patients. Full article

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16 pages, 1748 KiB

Open AccessArticle

Clinical Assay for the Early Detection of Colorectal Cancer Using Mass Spectrometric Wheat Germ Agglutinin Multiple Reaction Monitoring

by I-Jung Tsai, Emily Chia-Yu Su, I-Lin Tsai and Ching-Yu Lin

Cancers 2021, 13(9), 2190; https://doi.org/10.3390/cancers13092190 - 02 May 2021

Cited by 8 | Viewed by 3058

Abstract

Colorectal cancer (CRC) is currently the third leading cause of cancer-related mortality in the world. U.S. Food and Drug Administration-approved circulating tumor markers, including carcinoembryonic antigen, carbohydrate antigen (CA) 19-9 and CA125 were used as prognostic biomarkers of CRC that attributed to low [...] Read more.

Colorectal cancer (CRC) is currently the third leading cause of cancer-related mortality in the world. U.S. Food and Drug Administration-approved circulating tumor markers, including carcinoembryonic antigen, carbohydrate antigen (CA) 19-9 and CA125 were used as prognostic biomarkers of CRC that attributed to low sensitivity in diagnosis of CRC. Therefore, our purpose is to develop a novel strategy for novel clinical biomarkers for early CRC diagnosis. We used mass spectrometry (MS) methods such as nanoLC-MS/MS, targeted LC-MS/MS, and stable isotope-labeled multiple reaction monitoring (MRM) MS coupled to test machine learning algorithms and logistic regression to analyze plasma samples from patients with early-stage CRC, late-stage CRC, and healthy controls (HCs). On the basis of our methods, 356 peptides were identified, 6 differential expressed peptides were verified, and finally three peptides corresponding wheat germ agglutinin (WGA)-captured proteins were semi-quantitated in 286 plasma samples (80 HCs and 206 CRCs). The novel peptide biomarkers combination of PF4^54–62, ITIH4^429–438, and APOE^198–207 achieved sensitivity 84.5%, specificity 97.5% and an AUC of 0.96 in CRC diagnosis. In conclusion, our study demonstrated that WGA-captured plasma PF4^54–62, ITIH4^429–438, and APOE^198–207 levels in combination may serve as highly effective early diagnostic biomarkers for patients with CRC. Full article

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11 pages, 603 KiB

Open AccessReview

Biomarker-Guided Anti-EGFR Rechallenge Therapy in Metastatic Colorectal Cancer

by Davide Ciardiello, Giulia Martini, Vincenzo Famiglietti, Stefania Napolitano, Vincenzo De Falco, Teresa Troiani, Tiziana Pia Latiano, Javier Ros, Elena Elez Fernandez, Pietro Paolo Vitiello, Evaristo Maiello, Fortunato Ciardiello and Erika Martinelli

Cancers 2021, 13(8), 1941; https://doi.org/10.3390/cancers13081941 - 17 Apr 2021

Cited by 25 | Viewed by 4744 | Correction

Abstract

The prognosis of patients with metastatic colorectal cancer (mCRC) who progressed to the first and the second lines of treatment is poor. Thus, new therapeutic strategies are needed. During the last years, emerging evidence suggests that retreatment with anti-epidermal growth factor receptor (EGFR) [...] Read more.

The prognosis of patients with metastatic colorectal cancer (mCRC) who progressed to the first and the second lines of treatment is poor. Thus, new therapeutic strategies are needed. During the last years, emerging evidence suggests that retreatment with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MAbs) in the third line of mCRC patients, that have previously obtained clinical benefit by first-line therapy with anti-EGFR MAbs plus chemotherapy, could lead to prolonged survival. The rationale beyond this “rechallenge” strategy is that, after disease progression to first line EGFR-based therapy, a treatment break from anti-EGFR drugs results in RAS mutant cancer cell decay, restoring the sensitivity of cancer cells to cetuximab and panitumumab. In fact, rechallenge treatment with anti-EGFR drugs has shown promising clinical activity, particularly in patients with plasma RAS and BRAF wild type circulating tumor DNA, as defined by liquid biopsy analysis at baseline treatment. The aim of this review is to analyze the current knowledge on rechallenge and to investigate the role of novel biomarkers that can guide the appropriate selection of patients that could benefit from this therapeutic strategy. Finally, we discuss on-going trials and future perspectives. Full article

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17 pages, 5052 KiB

Open AccessArticle

A Network Pharmacological Approach to Reveal the Pharmacological Targets and Its Associated Biological Mechanisms of Prunetin-5-O-Glucoside against Gastric Cancer

by Preethi Vetrivel, Rajeswari Murugesan, Pritam Bhagwan Bhosale, Sang Eun Ha, Hun Hwan Kim, Jeong Doo Heo and Gon Sup Kim

Cancers 2021, 13(8), 1918; https://doi.org/10.3390/cancers13081918 - 15 Apr 2021

Cited by 13 | Viewed by 3659

Abstract

Gastric cancer (GC) is an aggressive malignancy with increased mortality rate and low treatment options. Increasing evidence suggests that network pharmacology will be a novel method for identifying the systemic mechanism of therapeutic compounds in diseases like cancer. The current study aimed to [...] Read more.

