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11 pages, 4103 KiB

Open AccessArticle

Imaging of Indocyanine Green-Human Serum Albumin (ICG-HSA) Complex in Secreted Protein Acidic and Rich in Cysteine (SPARC)-Expressing Glioblastoma

by Hye Jung Jang, Myung Geun Song, Cho Rong Park, Hyewon Youn, Yun-Sang Lee, Gi Jeong Cheon and Keon Wook Kang

Int. J. Mol. Sci. 2023, 24(1), 850; https://doi.org/10.3390/ijms24010850 - 03 Jan 2023

Cited by 5 | Viewed by 2047

Abstract

Glioblastoma is the most common and fatal primary glioma and has a severe prognosis. It is a challenge for neurosurgeons to remove brain tumor tissues completely by resection. Meanwhile, fluorescence-guided surgery (FGS) is a technique used in glioma surgery to enhance the visualization [...] Read more.

Glioblastoma is the most common and fatal primary glioma and has a severe prognosis. It is a challenge for neurosurgeons to remove brain tumor tissues completely by resection. Meanwhile, fluorescence-guided surgery (FGS) is a technique used in glioma surgery to enhance the visualization of tumor edges to clarify the extent of tumor resection. Indocyanine green (ICG) is the only FDA-approved NIR fluorescent agent. It non-covalently binds to human serum albumin (HSA). Secreted protein acidic and rich in cysteine (SPARC) is an extracellular glycoprotein expressed in gliomas and binds to albumin, suggesting that it plays an important role in tumor uptake of the ICG-HSA complex. Here we demonstrate the binding properties of HSA or SPARC to ICG using surface plasmon resonance and saturation binding assay. According to in vitro and in vivo studies, the results showed that the uptake of ICG-HSA complex was higher in SPARC-expressing glioblastoma cell line and tumor region compared with the uptake of free ICG. Here, we visualized the SPARC-dependent uptake of ICG and ICG-HSA complex in U87MG. Our results demonstrated that the ICG-HSA complex is likely to be used as an efficient imaging agent targeting SPARC-expressing tumors, especially glioblastoma. Full article

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

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10 pages, 3254 KiB

Open AccessArticle

Evaluation of Alternative Risk Stratification Systems in a Large Series of Solitary Fibrous Tumors with Molecular Findings and Ki-67 Index Data: Do They Improve Risk Assessment?

by Isidro Machado, Álvaro Blázquez Bujeda, Francisco Giner, María Gema Nieto Morales, Julia Cruz, Javier Lavernia, Samuel Navarro, Antonio Ferrandez, Amparo Ruiz-Sauri and Antonio Llombart-Bosch

Int. J. Mol. Sci. 2023, 24(1), 439; https://doi.org/10.3390/ijms24010439 - 27 Dec 2022

Cited by 2 | Viewed by 1397

Abstract

The clinical evolution of solitary fibrous tumors (SFTs) is often uncertain and several risk stratification systems (RSS) have been proposed. The Demicco et al. RSS is the most frequently implemented. In this study we aim to validate two alternative RSS (Sugita et al. [...] Read more.

The clinical evolution of solitary fibrous tumors (SFTs) is often uncertain and several risk stratification systems (RSS) have been proposed. The Demicco et al. RSS is the most frequently implemented. In this study we aim to validate two alternative RSS (Sugita et al. and G-Score) using results for the Demicco RSS from a previous study of 97 SFTs. In addition, we aim to determine whether reclassified cases had any distinctive molecular features. As the Sugita et al. system substitutes mitotic count with Ki-67 index we also investigated whether Ki-67 results for tissue microarrays are comparable to those obtained using whole tissue sections. In the present study we detected that many cases classified by Demicco RSS as low-risk were reclassified as intermediate risk using the new system (G-score RSS). Kaplan-Meier survival plots for G-Score RSS showed that the low-risk and intermediate-risk SFTs had a similar evolution that contrasted with the more aggressive high-risk group. Moreover, the similar evolution in both low and intermediate-risk groups occurred despite the G-score system being stricter in classifying low-risk tumors. We observed that Sugita RSS does not provide any better risk stratification in comparison with the Demicco RSS, and testing both RSS in our series produced similar Kaplan-Meier survival data. We found some discordant results when comparing whole sections and the corresponding tissue microarrays samples, finding the hotspot areas easier to locate in whole sections. Forty-one SFTs with initial low-risk assigned by the Demicco RSS were reclassified as intermediate-risk by G-score finding both TP53 and HTER mutations in four cases, only HTER mutation in 11 cases, and only TP53 mutation in 2 cases. All six cases of SFT classified as high-risk by both the Demicco and G-score RSS suffered recurrence/metastasis, and half showed both TP53 and HTER mutations. Five SFTs were categorized as low-risk by both Demicco and G-score, of which 4 cases revealed HTER mutation. Regarding the outcome of these 5 patients, two were lost to follow-up, and one of the remaining three patients suffered recurrence. We believe that although the presence of both TP53 and HTER mutations may confer or be related to poor evolution, the isolated presence of HTER mutation alone would not necessarily be related to poor outcome. The G-score RSS more accurately identified low-risk patients than the other two risk models evaluated in the present series. Late recurrence/metastasis may occasionally be observed even in low-risk SFTs categorized by stricter classification systems such as the G-score RSS. These findings support the possibility that additional, as yet unknown factors may influence the clinical evolution of SFTs. In conclusion, given the possibility of late recurrence, long-term follow-up is recommended for all SFT patients, even in cases classified as low risk by the stricter G-score system. An integration of clinical, radiological, pathological, and molecular findings may improve SFT risk stratification and better predict patient outcome. Full article

