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Molecular Advances in Cancer Therapy 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 16149

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Prof. Dr. Stamatios E. Theocharis

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First Department of Pathology, Medical School, University of Athens, Athens, Greece
Interests: apoptosis; metabolism; cytopathology; pathology; molecular pathology; immunohistochemistry
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Dear Colleagues,

Current anti-cancer research continues to unveil the molecular signatures that define tumor characteristics and behavior, increasingly shifting its focus on the complex molecular pathways implicated in tumorigenesis, cancer cell proliferation, lymph- and angiogenesis, tissue infiltration and dissemination to distant sites. Additionally, the delineation of cross-talk signals between malignant cells and different cells’ populations of the microenvironment, at both primary and metastatic sites, should contribute to the establishment of novel prognostic and predictive biomarkers.

Such data should lead to the development of novel, efficient, minimally invasive diagnostic procedures that aid in early disease detection, enabling also increasingly accurate assessment of prognosis and timely therapeutic interventions. Moreover, the early characterization and detection of remission signals should modify the previous therapeutic strategies, to a more effective, precisive treatment.

The application of specific drugs able to interfere with key signaling pathways implicated in carcinogenesis has yielded promising results, that should further contribute to noteworthy improvement of patients' outcome.

In the current issue we welcome research and review articles focusing on diverse molecular mechanisms implicated in different steps of carcinogenesis and could serve as therapeutic targets.

Prof. Dr. Stamatios E. Theocharis
Guest Editor

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Keywords

cancer therapy
tumorigenesis
immunotherapy
targeted therapy
chemotherapy
anti-cancer drugs
tumor microenvironment

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Published Papers (7 papers)

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Research

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13 pages, 5852 KiB

Open AccessArticle

Longitudinal Transcription Profiling of Bladder Cancers Dictate the Response to BCG Treatment and Disease Progression

by Seo-Young Lee, Yun-Hee Lee, Tae-Min Kim and U-Syn Ha

Int. J. Mol. Sci. 2024, 25(1), 144; https://doi.org/10.3390/ijms25010144 - 21 Dec 2023

Viewed by 1646

Abstract

Although the intravesical instillation of Bacillus Calmette-Guerin (BCG) is widely used as adjuvant treatment for nonmuscle-invasive bladder cancers, the clinical benefit is variable across patients, and the molecular mechanisms underlying the sensitivity to BCG administration and disease progression are poorly understood. To establish the molecular signatures that predict the responsiveness and disease progression of bladder cancers treated with BCG, we performed transcriptome sequencing (RNA-seq) for 13 treatment-naïve and 22 post-treatment specimens obtained from 14 bladder cancer patients. To overcome disease heterogeneity, we used non-negative matrix factorization to identify the latent molecular features associated with drug responsiveness and disease progression. At least 12 molecular features were present, among which the immune-related feature was associated with drug responsiveness, indicating that pre-treatment anti-cancer immunity might dictate BCG responsiveness. We also identified disease progression-associated molecular features indicative of elevated cellular proliferation in post-treatment specimens. The progression-associated molecular features were validated in an extended cohort of BCG-treated bladder cancers. Our study advances understanding of the molecular mechanisms of BCG activity in bladder cancers and provides clinically relevant gene markers for evaluating and monitoring patients. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer Therapy 2.0)

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11 pages, 938 KiB

Open AccessArticle

TBM Hunter: Identify and Score Canonical, Extended, and Unconventional Tankyrase-Binding Motifs in Any Protein

by Christopher M. Clements, Samantha X. Shellman, Melody H. Shellman and Yiqun G. Shellman

Int. J. Mol. Sci. 2023, 24(23), 16964; https://doi.org/10.3390/ijms242316964 - 30 Nov 2023