Gastric cancer (GC) is an aggressive malignancy with increased mortality rate and low treatment options. Increasing evidence suggests that network pharmacology will be a novel method for identifying the systemic mechanism of therapeutic compounds in diseases like cancer. The current study aimed to use a network pharmacology approach to establish the predictive targets of prunetin-5-O-glucoside (PG) against gastric cancer and elucidate its biological mechanisms. Primarily, genes associated with the pathogenesis of GC was identified from the DiGeNET database and targets of PG was obtained from the Swiss target prediction database. In total, 65 correlative hits were identified as anti-gastric cancer targets of PG. Functional enrichment and pathway analysis revealed significant biological mechanisms of the targets. Interaction of protein network and cluster analysis using STRING resulted in three crucial interacting hub targets namely, HSP90AA1, CDK2, and MMP1. Additionally, the in vitro cytotoxic potential of PG was assessed on three gastric cancer cells (AGS, MKN-28, and SNU-484). Furthermore, the crucial targets were validated using molecular docking, followed by their expressions being evaluated by western blot and Human Protein Atlas. The findings indicate that the pharmacological action of PG against GC might be associated with the regulation of three core targets: HSP90AA1, CDK2, and MMP1. Thus, the network pharmacology undertaken in the current study established the core active targets of PG, which may be extensively applied with further validations for treatment in GC. Full article

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22 pages, 1000 KiB

Open AccessReview

CRISPR Screens in Synthetic Lethality and Combinatorial Therapies for Cancer

by Laia Castells-Roca, Eudald Tejero, Benjamín Rodríguez-Santiago and Jordi Surrallés

Cancers 2021, 13(7), 1591; https://doi.org/10.3390/cancers13071591 - 30 Mar 2021

Cited by 18 | Viewed by 5276

Abstract

Cancer is a complex disease resulting from the accumulation of genetic dysfunctions. Tumor heterogeneity causes the molecular variety that divergently controls responses to chemotherapy, leading to the recurrent problem of cancer reappearance. For many decades, efforts have focused on identifying essential tumoral genes [...] Read more.

Cancer is a complex disease resulting from the accumulation of genetic dysfunctions. Tumor heterogeneity causes the molecular variety that divergently controls responses to chemotherapy, leading to the recurrent problem of cancer reappearance. For many decades, efforts have focused on identifying essential tumoral genes and cancer driver mutations. More recently, prompted by the clinical success of the synthetic lethality (SL)-based therapy of the PARP inhibitors in homologous recombinant deficient tumors, scientists have centered their novel research on SL interactions (SLI). The state of the art to find new genetic interactions are currently large-scale forward genetic CRISPR screens. CRISPR technology has rapidly evolved to be a common tool in the vast majority of laboratories, as tools to implement CRISPR screen protocols are available to all researchers. Taking advantage of SLI, combinatorial therapies have become the ultimate model to treat cancer with lower toxicity, and therefore better efficiency. This review explores the CRISPR screen methodology, integrates the up-to-date published findings on CRISPR screens in the cancer field and proposes future directions to uncover cancer regulation and individual responses to chemotherapy. Full article

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26 pages, 4930 KiB

Open AccessArticle

Automatic Detection of the Circulating Cell-Free Methylated DNA Pattern of GCM2, ITPRIPL1 and CCDC181 for Detection of Early Breast Cancer and Surgical Treatment Response

by Sheng-Chao Wang, Li-Min Liao, Muhamad Ansar, Shih-Yun Lin, Wei-Wen Hsu, Chih-Ming Su, Yu-Mei Chung, Cai-Cing Liu, Chin-Sheng Hung and Ruo-Kai Lin

Cancers 2021, 13(6), 1375; https://doi.org/10.3390/cancers13061375 - 18 Mar 2021

Cited by 11 | Viewed by 3582

Abstract

The early detection of cancer can reduce cancer-related mortality. There is no clinically useful noninvasive biomarker for early detection of breast cancer. The aim of this study was to develop accurate and precise early detection biomarkers and a dynamic monitoring system following treatment. [...] Read more.

The early detection of cancer can reduce cancer-related mortality. There is no clinically useful noninvasive biomarker for early detection of breast cancer. The aim of this study was to develop accurate and precise early detection biomarkers and a dynamic monitoring system following treatment. We analyzed a genome-wide methylation array in Taiwanese and The Cancer Genome Atlas (TCGA) breast cancer (BC) patients. Most breast cancer-specific circulating methylated CCDC181, GCM2 and ITPRIPL1 biomarkers were found in the plasma. An automatic analysis process of methylated ccfDNA was established. A combined analysis of CCDC181, GCM2 and ITPRIPL1 (CGIm) was performed in R using Recursive Partitioning and Regression Trees to establish a new prediction model. Combined analysis of CCDC181, GCM2 and ITPRIPL1 (CGIm) was found to have a sensitivity level of 97% and an area under the curve (AUC) of 0.955 in the training set, and a sensitivity level of 100% and an AUC of 0.961 in the test set. The circulating methylated CCDC181, GCM2 and ITPRIPL1 was also significantly decreased after surgery (all p < 0.001). The aberrant methylation patterns of the CCDC181, GCM2 and ITPRIPL1 genes means that they are potential biomarkers for the detection of early BC and can be combined with breast imaging data to achieve higher accuracy, sensitivity and specificity, facilitating breast cancer detection. They may also be applied to monitor the surgical treatment response. Full article

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14 pages, 10331 KiB

Open AccessReview

Autophagy and Extracellular Vesicles in Colorectal Cancer: Interactions and Common Actors?

by Clément Auger, Niki Christou, Aude Brunel, Aurélie Perraud and Mireille Verdier

Cancers 2021, 13(5), 1039; https://doi.org/10.3390/cancers13051039 - 02 Mar 2021

Cited by 8 | Viewed by 3079

Abstract

Autophagy is a homeostatic process involved in the degradation of disabled proteins and organelles using lysosomes. This mechanism requires the recruitment of specialized proteins for vesicle trafficking, that may also be involved in other types of machinery such as the biogenesis and secretion [...] Read more.