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

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26 pages, 3220 KiB

Open AccessArticle

Systems Drug Design for Muscle Invasive Bladder Cancer and Advanced Bladder Cancer by Genome-Wide Microarray Data and Deep Learning Method with Drug Design Specifications

by Po-Wei Su and Bor-Sen Chen

Int. J. Mol. Sci. 2022, 23(22), 13869; https://doi.org/10.3390/ijms232213869 - 10 Nov 2022

Cited by 4 | Viewed by 1492

Abstract

Bladder cancer is the 10th most common cancer worldwide. Due to the lack of understanding of the oncogenic mechanisms between muscle-invasive bladder cancer (MIBC) and advanced bladder cancer (ABC) and the limitations of current treatments, novel therapeutic approaches are urgently needed. In this [...] Read more.

Bladder cancer is the 10th most common cancer worldwide. Due to the lack of understanding of the oncogenic mechanisms between muscle-invasive bladder cancer (MIBC) and advanced bladder cancer (ABC) and the limitations of current treatments, novel therapeutic approaches are urgently needed. In this study, we utilized the systems biology method via genome-wide microarray data to explore the oncogenic mechanisms of MIBC and ABC to identify their respective drug targets for systems drug discovery. First, we constructed the candidate genome-wide genetic and epigenetic networks (GWGEN) through big data mining. Second, we applied the system identification and system order detection method to delete false positives in candidate GWGENs to obtain the real GWGENs of MIBC and ABC from their genome-wide microarray data. Third, we extracted the core GWGENs from the real GWGENs by selecting the significant proteins, genes and epigenetics via the principal network projection (PNP) method. Finally, we obtained the core signaling pathways from the corresponding core GWGEN through the annotations of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway to investigate the carcinogenic mechanisms of MIBC and ABC. Based on the carcinogenic mechanisms, we selected the significant drug targets NFKB1, LEF1 and MYC for MIBC, and LEF1, MYC, NOTCH1 and FOXO1 for ABC. To design molecular drug combinations for MIBC and ABC, we employed a deep neural network (DNN)-based drug-target interaction (DTI) model with drug specifications. The DNN-based DTI model was trained by drug-target interaction databases to predict the candidate drugs for MIBC and ABC, respectively. Subsequently, the drug design specifications based on regulation ability, sensitivity and toxicity were employed as filter criteria for screening the potential drug combinations of Embelin and Obatoclax for MIBC, and Obatoclax, Entinostat and Imiquimod for ABC from their candidate drugs. In conclusion, we not only investigated the oncogenic mechanisms of MIBC and ABC, but also provided promising therapeutic options for MIBC and ABC, respectively. Full article

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

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16 pages, 3237 KiB

Open AccessArticle

Anti-PTK7 Monoclonal Antibodies Exhibit Anti-Tumor Activity at the Cellular Level and in Mouse Xenograft Models of Esophageal Squamous Cell Carcinoma

by Jae Hoon Kim, Won-Sik Shin, Se-Ra Lee, Sanggil Kim, So-Young Choi and Seung-Taek Lee

Int. J. Mol. Sci. 2022, 23(20), 12195; https://doi.org/10.3390/ijms232012195 - 13 Oct 2022

Cited by 4 | Viewed by 1713

Abstract

PTK7 is a catalytically defective receptor protein tyrosine kinase upregulated in various cancers, including esophageal squamous cell carcinoma (ESCC). In previous studies, we observed a positive correlation between PTK7 expression levels and tumorigenicity in various ESCC cell lines and xenograft mice with ESCC [...] Read more.

PTK7 is a catalytically defective receptor protein tyrosine kinase upregulated in various cancers, including esophageal squamous cell carcinoma (ESCC). In previous studies, we observed a positive correlation between PTK7 expression levels and tumorigenicity in various ESCC cell lines and xenograft mice with ESCC KYSE-30 cells. In this study, we analyzed the effects of anti-PTK7 monoclonal antibodies (mAbs) on the tumorigenic activity in KYSE-30 cells and in mouse xenograft models. PTK7 mAb-32 and mAb-43 bind with a high affinity to the extracellular domain of PTK7. PTK7 mAbs significantly reduced three-dimensional cell proliferation, adhesion, wound healing, and migration. PTK7 mAbs also reduce chemotactic invasiveness by decreasing MMP-9 secretion. PTK7 mAbs decreased actin cytoskeleton levels in the cortical region of KYSE-30 cells. PTK7 mAbs reduced the phosphorylation of ERK, SRC, and FAK. In a mouse xenograft model of ESCC using KYSE-30 cells, PTK7 mAbs reduced tumor growth in terms of volume, weight, and the number of Ki-67-positive cells. These results demonstrated that PTK7 mAbs can inhibit the tumorigenicity of ESCC at the cellular level and in vivo by blocking the function of PTK7. Considering the anticancer activities of PTK7 mAbs, we propose that PTK7 mAbs can be used in an effective treatment strategy for PTK7-positive malignancies, such as ESCC. Full article