Cited by 1 | Viewed by 1529

Abstract

Tankyrases, a versatile protein group within the poly(ADP-ribose) polymerase family, are essential for post-translational poly(ADP-ribosyl)ation, influencing various cellular functions and contributing to diseases, particularly cancer. Consequently, tankyrases have become important targets for anti-cancer drug development. Emerging approaches in drug discovery aim to disrupt interactions between tankyrases and their binding partners, which hinge on tankyrase-binding motifs (TBMs) within partner proteins and ankyrin repeat cluster domains within tankyrases. Our study addresses the challenge of identifying and ranking TBMs. We have conducted a comprehensive review of the existing literature, classifying TBMs into three distinct groups, each with its own scoring system. To facilitate this process, we introduce TBM Hunter—an accessible, web-based tool. This user-friendly platform provides a cost-free and efficient means to screen and assess potential TBMs within any given protein. TBM Hunter can handle individual proteins or lists of proteins simultaneously. Notably, our results demonstrate that TBM Hunter not only identifies known TBMs but also uncovers novel ones. In summary, our study offers an all-encompassing perspective on TBMs and presents an easy-to-use, precise, and free tool for identifying and evaluating potential TBMs in any protein, thereby enhancing research and drug development efforts focused on tankyrases. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer Therapy 2.0)

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15 pages, 3151 KiB

Open AccessArticle

Oxidative Stress in Xenograft Mouse Model Exposed to Dendrimers Decorated Polydopamine Nanoparticles and Targeted Chemo- and Photothermal Therapy

by Marta Witkowska, Radosław Mrówczyński, Bartosz Grześkowiak, Izabela Miechowicz and Ewa Florek

Int. J. Mol. Sci. 2023, 24(23), 16565; https://doi.org/10.3390/ijms242316565 - 21 Nov 2023

Cited by 2 | Viewed by 1407

Abstract

Polydopamine (PDA)-based nanostructures are used for biomedical purposes. A hybrid drug nanocarrier based on a PDA decorated with polyamidoamine (PAMAM) dendrimers G 3.0 (DG3) followed by a connection with glycol (PEG) moieties, folic acid (FA), and drug doxorubicin (DOX) was used for combined chemo- and photothermal therapy (CT-PTT) of liver cancer. Oxidative stress plays a crucial role in the development of cancer, and PDA seems to have the ability to both donate and accept electrons. We investigated oxidative stress in organs by evaluating oxidative stress markers in vivo. In the liver, the level of reduced glutathione (GSH) was lower and the level of Trolox equivalent antioxidant capacity (TEAC) was higher in the group receiving doxorubicin encapsulated in PDA nanoparticles with phototherapy (PDA@DG3@PEG@FA@DOX + PTT) compared to the control group. The concentration of thiobarbituric acid reactive substances (TBARS) in livers, was higher in the group receiving PDA coated with PAMAM dendrimers and functionalized with PEG and FA (PDA@DG3@PEG@FA) than in other groups. Markers in the brain also showed lower levels of GSH in the PDA@DG3@PEG@FA group than in the control group. Markers of oxidative stress indicated changes in the organs of animals receiving PDA nanoparticles with PAMAM dendrimers functionalized with FA in CT-PTT of liver cancer under in vivo conditions. Our work will provide insights into oxidative stress, which can be an indicator of the toxic potential of PDA nanoparticles and provide new strategies to improve existing therapies. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer Therapy 2.0)

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21 pages, 5720 KiB

Open AccessArticle

High Tumor-Infiltrating Lymphocyte Count Is Associated with Distinct Gene Expression Profile and Longer Patient Survival in Advanced Ovarian Cancer

by Andras Jozsef Barna, Zoltan Herold, Miklos Acs, Sandor Bazsa, Jozsef Gajdacsi, Tamas Marton Garay, Magdolna Herold, Lilla Madaras, Dorottya Muhl, Akos Nagy, Attila Marcell Szasz and Magdolna Dank

Int. J. Mol. Sci. 2023, 24(18), 13684; https://doi.org/10.3390/ijms241813684 - 5 Sep 2023

Cited by 2 | Viewed by 1917

Abstract

Cancer-related immunity plays a significant role in the outcome of ovarian cancer, but the exact mechanisms are not fully explored. A retrospective, real-life observational study was conducted including 57 advanced ovarian cancer patients. Immunohistochemistry for CD4⁺, CD8⁺, and CD45⁺ was used for assessing tumor-infiltrating immune cells. Furthermore, an immune-related gene expression assay was performed on 12–10 samples from patients with less than and more than 1-year overall survival (OS), respectively. A higher number of CD4⁺ (p = 0.0028) and CD45⁺ (p = 0.0221) immune cells within the tumor microenvironment were associated with longer OS of patients. In a multivariate setting, higher CD4⁺ T cell infiltration predicted longer OS (p = 0.0392). Twenty-three differentially expressed genes—involved in antigen presentation, costimulatory signaling, matrix remodeling, metastasis formation, and myeloid cell activity—were found when comparing the prognostic groups. It was found that tumor-infiltrating immune cell counts are associated with peculiar gene expression patterns and bear prognostic information in ovarian cancer. SOX11 expression emerged and was validated as a predictive marker for OS. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer Therapy 2.0)