Autophagy is a homeostatic process involved in the degradation of disabled proteins and organelles using lysosomes. This mechanism requires the recruitment of specialized proteins for vesicle trafficking, that may also be involved in other types of machinery such as the biogenesis and secretion of extracellular vesicles (EVs), and particularly small EVs called exosomes. Among these proteins, Rab-GTPases may operate in both pathways, thus representing an interesting avenue for further study regarding the interaction between autophagy and extracellular vesicle machinery. Both mechanisms are involved in the development of colorectal cancer (CRC), particularly in cancer stem cell (CSC) survival and communication, although they are not specific to CRC or CSCs. This highlights the importance of studying the crosstalk between autophagy and EVs biogenesis and release. Full article

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21 pages, 3831 KiB

Open AccessArticle

IRF8 Is an AML-Specific Susceptibility Factor That Regulates Signaling Pathways and Proliferation of AML Cells

by Franziska Liss, Miriam Frech, Ying Wang, Gavin Giel, Sabrina Fischer, Clara Simon, Lisa Marie Weber, Andrea Nist, Thorsten Stiewe, Andreas Neubauer, Andreas Burchert and Robert Liefke

Cancers 2021, 13(4), 764; https://doi.org/10.3390/cancers13040764 - 12 Feb 2021

Cited by 11 | Viewed by 3858

Abstract

Personalized treatment of acute myeloid leukemia (AML) that target individual aberrations strongly improved the survival of AML patients. However, AML is still one of the most lethal cancer diseases of the 21st century, demonstrating the need to find novel drug targets and to [...] Read more.

Personalized treatment of acute myeloid leukemia (AML) that target individual aberrations strongly improved the survival of AML patients. However, AML is still one of the most lethal cancer diseases of the 21st century, demonstrating the need to find novel drug targets and to explore alternative treatment strategies. Upon investigation of public perturbation data, we identified the transcription factor IRF8 as a novel AML-specific susceptibility gene in humans. IRF8 is upregulated in a subset of AML cells and its deletion leads to impaired proliferation in those cells. Consistently, high IRF8 expression is associated with poorer patients’ prognoses. Combining gene expression changes upon IRF8 deletion and the genome-wide localization of IRF8 in the AML cell line MV4-11, we demonstrate that IRF8 directly regulates key signaling molecules, such as the kinases SRC and FAK, the transcription factors RUNX1 and IRF5, and the cell cycle regulator Cyclin D1. IRF8 loss impairs AML-driving signaling pathways, including the WNT, Chemokine, and VEGF signaling pathways. Additionally, many members of the focal adhesion pathway showed reduced expression, providing a putative link between high IRF8 expression and poor prognosis. Thus, this study suggests that IRF8 could serve as a biomarker and potential molecular target in a subset of human AMLs. Full article

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16 pages, 6607 KiB

Open AccessArticle

Discovery and Proof-of-Concept Study of Nuclease Activity as a Novel Biomarker for Breast Cancer Tumors

by Luiza I. Hernandez, Marcos J. Araúzo-Bravo, Daniela Gerovska, Ricardo Rezola Solaun, Isabel Machado, Alien Balian, Juliana Botero, Tania Jiménez, Olaia Zuriarrain Bergara, Lide Larburu Gurruchaga, Ander Urruticoechea and Frank J. Hernandez

Cancers 2021, 13(2), 276; https://doi.org/10.3390/cancers13020276 - 13 Jan 2021

Cited by 8 | Viewed by 3336

Abstract

Breast cancer is one of the most common pathologies diagnosed in the clinical practice. Despite major advancements in diagnostic approaches, there is no widely accepted biomarker in the clinical practice that can diagnose breast malignancy. Confirmatory diagnosis still relies on the pathological assessment [...] Read more.

Breast cancer is one of the most common pathologies diagnosed in the clinical practice. Despite major advancements in diagnostic approaches, there is no widely accepted biomarker in the clinical practice that can diagnose breast malignancy. Confirmatory diagnosis still relies on the pathological assessment of tissue biopsies by expert pathologists. Thus, there is an unmet need for new types of biomarkers and novel platform technologies that can be easily and robustly integrated into the clinic and that can assist pathologists. Herein, we show that nuclease activity associated to malignant tumors can be used as a novel biomarker in breast cancer, which can be detected via specific degradation of nucleic acid probes. In this study we have identified a set of three chemically modified nucleic acid probes that can diagnose malignancy in biopsy samples with high accuracy (89%), sensitivity (82%) and specificity (94%). This work represents a breakthrough for the potential clinical use of nuclease activity as biomarker, which can be detected via nucleic acids probes, for the clinical diagnosis of malignancy in breast tissue biopsies. This platform technology could be readily implemented into the clinic as adjunct to histopathological diagnostic. Full article

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2020

Jump to: 2023, 2022, 2021

21 pages, 1675 KiB

Open AccessReview

Premature MicroRNA-Based Therapeutic: A “One-Two Punch” against Cancers

by Luyue Chen, Kai Huang, Kaikai Yi, Yanlin Huang, Xinhua Tian and Chunsheng Kang

Cancers 2020, 12(12), 3831; https://doi.org/10.3390/cancers12123831 - 18 Dec 2020

Cited by 3 | Viewed by 2228

Abstract

Up-to-date knowledge regarding the biogenesis and functioning of microRNAs (miRNAs) has provided a much more comprehensive and concrete view of miRNA biology than anyone ever expected. Diverse genetic origins and biogenesis pathways leading to functional miRNAs converge on the synthesis of ≈21-nucleotide RNA [...] Read more.