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

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15 pages, 3242 KiB

Open AccessArticle

Unraveling the Role of Histone Variant CENP-A and Chaperone HJURP Expression in Thymic Epithelial Neoplasms

by Georgia Levidou, Konstantinos Palamaris, Alexandros G. Sykaras, Georgios Andreadakis, Christos Masaoutis, Irene Theochari, Penelope Korkolopoulou, Dimitra Rontogianni and Stamatios Theocharis

Int. J. Mol. Sci. 2022, 23(15), 8339; https://doi.org/10.3390/ijms23158339 - 28 Jul 2022

Cited by 3 | Viewed by 1627

Abstract

Background: Recent advances demonstrate the role of chromatin regulators, including histone variants and histone chaperones, in cancer initiation and progression. Methods: Histone H3K4me3, histone variant centromere protein (CENP-A) and histone chaperones Holliday junction recognition protein (HJURP) as well as DAXX expression were examined [...] Read more.

Background: Recent advances demonstrate the role of chromatin regulators, including histone variants and histone chaperones, in cancer initiation and progression. Methods: Histone H3K4me3, histone variant centromere protein (CENP-A) and histone chaperones Holliday junction recognition protein (HJURP) as well as DAXX expression were examined immunohistochemically in 95 thymic epithelial tumor (TET) specimens. Our results were compared with the expression profile of DAXX, HJURP and CENP-A in gene expression profiling interactive analysis (GEPIA2). Results: The lymphocyte-poor B3- and C-type TETs were more frequently DAXX negative (p = 0.043). B3 and C-Type TETs showed higher cytoplasmic and nuclear CENP-A (p = 0.007 and p = 0.002) and higher cytoplasmic HJURP H-score (p < 0.001). Higher nuclear CENP-A and cytoplasmic HJURP expression was associated with advanced Masaoka–Koga stage (p = 0.048 and p < 0.001). A positive correlation between HJURP and CENP-A was also observed. The presence of cytoplasmic CENP-A expression was correlated with a favorable overall survival (p = 0.03). CENP-A overexpression in survival analysis of TCGA TETs showed similar results. H3K4me3 expression was not associated with any clinicopathological parameters. Conclusions: Our results suggest a significant interaction between CENP-A and HJURP in TETs. Moreover, we confirmed the presence of a cytoplasmic CENP-A immunolocalization, suggesting also a possible favorable prognostic value of this specific immunostaining pattern. Full article

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

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15 pages, 3070 KiB

Open AccessArticle

Expression of Irisin/FNDC5 in Breast Cancer

by Kamil Cebulski, Katarzyna Nowińska, Karolina Jablońska, Hanna Romanowicz, Beata Smolarz, Piotr Dzięgiel and Marzenna Podhorska-Okołów

Int. J. Mol. Sci. 2022, 23(7), 3530; https://doi.org/10.3390/ijms23073530 - 24 Mar 2022

Cited by 9 | Viewed by 2415

Abstract

Irisin is a myokine formed from fibronectin type III domain-containing protein 5 (FNDC5), which can be found in various cancer tissues. FNDC5 and irisin levels have been poorly studied in the tumor tissues of breast cancer (BC). The aim of this study was [...] Read more.

Irisin is a myokine formed from fibronectin type III domain-containing protein 5 (FNDC5), which can be found in various cancer tissues. FNDC5 and irisin levels have been poorly studied in the tumor tissues of breast cancer (BC). The aim of this study was to determine the levels of irisin expression in BC tissues and compare them to clinicopathological factors and Ki-67 and PGC-1α expression levels. Tissue microarrays (TMAs) with 541 BC tissues and 61 samples of non-malignant breast disease (NMBD; control) were used to perform immunohistochemical reactions. FNDC5 gene expression was measured in 40 BC tissue samples, 40 samples from the cancer margin, and 16 NMBD samples. RT-PCR was performed for the detection of FNDC5 gene expression. Higher irisin expression was found in BC patients compared to normal breast tissue. FNDC5/irisin expression was higher in patients without lymph node metastases. Longer overall survival was observed in patients with higher irisin expression levels. FNDC5/irisin expression was increased in BC tissues and its high level was a good prognostic factor for survival in BC patients. Full article

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

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19 pages, 4318 KiB

Open AccessArticle

PRP4 Induces Epithelial–Mesenchymal Transition and Drug Resistance in Colon Cancer Cells via Activation of p53

by Salman Ul Islam, Muhammad Bilal Ahmed, Jong-Kyung Sonn, Eun-Jung Jin and Young-Sup Lee

Int. J. Mol. Sci. 2022, 23(6), 3092; https://doi.org/10.3390/ijms23063092 - 13 Mar 2022

Cited by 9 | Viewed by 2964

Abstract

Pre-mRNA processing factor 4B (PRP4) promotes pre-mRNA splicing and signal transduction. Recent studies have shown that PRP4 modulates the assembly of actin cytoskeleton in cancer cells and induces epithelial–mesenchymal transition (EMT) and drug resistance. PRP4 displays kinase domain-like cyclin-dependent kinases and mitogen-activated protein [...] Read more.