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17 pages, 2980 KiB

Open AccessArticle

Protein Tyrosine Phosphatase Non-Receptor 11 (PTPN11/Shp2) as a Driver Oncogene and a Novel Therapeutic Target in Non-Small Cell Lung Cancer (NSCLC)

by Cathy E. Richards, Yasir Y. Elamin, Aoife Carr, Kathy Gately, Shereen Rafee, Mattia Cremona, Emer Hanrahan, Robert Smyth, Daniel Ryan, Ross K. Morgan, Susan Kennedy, Lance Hudson, Joanna Fay, Kenneth O’Byrne, Bryan T. Hennessy and Sinead Toomey

Int. J. Mol. Sci. 2023, 24(13), 10545; https://doi.org/10.3390/ijms241310545 - 23 Jun 2023

Cited by 5 | Viewed by 3073

Abstract

PTPN11 encodes the SHP2 protein tyrosine phosphatase that activates the mitogen-activated protein kinase (MAPK) pathway upstream of KRAS and MEK. PTPN11/Shp2 somatic mutations occur frequently in Juvenile myelomonocytic leukaemia (JMML); however, the role of mutated PTPN11 in lung cancer tumourigenesis and its utility as a therapeutic target has not been fully addressed. We applied mass-spectrometry-based genotyping to DNA extracted from the tumour and matched the normal tissue of 356 NSCLC patients (98 adenocarcinomas (LUAD) and 258 squamous cell carcinomas (LUSC)). Further, PTPN11 mutation cases were identified in additional cohorts, including TCGA, Broad, and MD Anderson datasets and the COSMIC database. PTPN11 constructs harbouring PTPN11 E76A, A72D and C459S mutations were stably expressed in IL-3 dependent BaF3 cells and NSCLC cell lines (NCI-H1703, NCI-H157, NCI-H1299). The MAPK and PI3K pathway activation was evaluated using Western blotting. PTPN11/Shp2 phosphatase activity was measured in whole-cell protein lysates using an Shp2 assay kit. The Shp2 inhibitor (SHPi) was assessed both in vitro and in vivo in a PTPN11-mutated cell line for improved responses to MAPK and PI3K targeting therapies. Somatic PTPN11 hotspot mutations occurred in 4/98 (4.1%) adenocarcinomas and 7/258 (2.7%) squamous cells of 356 NSCLC patients. Additional 26 PTPN11 hotspot mutations occurred in 23 and 3 adenocarcinomas and squamous cell carcinoma, respectively, across the additional cohorts. Mutant PTPN11 significantly increased the IL-3 independent survival of Ba/F3 cells compared to wildtype PTPN11 (p < 0.0001). Ba/F3, NCI-H1703, and NCI-H157 cells expressing mutant PTPN11 exhibited increased PTPN11/Shp2 phosphatase activity and phospho-ERK1/2 levels compared to cells expressing wildtype PTPN11. The transduction of the PTPN11 inactivating mutation C459S into NSCLC cell lines led to decreased phospho-ERK, as well as decreased phospho-AKT in the PTPN11-mutated NCI-H661 cell line. NCI-H661 cells (PTPN11-mutated, KRAS-wild type) were significantly more sensitive to growth inhibition by the PI3K inhibitor copanlisib (IC50: 13.9 ± 4.7 nM) compared to NCI-H1703 (PTPN11/KRAS-wild type) cells (IC50: >10,000 nM). The SHP2 inhibitor, in combination with the PI3K targeting therapy copanlisib, showed no significant difference in tumour development in vivo; however, this significantly prevented MAPK pathway induction in vitro (p < 0.0001). PTPN11/Shp2 demonstrated the in vitro features of a driver oncogene and could potentially sensitize NSCLC cells to PI3K inhibition and inhibit MAPK pathway activation following PI3K pathway targeting. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer Therapy 2.0)