Up-to-date knowledge regarding the biogenesis and functioning of microRNAs (miRNAs) has provided a much more comprehensive and concrete view of miRNA biology than anyone ever expected. Diverse genetic origins and biogenesis pathways leading to functional miRNAs converge on the synthesis of ≈21-nucleotide RNA duplex, almost all of which are processed from long premature sequences in a DICER- and/or DROSHA-dependent manner. Formerly, it was assumed that one mature strand of the duplex is preferentially selected for entry into the silencing complex, and the paired passenger strands (miRNA*) are subjected to degradation. However, given the consolidated evidence of substantial regulatory activity of miRNA* species, currently, this preconception has been overturned. Here, we see the caveat and opportunity toward exogenously manipulating the expression of premature miRNA, leading to simultaneous upregulation or downregulation of dual regulatory strands due to altered expressions. The caveat is the overlooked miRNA* interference while manipulating the expression of a target miRNA at the premature stage, wherein lies the opportunity. If the dual strands of a pre-miRNA function synergistically, the overlooked miRNA* interference may inversely optimize the therapeutic performance. Insightfully, targeting the premature miRNAs may serve as the “one-two punch” against diseases, especially cancers, and this has been discussed in detail in this review. Full article

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20 pages, 3752 KiB

Open AccessArticle

Functional Dependency Analysis Identifies Potential Druggable Targets in Acute Myeloid Leukemia

by Yujia Zhou, Gregory P. Takacs, Jatinder K. Lamba, Christopher Vulpe and Christopher R. Cogle

Cancers 2020, 12(12), 3710; https://doi.org/10.3390/cancers12123710 - 10 Dec 2020

Cited by 5 | Viewed by 3210

Abstract

Refractory disease is a major challenge in treating patients with acute myeloid leukemia (AML). Whereas the armamentarium has expanded in the past few years for treating AML, long-term survival outcomes have yet to be proven. To further expand the arsenal for treating AML, [...] Read more.

Refractory disease is a major challenge in treating patients with acute myeloid leukemia (AML). Whereas the armamentarium has expanded in the past few years for treating AML, long-term survival outcomes have yet to be proven. To further expand the arsenal for treating AML, we searched for druggable gene targets in AML by analyzing screening data from a lentiviral-based genome-wide pooled CRISPR-Cas9 library and gene knockout (KO) dependency scores in 15 AML cell lines (HEL, MV411, OCIAML2, THP1, NOMO1, EOL1, KASUMI1, NB4, OCIAML3, MOLM13, TF1, U937, F36P, AML193, P31FUJ). Ninety-four gene KOs met the criteria of (A) specifically essential to AML cell survival, (B) non-essential in non-AML cells, and (C) druggable according to three-dimensional (3D) modeling or ligand-based druggability scoring. Forty-four of 94 gene-KOs (47%) had an already-approved drug match and comprised a drug development list termed “deKO.” Fifty of 94 gene-KOs (53%) had no drug in development and comprised a drug discovery list termed “disKO.” STRING analysis and gene ontology categorization of the disKO targets preferentially cluster in the metabolic processes of UMP biosynthesis, IMP biosynthesis, dihydrofolate metabolism, pyrimidine nucleobase biosynthesis, vitellogenesis, and regulation of T cell differentiation and hematopoiesis. Results from this study serve as a testable compendium of AML drug targets that, after validation, may be translated into new therapeutics. Full article

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21 pages, 4985 KiB

Open AccessArticle

ZIP4 Is a Novel Cancer Stem Cell Marker in High-Grade Serous Ovarian Cancer

by Qipeng Fan, Wen Zhang, Robert E. Emerson and Yan Xu

Cancers 2020, 12(12), 3692; https://doi.org/10.3390/cancers12123692 - 09 Dec 2020

Cited by 13 | Viewed by 2545

Abstract

High-grade serous ovarian cancer (HGSOC) is one of the most deadly and heterogenic cancers. We have recently shown that ZIP4 (gene name SLC39A4), a zinc transporter, is functionally involved in cancer stem cell (CSC)-related cellular activities in HGSOC. Here, we identified ZIP4 [...] Read more.

High-grade serous ovarian cancer (HGSOC) is one of the most deadly and heterogenic cancers. We have recently shown that ZIP4 (gene name SLC39A4), a zinc transporter, is functionally involved in cancer stem cell (CSC)-related cellular activities in HGSOC. Here, we identified ZIP4 as a novel CSC marker in HGSOC. Fluorescence-activated cell sorter (FACS)-sorted ZIP4⁺, but not ZIP4⁻ cells, formed spheroids and displayed self-renewing and differentiation abilities. Over-expression of ZIP4 conferred drug resistance properties in vitro. ZIP4⁺, but not ZIP4⁻ cells, formed tumors/ascites in vivo. We conducted limiting dilution experiments and showed that 100–200 ZIP4⁺ cells from both PE04 and PEA2 cells formed larger tumors than those from 100–200 ALDH⁺ cells in mice. Mechanistically, we found that ZIP4 was an upstream regulator of another CSC-marker, NOTCH3, in HGSOC cells. NOTCH3 was functionally involved in spheroid formation in vitro and tumorigenesis in vivo in HGSOC. Genetic compensation studies showed that NOTCH3, but not NOTCH1, was a critical downstream mediator of ZIP4. Furthermore, NOTCH3, but not NOTCH1, physically bound to ZIP4. Collectively, our data suggest that ZIP4 is a novel CSC marker and the new ZIP4-NOTCH3 axis represents important therapeutic targets in HGSOC. Full article

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15 pages, 7856 KiB

Open AccessArticle

by Haoyu Ren, Jiang Zhu, Haochen Yu, Alexandr V. Bazhin, Christoph Benedikt Westphalen, Bernhard W. Renz, Sven N. Jacob, Christopher Lampert, Jens Werner, Martin K. Angele and Florian Bösch

Cancers 2020, 12(12), 3685; https://doi.org/10.3390/cancers12123685 - 08 Dec 2020

Cited by 26 | Viewed by 3568

Abstract

Increasing evidence indicates that angiogenesis is crucial in the development and progression of gastric cancer (GC). This study aimed to develop a prognostic relevant angiogenesis-related gene (ARG) signature and a nomogram. The expression profile of the 36 ARGs and clinical information of 372 [...] Read more.