Pre-mRNA processing factor 4B (PRP4) promotes pre-mRNA splicing and signal transduction. Recent studies have shown that PRP4 modulates the assembly of actin cytoskeleton in cancer cells and induces epithelial–mesenchymal transition (EMT) and drug resistance. PRP4 displays kinase domain-like cyclin-dependent kinases and mitogen-activated protein kinases, making it capable of phosphorylating p53 and other target proteins. In the current study, we report that PRP4 induces drug resistance and EMT via direct binding to the p53 protein, inducing its phosphorylation. Moreover, PRP4 overexpression activates the transcription of miR-210 in a hypoxia-inducible factor 1α (HIF-1α)-dependent manner, which activates p53. The involvement of miR-210 in the activation of p53 was confirmed by utilizing si-miR210. si-miR210 blocked the PRP4-activated cell survival pathways and reversed the PRP4-induced EMT phenotype. Moreover, we used deferoxamine as a hypoxia-mimetic agent, and si-HIF to silence HIF-1α. This procedure demonstrated that PRP4-induced EMT and drug resistance emerged in response to consecutive activation of HIF-1α, miR-210, and p53 by PRP4 overexpression. Collectively, our findings suggest that the PRP4 contributes to EMT and drug resistance induction via direct interactions with p53 and actions that promote upregulation of HIF-1α and miR-210. We conclude that PRP4 is an essential factor promoting cancer development and progression. Specific PRP4 inhibition could benefit patients with colon cancer. Full article

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

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17 pages, 5774 KiB

Open AccessArticle

The Mitochondrial PHB2/OMA1/DELE1 Pathway Cooperates with Endoplasmic Reticulum Stress to Facilitate the Response to Chemotherapeutics in Ovarian Cancer

by Meiyu Cheng, Huimei Yu, Qinghuan Kong, Bingrong Wang, Luyan Shen, Delu Dong and Liankun Sun

Int. J. Mol. Sci. 2022, 23(3), 1320; https://doi.org/10.3390/ijms23031320 - 25 Jan 2022

Cited by 11 | Viewed by 4115

Abstract

Interactions between the mitochondrial inner and outer membranes and between mitochondria and other organelles closely correlates with the sensitivity of ovarian cancer to cisplatin and other chemotherapeutic drugs. However, the underlying mechanism remains unclear. Recently, the mitochondrial protease OMA1, which regulates internal and [...] Read more.

Interactions between the mitochondrial inner and outer membranes and between mitochondria and other organelles closely correlates with the sensitivity of ovarian cancer to cisplatin and other chemotherapeutic drugs. However, the underlying mechanism remains unclear. Recently, the mitochondrial protease OMA1, which regulates internal and external signals in mitochondria by cleaving mitochondrial proteins, was shown to be related to tumor progression. Therefore, we evaluated the effect of OMA1 on the response to chemotherapeutics in ovarian cancer cells and the mouse subcutaneous tumor model. We found that OMA1 activation increased ovarian cancer sensitivity to cisplatin in vivo and in vitro. Mechanistically, in ovarian cancer, OMA1 cleaved optic atrophy 1 (OPA1), leading to mitochondrial inner membrane cristae remodeling. Simultaneously, OMA1 induced DELE1 cleavage and its cytoplasmic interaction with EIF2AK1. We also demonstrated that EIF2AK1 cooperated with the ER stress sensor EIF2AK3 to amplify the EIF2S1/ATF4 signal, resulting in the rupture of the mitochondrial outer membrane. Knockdown of OMA1 attenuated these activities and reversed apoptosis. Additionally, we found that OMA1 protease activity was regulated by the prohibitin 2 (PHB2)/stomatin-like protein 2 (STOML2) complex. Collectively, OMA1 coordinates the mitochondrial inner and outer membranes to induce ovarian cancer cell death. Thus, activating OMA1 may be a novel treatment strategy for ovarian cancer. Full article

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

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Review

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21 pages, 2157 KiB

Open AccessReview

Exploring the Multi-Faceted Role of Sirtuins in Glioblastoma Pathogenesis and Targeting Options

by Elena Kunadis and Christina Piperi

Int. J. Mol. Sci. 2022, 23(21), 12889; https://doi.org/10.3390/ijms232112889 - 25 Oct 2022

Cited by 7 | Viewed by 2075

Abstract

Recent advances in glioblastoma (GB) research have shed light on the molecular characteristics, the defected intracellular signaling pathways, and the genetic and epigenetic alterations involved in their pathogenesis. Despite constant efforts, GB remains an aggressive malignant tumor with limited therapeutic approaches, poor prognosis, [...] Read more.