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12 pages, 3025 KiB

Open AccessArticle

Establishment of Mucoepidermoid Carcinoma Cell Lines from Surgical and Recurrence Biopsy Specimens

by Shunpei Yamanaka, Susumu Suzuki, Hideaki Ito, Karnan Sivasundaram, Ichiro Hanamura, Ikuko Okubo, Kazuhiro Yoshikawa, Shoya Ono, Taishi Takahara, Akira Satou, Toyonori Tsuzuki, Ryuzo Ueda, Tetsuya Ogawa and Yasushi Fujimoto

Int. J. Mol. Sci. 2023, 24(2), 1722; https://doi.org/10.3390/ijms24021722 - 15 Jan 2023

Cited by 1 | Viewed by 3150

Abstract

Patients with advanced/recurrent mucoepidermoid carcinoma (MEC) have a poor prognosis. This study aimed to establish and characterize human mucoepidermoid carcinoma cell lines from the initial surgical specimen and biopsy specimen upon recurrence from the same patient to provide a resource for MEC research. MEC specimens from the initial surgical procedure and biopsy upon recurrence were used to establish cell lines. The established cell lines were cytogenetically characterized using multi-color fluorescence in situ hybridization and detection, and the sequence of the CRTC1-MAML2 chimeric gene was determined. Furthermore, the susceptibility of head and neck mucoepidermoid carcinoma to standard treatment drugs such as cisplatin, 5-fluorouracil, and cetuximab was investigated. We successfully established unique MEC cell lines, AMU-MEC1, from an initial surgical specimen and AMU-MEC1-R1 and AMU-MEC1-R2 from the recurrent biopsy specimen in the same patient. These cell lines exhibited epithelial morphology and developed in vitro-like cobblestones. They shared eight chromosomal abnormalities, including der(19)ins(19;11)(p13;?), which resulted in a chimeric CRTC1-MAML2 gene, indicating the same origin of the cell lines. The susceptibility of all cell lines to cisplatin and 5-fluorouracil was low. Interestingly, EGFR dependency for cell growth decreased in AMU-MEC-R1 and AMU-MEC-R2 but was retained in AMU-MEC1. These cytogenetic and biochemical findings suggest that the established cell lines can be used to investigate the disease progression mechanisms and develop novel therapeutics for MEC. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer Therapy 2.0)

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Review

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12 pages, 1234 KiB

Open AccessReview

May EPH/Ephrin Targeting Revolutionize Lung Cancer Treatment?

by Iason Psilopatis, Ioannis Karniadakis, Konstantinos Stylianos Danos, Kleio Vrettou, Kleita Michaelidou, Konstantinos Mavridis, Sofia Agelaki and Stamatios Theocharis

Int. J. Mol. Sci. 2023, 24(1), 93; https://doi.org/10.3390/ijms24010093 - 21 Dec 2022

Cited by 7 | Viewed by 2570

Abstract

Lung cancer (LC) is the leading cause of cancer death in the United States. Erythropoietin-producing hepatocellular receptors (EPHs) comprise the largest receptor tyrosine kinases (RTKs) family in mammals. EPHs along with their ligands, EPH-family receptor-interacting proteins (ephrins), have been found to be either up- or downregulated in LC cells, hence exhibiting a defining role in LC carcinogenesis and tumor progression. In their capacity as membrane-bound molecules, EPHs/ephrins may represent feasible targets in the context of precision cancer treatment. In order to investigate available therapeutics targeting the EPH/ephrin system in LC, a literature review was conducted, using the MEDLINE, LIVIVO, and Google Scholar databases. EPHA2 is the most well-studied EPH/ephrin target in LC treatment. The targeting of EPHA2, EPHA3, EPHA5, EPHA7, EPHB4, EPHB6, ephrin-A1, ephrin-A2, ephrin-B2, and ephrin-B3 in LC cells or xenograft models not only directly correlates with a profound LC suppression but also enriches the effects of well-established therapeutic regimens. However, the sole clinical trial incorporating a NSCLC patient could not describe objective anti-cancer effects after anti-EPHA2 antibody administration. Collectively, EPHs/ephrins seem to represent promising treatment targets in LC. However, large clinical trials still need to be performed, with a view to examining the effects of EPH/ephrin targeting in the clinical setting. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer Therapy 2.0)

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