Increasing evidence indicates that angiogenesis is crucial in the development and progression of gastric cancer (GC). This study aimed to develop a prognostic relevant angiogenesis-related gene (ARG) signature and a nomogram. The expression profile of the 36 ARGs and clinical information of 372 GC patients were extracted from The Cancer Genome Atlas (TCGA). Consensus clustering was applied to divide patients into clusters 1 and 2. Least absolute shrinkage and selection operator (LASSO) Cox regression analyses were used to identify the survival related ARGs and establish prognostic gene signatures, respectively. The Asian Cancer Research Group (ACRG) (n = 300) was used for external validation. Risk score of ARG signatures was calculated, and a prognostic nomogram was developed. Gene set enrichment analysis of the ARG model risk score was performed. Cluster 2 patients had more advanced clinical stage and shorter survival rates. ARG signatures carried prognostic relevance in both cohorts. Moreover, ARG-risk score was proved as an independent prognostic factor. The predictive value of the nomogram incorporating the risk score and clinicopathological features was superior to tumor, lymph node, metastasis (TNM) staging. The high-risk score group was associated with several cancer and metastasis-related pathways. The present study suggests that ARG-based nomogram could serve as effective prognostic biomarkers and allow a more precise risk stratification. Full article

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20 pages, 1237 KiB

Open AccessReview

Integrating Circulating Biomarkers in the Immune Checkpoint Inhibitor Treatment in Lung Cancer

by Boris Duchemann, Jordi Remon, Marie Naigeon, Laura Mezquita, Roberto Ferrara, Lydie Cassard, Jean Mehdi Jouniaux, Lisa Boselli, Jonathan Grivel, Edouard Auclin, Aude Desnoyer, Benjamin Besse and Nathalie Chaput

Cancers 2020, 12(12), 3625; https://doi.org/10.3390/cancers12123625 - 03 Dec 2020

Cited by 26 | Viewed by 3350

Abstract

Immune checkpoint inhibitors are now a cornerstone of treatment for non-small cell lung cancer (NSCLC). Tissue-based assays, such as Programmed cell death protein 1 (PD-L1) expression or mismatch repair deficiency/microsatellite instability (MMRD/MSI) status, are approved as treatment drivers in various settings, and represent [...] Read more.

Immune checkpoint inhibitors are now a cornerstone of treatment for non-small cell lung cancer (NSCLC). Tissue-based assays, such as Programmed cell death protein 1 (PD-L1) expression or mismatch repair deficiency/microsatellite instability (MMRD/MSI) status, are approved as treatment drivers in various settings, and represent the main field of research in biomarkers for immunotherapy. Nonetheless, responses have been observed in patients with negative PD-L1 or low tumor mutational burden. Some aspects of biomarker use remain poorly understood and sub-optimal, in particular tumoral heterogeneity, time-evolving sampling, and the ability to detect patients who are unlikely to respond. Moreover, tumor biopsies offer little insight into the host’s immune status. Circulating biomarkers offer an alternative non-invasive solution to address these pitfalls. Here, we summarize current knowledge on circulating biomarkers while using liquid biopsies in patients with lung cancer who receive treatment with immune checkpoint inhibitors, in terms of their potential as being predictive of outcome as well as their role in monitoring ongoing treatment. We address host biomarkers, notably circulating immune cells and soluble systemic immune and inflammatory markers, and also review tumor markers, including blood-based tumor mutational burden, circulating tumor cells, and circulating tumor DNA. Technical requirements are discussed along with the current limitations that are associated with these promising biomarkers. Full article

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16 pages, 7608 KiB

Open AccessArticle

A Novel Pipeline for Drug Repurposing for Bladder Cancer Based on Patients’ Omics Signatures

by Marika Mokou, Vasiliki Lygirou, Ioanna Angelioudaki, Nikolaos Paschalidis, Rafael Stroggilos, Maria Frantzi, Agnieszka Latosinska, Aristotelis Bamias, Michèle J. Hoffmann, Harald Mischak and Antonia Vlahou

Cancers 2020, 12(12), 3519; https://doi.org/10.3390/cancers12123519 - 26 Nov 2020

Cited by 14 | Viewed by 2973

Abstract

Multi-omics signatures of patients with bladder cancer (BC) can guide the identification of known de-risked therapeutic compounds through drug repurposing, an approach not extensively explored yet. In this study, we target drug repurposing in the context of BC, driven by tissue omics signatures. [...] Read more.