Recent advances in glioblastoma (GB) research have shed light on the molecular characteristics, the defected intracellular signaling pathways, and the genetic and epigenetic alterations involved in their pathogenesis. Despite constant efforts, GB remains an aggressive malignant tumor with limited therapeutic approaches, poor prognosis, and a low survival rate. Emerging evidence points towards the crucial impact of epigenetic post-translational modifications in cancer development with emphasis on the regulatory role of histone deacetylation in several key cellular processes, including metabolic pathways, regulation of stress response, senescence, proliferation, DNA repair, and apoptosis. The silent information regulator proteins (Sirtuins) are deacetylases of histone and non-histone proteins that have been recently implicated in the initiation as well as in the progression of GB. Herein, we provide a critical overview of the emerging functional role and mechanism of action of the seven Sirtuins (SIRT1-7) in GB and discuss their potential targeting options in clinical practice. Full article

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

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18 pages, 19428 KiB

Open AccessReview

Mechanism and Function of Circular RNA in Regulating Solid Tumor Radiosensitivity

by Junchao Huang, Huihui Sun, Zike Chen, Yingjie Shao and Wendong Gu

Int. J. Mol. Sci. 2022, 23(18), 10444; https://doi.org/10.3390/ijms231810444 - 09 Sep 2022

Cited by 1 | Viewed by 1437

Abstract

Radiotherapy is an important tool in the treatment of malignant tumors, and exploring how to make radiotherapy more effective is a new way to break through the current bottleneck in the development of radiation oncology. Circular RNAs (circRNAs) are a special class of [...] Read more.

Radiotherapy is an important tool in the treatment of malignant tumors, and exploring how to make radiotherapy more effective is a new way to break through the current bottleneck in the development of radiation oncology. Circular RNAs (circRNAs) are a special class of endogenous non-coding RNAs. Numerous studies have shown that circRNAs have shown great potential in regulating the biological functions of tumors, including proliferation, migration, invasion, and treatment resistance, and that differences in their expression levels are closely related to the clinical prognosis of tumor patients. This review systematically compares the mechanisms of circRNAs in the process of tumor development and radiosensitivity and provides insight into the clinical translation of circRNAs in radiotherapy. Full article

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

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11 pages, 706 KiB

Open AccessReview

Unraveling the Immune Microenvironment of Thymic Epithelial Tumors: Implications for Autoimmunity and Treatment

by Christos Masaoutis, Kostas Palamaris, Stefania Kokkali, Georgia Levidou and Stamatios Theocharis

Int. J. Mol. Sci. 2022, 23(14), 7864; https://doi.org/10.3390/ijms23147864 - 16 Jul 2022

Cited by 9 | Viewed by 2248

Abstract

Thymic Epithelial Tumors (TETs) represent a rare tumor family, originating from the epithelial component of the thymus gland. Clinicopathologically, they are segregated into six major subtypes, associated with distinct histological features and clinical outcomes. Their emergence and evolution are accompanied by the generation [...] Read more.

Thymic Epithelial Tumors (TETs) represent a rare tumor family, originating from the epithelial component of the thymus gland. Clinicopathologically, they are segregated into six major subtypes, associated with distinct histological features and clinical outcomes. Their emergence and evolution are accompanied by the generation of a complex tumor microenvironment (TME), dominated by phenotypically and functionally divergent immune cellular subsets, in different maturation states and in analogies that vary significantly among different subtypes. These heterogenous leukocyte populations exert either immune-permissive and tumor-suppressive functions or vice versa, and the dynamic equilibrium established among them either dictates the tumor immune milieu towards an immune-tolerance state or enables the development of a productive spontaneous tumoricidal response. The immunologically “hot” microenvironment, defining a significant proportion of TETs, makes them a promising candidate for the implementation of immune checkpoint inhibitors (ICIs). A number of phase I and II clinical trials have already demonstrated significant, type-specific clinical efficacy of PD-L1 inhibitors, even though substantial limitations in their utilization derive from their immune-mediated adverse effects. Moreover, the completed clinical studies involved relatively restricted patient samples and an expansion in the enrolled cohorts is required, so that more trustworthy conclusions regarding the benefit from ICIs in TETs can be extracted. Full article

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

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18 pages, 2865 KiB

Open AccessReview

Clinical and Molecular Insights of Radiation-Induced Breast Sarcomas: Is There Hope on the Horizon for Effective Treatment of This Aggressive Disease?

by Stefania Kokkali, Jose Duran Moreno, Jerzy Klijanienko and Stamatios Theocharis

Int. J. Mol. Sci. 2022, 23(8), 4125; https://doi.org/10.3390/ijms23084125 - 08 Apr 2022

Cited by 7 | Viewed by 2385

Abstract

Radiation-induced breast sarcomas (RIBS) are rare entities representing <1% of all primary breast malignancies, limiting most reports to small retrospective case series. They constitute a heterogeneous group of neoplasms, with high-grade angiosarcoma being the most common subtype. Other sarcoma histotypes, such as undifferentiated [...] Read more.