Multi-omics signatures of patients with bladder cancer (BC) can guide the identification of known de-risked therapeutic compounds through drug repurposing, an approach not extensively explored yet. In this study, we target drug repurposing in the context of BC, driven by tissue omics signatures. To identify compounds that can reverse aggressive high-risk Non-Muscle Invasive BC (NMIBC) to less aggressive low-risk molecular subtypes, the next generation Connectivity Map (CMap) was employed using as input previously published proteomics and transcriptomics respective signatures. Among the identified compounds, the ATP-competitive inhibitor of mTOR, WYE-354, showed a consistently very high score for reversing the aggressive BC molecular signatures. WYE-354 impact was assessed in a panel of eight multi-origin BC cell lines and included impaired colony growth and proliferation rate without any impact on apoptosis. Overall, with this study we introduce a promising pipeline for the repurposing of drugs for BC treatment, based on patients’ omics signatures. Full article

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16 pages, 3327 KiB

Open AccessArticle

In Silico and In Vitro Analysis of lncRNA XIST Reveals a Panel of Possible Lung Cancer Regulators and a Five-Gene Diagnostic Signature

by Periklis Katopodis, Qiduo Dong, Heerni Halai, Cristian I. Fratila, Andreas Polychronis, Vladimir Anikin, Cristina Sisu and Emmanouil Karteris

Cancers 2020, 12(12), 3499; https://doi.org/10.3390/cancers12123499 - 24 Nov 2020

Cited by 9 | Viewed by 4350

Abstract

Long non-coding RNAs (lncRNAs) perform a wide functional repertoire of roles in cell biology, ranging from RNA editing to gene regulation, as well as tumour genesis and tumour progression. The lncRNA X-inactive specific transcript (XIST) is involved in the aetiopathogenesis of non-small cell [...] Read more.

Long non-coding RNAs (lncRNAs) perform a wide functional repertoire of roles in cell biology, ranging from RNA editing to gene regulation, as well as tumour genesis and tumour progression. The lncRNA X-inactive specific transcript (XIST) is involved in the aetiopathogenesis of non-small cell lung cancer (NSCLC). However, its role at the molecular level is not fully elucidated. The expression of XIST and co-regulated genes TSIX, hnRNPu, Bcl-2, and BRCA1 analyses in lung cancer (LC) and controls were performed in silico. Differentially expressed genes (DEGs) were determined using RNA-seq in H1975 and A549 NSCLC cell lines following siRNA for XIST. XIST exhibited sexual dimorphism, being up-regulated in females compared to males in both control and LC patient cohorts. RNA-seq revealed 944 and 751 DEGs for A549 and H1975 cell lines, respectively. These DEGs are involved in signal transduction, cell communication, energy pathways, and nucleic acid metabolism. XIST expression associated with TSIX, hnRNPu, Bcl-2, and BRCA1 provided a strong collective feature to discriminate between controls and LC, implying a diagnostic potential. There is a much more complex role for XIST in lung cancer. Further studies should concentrate on sex-specific changes and investigate the signalling pathways of the DEGs following silencing of this lncRNA. Full article

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19 pages, 13794 KiB

Open AccessArticle

Modulation of de Novo Lipogenesis Improves Response to Enzalutamide Treatment in Prostate Cancer

by Mohamed Amine Lounis, Benjamin Péant, Kim Leclerc-Desaulniers, Dwaipayan Ganguli, Caroline Daneault, Matthieu Ruiz, Amina Zoubeidi, Anne-Marie Mes-Masson and Fred Saad

Cancers 2020, 12(11), 3339; https://doi.org/10.3390/cancers12113339 - 11 Nov 2020

Cited by 15 | Viewed by 3023

Abstract

De novo lipogenesis (DNL) is now considered as a hallmark of cancer. The overexpression of key enzymes of DNL is characteristic of both primary and advanced disease and may play an important role in resistance to therapies. Here, we showed that DNL is [...] Read more.

De novo lipogenesis (DNL) is now considered as a hallmark of cancer. The overexpression of key enzymes of DNL is characteristic of both primary and advanced disease and may play an important role in resistance to therapies. Here, we showed that DNL is highly enhanced in castrate resistant prostate cancer (CRPC) cells compared to hormone sensitive and enzalutamide resistant cells. This observation suggests that this pathway plays an important role in the initiation of aggressive prostate cancer and in the development of enzalutamide resistance. Importantly, here we show that both prostate cancer cells sensitive and resistant to enzalutamide are dependent on DNL to proliferate. We next combined enzalutamide with an inhibitor of Stearoyl CoA Desaturase 1 (SCD1), an important enzyme in DNL, and observed significantly reduced tumor growth caused by the important change in tumoral lipid desaturation. Our findings suggest that the equilibrium between monounsaturated fatty acids and saturated fatty acids is essential in the establishment of the more aggressive prostate cancer phenotype and that the combination therapy induces a disruption of this equilibrium leading to an important decrease of cell proliferation. These findings provide new insights into the role of DNL in the progression of prostate cancer cells. The study also provides the rationale for the use of an inhibitor of SCD1 in combination with enzalutamide to improve response, delay enzalutamide resistance and improve disease free progression. Full article

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13 pages, 4848 KiB

Open AccessArticle

PUMA and NOXA Expression in Tumor-Associated Benign Prostatic Epithelial Cells Are Predictive of Prostate Cancer Biochemical Recurrence

by Sylvie Clairefond, Benjamin Péant, Véronique Ouellet, Véronique Barrès, Zhe Tian, Dominique Trudel, Pierre I. Karakiewicz, Anne-Marie Mes-Masson and Fred Saad

Cancers 2020, 12(11), 3187; https://doi.org/10.3390/cancers12113187 - 29 Oct 2020

Cited by 4 | Viewed by 2565

Abstract

Background: Given that treatment decisions in prostate cancer (PC) are often based on risk, there remains a need to find clinically relevant prognostic biomarkers to stratify PC patients. We evaluated PUMA and NOXA expression in benign and tumor regions of the prostate using [...] Read more.

Background: Given that treatment decisions in prostate cancer (PC) are often based on risk, there remains a need to find clinically relevant prognostic biomarkers to stratify PC patients. We evaluated PUMA and NOXA expression in benign and tumor regions of the prostate using immunofluorescence techniques and determined their prognostic significance in PC. Methods: PUMA and NOXA expression levels were quantified on six tissue microarrays (TMAs) generated from radical prostatectomy samples (n = 285). TMAs were constructed using two cores of benign tissue and two cores of tumor tissue from each patient. Association between biomarker expression and biochemical recurrence (BCR) at 3 years was established using log-rank (LR) and multivariate Cox regression analyses. Results: Kaplan–Meier analysis showed a significant association between BCR and extreme levels (low or high) of PUMA expression in benign epithelial cells (LR = 8.831, p = 0.003). Further analysis revealed a significant association between high NOXA expression in benign epithelial cells and BCR (LR = 14.854, p < 0.001). The combination of extreme PUMA and high NOXA expression identified patients with the highest risk of BCR (LR = 16.778, p < 0.001) in Kaplan–Meier and in a multivariate Cox regression analyses (HR: 2.935 (1.645–5.236), p < 0.001). Conclusions: The combination of PUMA and NOXA protein expression in benign epithelial cells was predictive of recurrence following radical prostatectomy and was independent of PSA at diagnosis, Gleason score and pathologic stage. Full article

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21 pages, 2196 KiB

Open AccessArticle

Inflammatory Breast Cancer: Clinical Implications of Genomic Alterations and Mutational Profiling

by Flávia L. C. Faldoni, Rolando A. R. Villacis, Luisa M. Canto, Carlos E. Fonseca-Alves, Sarah S. Cury, Simon J. Larsen, Mads M. Aagaard, Cristiano P. Souza, Cristovam Scapulatempo-Neto, Cynthia A. B. T. Osório, Jan Baumbach, Fabio A. Marchi and Silvia R. Rogatto

Cancers 2020, 12(10), 2816; https://doi.org/10.3390/cancers12102816 - 30 Sep 2020

Cited by 12 | Viewed by 3029

Abstract

Inflammatory breast cancer (IBC) is a rare and aggressive type of breast cancer whose molecular basis is poorly understood. We performed a comprehensive molecular analysis of 24 IBC biopsies naïve of treatment, using a high-resolution microarray platform and targeted next-generation sequencing (105 cancer-related [...] Read more.

Inflammatory breast cancer (IBC) is a rare and aggressive type of breast cancer whose molecular basis is poorly understood. We performed a comprehensive molecular analysis of 24 IBC biopsies naïve of treatment, using a high-resolution microarray platform and targeted next-generation sequencing (105 cancer-related genes). The genes more frequently affected by gains were MYC (75%) and MDM4 (71%), while frequent losses encompassed TP53 (71%) and RB1 (58%). Increased MYC and MDM4 protein expression levels were detected in 18 cases. These genes have been related to IBC aggressiveness, and MDM4 is a potential therapeutic target in IBC. Functional enrichment analysis revealed genes associated with inflammatory regulation and immune response. High homologous recombination (HR) deficiency scores were detected in triple-negative and metastatic IBC cases. A high telomeric allelic imbalance score was found in patients having worse overall survival (OS). The mutational profiling was compared with non-IBC (TCGA, n = 250) and IBC (n = 118) from four datasets, validating our findings. Higher frequency of TP53 and BRCA2 variants were detected compared to non-IBC, while PIKC3A showed similar frequency. Variants in mismatch repair and HR genes were associated with worse OS. Our study provided a framework for improved diagnosis and therapeutic alternatives for this aggressive tumor type. Full article

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14 pages, 1455 KiB

Open AccessArticle

ITPKC as a Prognostic and Predictive Biomarker of Neoadjuvant Chemotherapy for Triple Negative Breast Cancer

by Masanori Oshi, Stephanie Newman, Vijayashree Murthy, Yoshihisa Tokumaru, Li Yan, Ryusei Matsuyama, Itaru Endo and Kazuaki Takabe

Cancers 2020, 12(10), 2758; https://doi.org/10.3390/cancers12102758 - 25 Sep 2020

Cited by 32 | Viewed by 3609

Abstract

Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with higher mortality than the others. Pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) is considered as a surrogate to predict survival. Inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) is [...] Read more.

Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with higher mortality than the others. Pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) is considered as a surrogate to predict survival. Inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) is a negative regulator of T cell activation, and reduction in ITPKC function is known to promote Kawasaki disease. Given the role of tumor infiltrating lymphocytes in NAC and since TNBC has the most abundant immune cell infiltration in breast cancer, we hypothesized that the ITPKC expression level is associated with NAC response and prognosis in TNBC. The ITPKC gene was expressed in the mammary gland, but its expression was highest in breast cancer cells among other stromal cells in a bulk tumor. ITPKC expression was highest in TNBC, associated with its survival, and was its independent prognostic factor. Although high ITPKC was not associated with immune function nor with any immune cell fraction, low ITPKC significantly enriched cell proliferation-related gene sets in TNBC. TNBC with low ITPKC achieved a significantly higher pCR rate after NAC. To the best of our knowledge, this is the first report to demonstrate that ITPKC gene expression may be useful as a prognostic and predictive biomarker in TNBC. Full article

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27 pages, 2354 KiB

Open AccessReview

Role of Anillin in Tumour: From a Prognostic Biomarker to a Novel Target

by Nguyen Minh Tuan and Chang Hoon Lee

Cancers 2020, 12(6), 1600; https://doi.org/10.3390/cancers12061600 - 17 Jun 2020

Cited by 27 | Viewed by 4791

Abstract

Anillin (ANLN), an actin-binding protein, reportedly plays a vital role in cell proliferation and migration, particularly in cytokinesis. Although there have been findings pointing to a contribution of ANLN to the development of cancer, the association of ANLN to cancer remains not fully [...] Read more.