Radiation-induced breast sarcomas (RIBS) are rare entities representing <1% of all primary breast malignancies, limiting most reports to small retrospective case series. They constitute a heterogeneous group of neoplasms, with high-grade angiosarcoma being the most common subtype. Other sarcoma histotypes, such as undifferentiated pleomorphic sarcoma and leiomyosarcoma, can also be identified. Radiation-induced breast angiosarcoma (RIBA) has an incidence of approximately 0.1% after breast-conserving therapy and arises mainly from the dermis of the irradiated breast. MYC gene amplification is highly indicative of secondary breast angiosarcomas. Their clinical presentation often mimics benign port-radiation lesions, leading to a delay in diagnosis and a lost window of opportunity for cure. Surgery with negative margins is the mainstay of treatment of localized RIBS. In the case of angiosarcoma, technical difficulties, including multifocality, infiltrative margins, and difficulty in assessing tumor margins, render surgical treatment quite challenging. A limited number of studies showed that adjuvant radiation therapy reduces local recurrences; therefore, it is proposed by many groups for large, high-grade tumors. Chemotherapy has been evaluated retrospectively in a small subset of patients, with some evidence supporting its use in angiosarcoma patients. Approximately half of patients with RIBA will show local recurrence. In the advanced setting, different therapeutic options are discussed in the review, including chemotherapy, antiangiogenic therapy, and immunotherapy, whereas the need for further research on molecular therapeutic targets is pointed out. Full article

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

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21 pages, 653 KiB

Open AccessReview

Thymic Epithelial Neoplasms: Focusing on the Epigenetic Alterations

by Iason Psilopatis, Alexandros Pergaris, Kleio Vrettou, Stamatios Theocharis and Constantinos Troungos

Int. J. Mol. Sci. 2022, 23(7), 4045; https://doi.org/10.3390/ijms23074045 - 06 Apr 2022

Cited by 10 | Viewed by 3058

Abstract

Thymic Epithelial Neoplasms (TENs) represent the most common tumors of the thymus gland. Epigenetic alterations are generally involved in initiation and progression of various cancer entities. However, little is known about the role of epigenetic modifications in TENs. In order to identify relevant [...] Read more.

Thymic Epithelial Neoplasms (TENs) represent the most common tumors of the thymus gland. Epigenetic alterations are generally involved in initiation and progression of various cancer entities. However, little is known about the role of epigenetic modifications in TENs. In order to identify relevant studies, a literature review was conducted using the MEDLINE and LIVIVO databases. The search terms thymoma, thymic carcinoma, thymic epithelial neoplasm, epigenetics, DNA methylation, HDAC and miRNA were employed and we were able to identify forty studies focused on TENs and published between 1997 and 2021. Aberrant epigenetic alterations seem to be involved in the tumorigenesis of thymomas and thymic carcinomas, with numerous studies reporting on non-coding RNA clusters and altered gene methylation as possible biomarkers in different types of TENs. Interestingly, Histone Deacetylase Inhibitors have shown potent antitumor effects in clinical trials, thus possibly representing effective epigenetic therapeutic agents in TENs. Additional studies in larger patient cohorts are, nevertheless, needed to verify the clinical utility and safety of novel epigenetic agents in the treatment of patients with TENs. Full article

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

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22 pages, 737 KiB

Open AccessReview

Tumor Microenvironment of Hepatocellular Carcinoma: Challenges and Opportunities for New Treatment Options

by Zuzanna Sas, Ewa Cendrowicz, Isabel Weinhäuser and Tomasz P. Rygiel

Int. J. Mol. Sci. 2022, 23(7), 3778; https://doi.org/10.3390/ijms23073778 - 29 Mar 2022

Cited by 48 | Viewed by 6039

Abstract

The prevalence of liver cancer is constantly rising, with increasing incidence and mortality in Europe and the USA in recent decades. Among the different subtypes of liver cancers, hepatocellular carcinoma (HCC) is the most commonly diagnosed liver cancer. Besides advances in diagnosis and [...] Read more.

The prevalence of liver cancer is constantly rising, with increasing incidence and mortality in Europe and the USA in recent decades. Among the different subtypes of liver cancers, hepatocellular carcinoma (HCC) is the most commonly diagnosed liver cancer. Besides advances in diagnosis and promising results of pre-clinical studies, HCC remains a highly lethal disease. In many cases, HCC is an effect of chronic liver inflammation, which leads to the formation of a complex tumor microenvironment (TME) composed of immune and stromal cells. The TME of HCC patients is a challenge for therapies, as it is involved in metastasis and the development of resistance. However, given that the TME is an intricate system of immune and stromal cells interacting with cancer cells, new immune-based therapies are being developed to target the TME of HCC. Therefore, understanding the complexity of the TME in HCC will provide new possibilities to design novel and more effective immunotherapeutics and combinatorial therapies to overcome resistance to treatment. In this review, we describe the role of inflammation during the development and progression of HCC by focusing on TME. We also describe the most recent therapeutic advances for HCC and possible combinatorial treatment options. Full article