Anillin (ANLN), an actin-binding protein, reportedly plays a vital role in cell proliferation and migration, particularly in cytokinesis. Although there have been findings pointing to a contribution of ANLN to the development of cancer, the association of ANLN to cancer remains not fully understood. Here, we gather evidence to determine the applicability of ANLN as a prognostic tool for some types of cancer, and the impact that ANLN has on the hallmarks of cancer. We searched academic repositories including PubMed and Google Scholar to find and review studies related to cancer and ANLN. The conclusion is that ANLN could be a potent target for cancer treatment, but the roles ANLN, other than in cytokinesis and its influence on tumour microenvironment remodeling in cancer development, must be further elucidated, and specific ANLN inhibitors should be found. Full article

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20 pages, 4638 KiB

Open AccessEditor’s ChoiceArticle

A Novel 4-gene Score to Predict Survival, Distant Metastasis and Response to Neoadjuvant Therapy in Breast Cancer

by Masanori Oshi, Eriko Katsuta, Li Yan, John M.L. Ebos, Omar M. Rashid, Ryusei Matsuyama, Itaru Endo and Kazuaki Takabe

Cancers 2020, 12(5), 1148; https://doi.org/10.3390/cancers12051148 - 02 May 2020

Cited by 46 | Viewed by 5327

Abstract

We generated a 4-gene score with genes upregulated in LM2-4, a metastatic variant of MDA-MB-231 (DOK 4, HCCS, PGF, and SHCBP1) that was strongly associated with disease-free survival (DFS) in TCGA cohort (hazard ratio [HR]>1.2, p < 0.02). The 4-gene score correlated with [...] Read more.

We generated a 4-gene score with genes upregulated in LM2-4, a metastatic variant of MDA-MB-231 (DOK 4, HCCS, PGF, and SHCBP1) that was strongly associated with disease-free survival (DFS) in TCGA cohort (hazard ratio [HR]>1.2, p < 0.02). The 4-gene score correlated with overall survival of TCGA (HR = 1.44, p < 0.001), which was validated with DFS and disease-specific survival of METABRIC cohort. The 4-gene score was able to predict worse survival or clinically aggressive tumors, such as high Nottingham pathological grade and advanced cancer staging. High score was associated with worse survival in the hormonal receptor (HR)-positive/Her2-negative subtype. High score enriched cell proliferation-related gene sets in GSEA. The score was high in primary tumors that originated, in and metastasized to, brain and lung, and it predicted worse progression-free survival for metastatic tumors. Good tumor response to neoadjuvant chemotherapy or hormonal therapy was accompanied by score reduction. High scores were also predictive of response to neoadjuvant chemotherapy for HR-positive/Her2-negative subtype. High score tumors had increased expression of T cell exhaustion marker genes, suggesting that the score may also be a biomarker for immunotherapy response. Our novel 4-gene score with both prognostic and predictive values may, therefore, be clinically useful particularly in HR-positive breast cancer. Full article

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12 pages, 2709 KiB

Open AccessArticle

An Explorative Analysis of ABCG2/TOP-1 mRNA Expression as a Biomarker Test for FOLFIRI Treatment in Stage III Colon Cancer Patients: Results from Retrospective Analyses of the PETACC-3 Trial

by Jan Stenvang, Eva Budinská, Eric van Cutsem, Fred Bosman, Vlad Popovici and Nils Brünner

Cancers 2020, 12(4), 977; https://doi.org/10.3390/cancers12040977 - 15 Apr 2020

Cited by 5 | Viewed by 2913

Abstract

Biomarker-guided treatment for patients with colon cancer is needed. We tested ABCG2 and topoisomerase 1 (TOP1) mRNA expression as predictive biomarkers for irinotecan benefit in the PETACC-3 patient cohort. The present study included 580 patients with mRNA expression data from Stage III colon [...] Read more.

Biomarker-guided treatment for patients with colon cancer is needed. We tested ABCG2 and topoisomerase 1 (TOP1) mRNA expression as predictive biomarkers for irinotecan benefit in the PETACC-3 patient cohort. The present study included 580 patients with mRNA expression data from Stage III colon cancer samples from the PETACC-3 study, which randomized the patients to Fluorouracil/leucovorin (5FUL) +/− irinotecan. The primary end-points were recurrence free survival (RFS) and overall survival (OS). Patients were divided into one group with high ABCG2 expression (above median) and low TOP-1 expression (below 75 percentile) (“resistant”) (n = 216) and another group including all other combinations of these two genes (“sensitive”) (n = 364). The rationale for the cut-offs were based on the distribution of expression levels in the PETACC-3 Stage II set of patients, where ABCG2 was unimodal and TOP1 was bimodal with a high expression level mode in the top quarter of the patients. Cox proportional hazards regression was used to estimate the hazard ratios and the association between variables and end-points and log-rank tests to assess the statistical significance of differences in survival between groups. Kaplan-Meier estimates of the survival functions were used for visualization and estimation of survival rates at specific time points. Significant differences were found for both RFS (Hazard ratio (HR): 0.63 (0.44–0.92); p = 0.016) and OS (HR: 0.60 (0.39–0.93); p = 0.02) between the two biomarker groups when the patients received FOLFIRI (5FUL+irinotecan). Considering only the Microsatellite Stable (MSS) and Microsatellite Instability-Low (MSI-L) patients (n = 470), the differences were even more pronounced. In contrast, no significant differences were observed between the groups when patients received 5FUL alone. This study shows that the combination of ABCG2 and TOP1 gene expression significantly divided the Stage III colon cancer patients into two groups regarding benefit from adjuvant treatment with FOLFIRI but not 5FUL. Full article

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