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

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20 pages, 1045 KiB

Open AccessReview

Histone Deacetylase (HDAC) Inhibitors: A Promising Weapon to Tackle Therapy Resistance in Melanoma

by Kostas Palamaris, Myrto Moutafi, Hariklia Gakiopoulou and Stamatios Theocharis

Int. J. Mol. Sci. 2022, 23(7), 3660; https://doi.org/10.3390/ijms23073660 - 27 Mar 2022

Cited by 16 | Viewed by 5468

Abstract

Melanoma is an aggressive malignant tumor, arising more commonly on the skin, while it can also occur on mucosal surfaces and the uveal tract of the eye. In the context of the unresectable and metastatic cases that account for the vast majority of [...] Read more.

Melanoma is an aggressive malignant tumor, arising more commonly on the skin, while it can also occur on mucosal surfaces and the uveal tract of the eye. In the context of the unresectable and metastatic cases that account for the vast majority of melanoma-related deaths, the currently available therapeutic options are of limited value. The exponentially increasing knowledge in the field of molecular biology has identified epigenetic reprogramming and more specifically histone deacetylation (HDAC), as a crucial regulator of melanoma progression and as a key driver in the emergence of drug resistance. A variety of HDAC inhibitors (HDACi) have been developed and evaluated in multiple solid and hematologic malignancies, showing promising results. In melanoma, various experimental models have elucidated a critical role of histone deacetylases in disease pathogenesis. They could, therefore, represent a promising novel therapeutic approach for advanced disease. A number of clinical trials assessing the efficacy of HDACi have already been completed, while a few more are in progress. Despite some early promising signs, a lot of work is required in the field of clinical studies, and larger patient cohorts are needed in order for more valid conclusions to be extracted, regarding the potential of HDACi as mainstream treatment options for melanoma. Full article

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

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17 pages, 920 KiB

Open AccessReview

Exosomes in the Treatment of Pancreatic Cancer: A Moonshot to PDAC Treatment?

by Stavros P. Papadakos, Nikolaos Dedes, Alexandros Pergaris, Maria Gazouli and Stamatios Theocharis

Int. J. Mol. Sci. 2022, 23(7), 3620; https://doi.org/10.3390/ijms23073620 - 25 Mar 2022

Cited by 11 | Viewed by 3216

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) constitutes a leading cause of cancer death globally. Its mortality remains unaltered despite the considerable scientific progress made in the fields of diagnostics and treatment. Exosomes comprise of small extracellular vesicles secreted by nearly all cells; their cargo contains [...] Read more.

Pancreatic Ductal Adenocarcinoma (PDAC) constitutes a leading cause of cancer death globally. Its mortality remains unaltered despite the considerable scientific progress made in the fields of diagnostics and treatment. Exosomes comprise of small extracellular vesicles secreted by nearly all cells; their cargo contains a vast array of biomolecules, such as proteins and microRNAs. It is currently established that their role as messengers is central to a plethora of both physiologic and pathologic processes. Accumulating data have shed light on their contributions to carcinogenesis, metastasis, and immunological response. Meanwhile, the advancement of personalized targeted therapies into everyday clinical practice necessitates the development of cost-efficient treatment approaches. The role of exosomes is currently being extensively investigated towards this direction. This review aims to summarize the current pre-clinical and clinical evidence regarding the effects of exosomal applications in the timely diagnosis, prognosis, and therapeutic management of pancreatic cancer. Full article

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

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18 pages, 1259 KiB

Open AccessReview

Immunotherapy for Cervical Cancer: Are We Ready for Prime Time?

by Margherita Turinetto, Anna A. Valsecchi, Valentina Tuninetti, Giulia Scotto, Fulvio Borella and Giorgio Valabrega

Int. J. Mol. Sci. 2022, 23(7), 3559; https://doi.org/10.3390/ijms23073559 - 24 Mar 2022

Cited by 16 | Viewed by 3320

Abstract

The prognosis of invasive cervical cancer (CC) remains poor, with a treatment approach that has remained the same for several decades. Lately, a better understanding of the interactions between the disease and the host immune system has allowed researchers to focus on the [...] Read more.

The prognosis of invasive cervical cancer (CC) remains poor, with a treatment approach that has remained the same for several decades. Lately, a better understanding of the interactions between the disease and the host immune system has allowed researchers to focus on the employment of immune therapy in various clinical settings. The most advanced strategy is immune checkpoint inhibitors (ICIs) with numerous phase II and III trials recently concluded with very encouraging results, assessing single agent therapy, combinations with chemotherapy and radiotherapy. Apart from ICIs, several other compounds have gained the spotlight. Tumor Infiltrating Lymphocytes (TILs) due to their highly selective tumoricidal effect and manageable adverse effect profile have received the FDA’s Breakthrough Therapy designation in 2019. The antibody drug conjugate (ADC) Tisotumab-Vedotin has shown activity in metastatic CC relapsed after at least one line of chemotherapy, with a phase III trial currently actively enrolling patients. Moreover, the deeper understanding of the ever-changing immune landscape of CC carcinogenesis has resulted in the development of active therapeutic vaccines. This review highlights the different immunotherapeutic strategies being explored reflects on what role immunotherapy might have in therapeutic algorithms of CC and addresses the role of predictive biomarkers. Full article

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

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21 pages, 10620 KiB

Open AccessReview

The EPH/Ephrin System in Gynecological Cancers: Focusing on the Roots of Carcinogenesis for Better Patient Management

by Iason Psilopatis, Alexandros Pergaris, Kleio Vrettou, Gerasimos Tsourouflis and Stamatios Theocharis

Int. J. Mol. Sci. 2022, 23(6), 3249; https://doi.org/10.3390/ijms23063249 - 17 Mar 2022

Cited by 11 | Viewed by 2090

Abstract

Gynecological cancers represent some of the most common types of malignancy worldwide. Erythropoietin-producing hepatocellular receptors (EPHs) comprise the largest subfamily of receptor tyrosine kinases, binding membrane-bound proteins called ephrins. EPHs/ephrins exhibit widespread expression in different cell types, playing an important role in carcinogenesis. [...] Read more.

Gynecological cancers represent some of the most common types of malignancy worldwide. Erythropoietin-producing hepatocellular receptors (EPHs) comprise the largest subfamily of receptor tyrosine kinases, binding membrane-bound proteins called ephrins. EPHs/ephrins exhibit widespread expression in different cell types, playing an important role in carcinogenesis. The aim of the current review was to examine the dysregulation of the EPH/ephrin system in gynecological cancer, clarifying its role in ovarian, endometrial, and cervical carcinogenesis. In order to identify relevant studies, a literature review was conducted using the MEDLINE and LIVIVO databases. The search terms ephrin, ephrin receptor, ovarian cancer, endometrial cancer, and cervical cancer were employed and we were able to identify 57 studies focused on gynecological cancer and published between 2001 and 2021. All researched ephrins seemed to be upregulated in gynecological cancer, whereas EPHs showed either significant overexpression or extensive loss of expression in gynecological tumors, depending on the particular receptor. EPHA2, the most extensively studied EPH in ovarian cancer, exhibited overexpression both in ovarian carcinoma cell lines and patient tissue samples, while EPHB4 was found to be upregulated in endometrial cancer in a series of studies. EPHs/ephrins were shown to exert their role in different stages of gynecological cancer and to influence various clinicopathological parameters. The analysis of patients’ gynecological cancer tissue samples, most importantly, revealed the significant role of the EPH/ephrin system in the development and progression of gynecological cancer, as well as overall patient survival. In conclusion, the EPH/ephrin system represents a large family of biomolecules with promising applications in the fields of diagnosis, prognosis, disease monitoring, and treatment of gynecological cancer, with an established important clinical impact. Full article

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

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18 pages, 1572 KiB

Open AccessReview

Liquid Biopsy: A New Translational Diagnostic and Monitoring Tool for Musculoskeletal Tumors

by Argyris C. Hadjimichael, Alexandros Pergaris, Angelos Kaspiris, Athanasios F. Foukas and Stamatios E. Theocharis

Int. J. Mol. Sci. 2021, 22(21), 11526; https://doi.org/10.3390/ijms222111526 - 26 Oct 2021

Cited by 14 | Viewed by 2646

Abstract

Soft tissue and bone sarcomas represent a group of aggressive neoplasms often accompanied by dismal patient prognosis, especially when distant metastases are present. Moreover, effective treatment can pose a challenge, as recurrences are frequent and almost half of patients present with advanced disease. [...] Read more.

Soft tissue and bone sarcomas represent a group of aggressive neoplasms often accompanied by dismal patient prognosis, especially when distant metastases are present. Moreover, effective treatment can pose a challenge, as recurrences are frequent and almost half of patients present with advanced disease. Researchers have unveiled the molecular abnormalities implicated in sarcomas’ carcinogenesis, paving the way for novel treatment strategies based on each individual tumor’s characteristics. Therefore, the development of new techniques aiding in early disease detection and tumor molecular profiling is imperative. Liquid biopsy refers to the sampling and analysis of patients’ fluids, such as blood, to identify tumor biomarkers, through a variety of methods, including qRT-PCR, qPCR, droplet digital PCR, magnetic microbeads and digital PCR. Assessment of circulating tumor cells (CTCs), circulating free DNA (ctDNA), micro RNAs (miRs), long non-coding RNAs (lncRNAs), exosomes and exosome–associated proteins can yield a plethora of information on tumor molecular signature, histologic type and disease stage. In addition, the minimal invasiveness of the procedure renders possible its wide application in the clinical setting, and, therefore, the early detection of the presence of tumors. In this review of the literature, we gathered information on biomarkers assessed through liquid biopsy in soft tissue and bone sarcoma patients and we present the information they can yield for each individual tumor type. Full article

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

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