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Special Issue "State-of-the-Art Molecular Oncology in UK"

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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 2022) | Viewed by 5363

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Special Issue Editors

Dr. Stergios Boussios

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Collection Editor

1. Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, King's College London, London SE1 9RT, UK
2. Medway NHS Foundation Trust, Windmill Road, Gillingham, Kent ME7 5NY, UK
3. Kent Medway Medical School, University of Kent, CT2 7LX, Canterbury, Kent, UK
4. AELIA Organization, 9(th)Km Thessaloniki-Thermi, 57001 Thessaloniki, Greece
Interests: ovarian cancer; cervical cancer; carcinoma of unknown primary; prostate cancer, renal cancer, colorectal cancer; cancer in pregnancy
Special Issues, Collections and Topics in MDPI journals

Dr. Christos Mikropoulos

E-Mail Website
Collection Editor

St Luke’s Cancer Unit, Royal Surrey Hospital, Guildford, UK
Interests: cancer genetics; biomarkers; SABR; brachytherapy

Special Issue Information

Dear Colleagues,

The basic research is focused on understanding the molecular mechanisms that govern cancer cell metastasis and treatment resistance. The improvement of our knowledge of the molecular mechanisms by defining pathways that influence cancer therapy and by developing new tools and therapeutics to prevent and treat effectively cancer is an ongoing effort. In the past few decades, oncological studies are evolving from traditional to Molecular Oncology.

Molecular Oncology is a rapidly growing field with a massive impact on basic science, medical application, and translational cancer research. Through the use of cutting edge technologies, Molecular Oncology aims to identify genes involved in the development of cancer. Researchers combine diverse techniques, ranging from genomics, computational biology, tumour imaging, in vitro and in vivo functional models, to study biological phenotypes. The proteins produced by these genes may serve as targets for novel therapeutic agents, or imaging scans. Molecular Oncology uses these combined techniques to validate the role of the novel candidate genes in the development of cancer.

This Topical Collection will bring together original research and review articles on Molecular Oncology, acknowledging the significant involvement scientists from the United Kingdom made to the research community in the Molecular Oncology field. The main feature of this Topical Collection is to provide an open-source sharing of significant works in the field of Molecular Oncology that can advance our understanding of carcinogenesis, novel molecular diagnostic technologies and targeted therapeutics. Special interest falls on novel mechanistic insights into cancer molecular pathways. The broad cancer community will have a forum for the publication of new discoveries, approaches, as well as state‐of‐the‐art technical developments, in basic and discovery‐driven translational cancer research.

Dr. Stergios Boussios
Dr. Christos Mikropoulos
Collection Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

DNA repair and genomic instability
tumour immunology and immune response
emerging technologies
cancer genetics and epigenetics
translational research
integration of basic science into medical trials
molecular pathology
cancer microenvironment

Published Papers (7 papers)

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Research

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Open AccessArticle

Biophysical Parameters Can Induce Epithelial-to-Mesenchymal Phenotypic and Genotypic Changes in HT-29 Cells: A Preliminary Study

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Int. J. Mol. Sci. 2023, 24(4), 3956; https://doi.org/10.3390/ijms24043956 - 16 Feb 2023

Viewed by 648

Abstract

Epithelial to mesenchymal transition (EMT) in cancer is the process described where cancer epithelial cells acquire mesenchymal properties which can lead to enhanced invasiveness. Three-dimensional cancer models often lack the relevant and biomimetic microenvironment parameters appropriate to the native tumour microenvironment thought to drive EMT. In this study, HT-29 epithelial colorectal cells were cultivated in different oxygen and collagen concentrations to investigate how these biophysical parameters influenced invasion patterns and EMT. Colorectal HT-29 cells were grown in physiological hypoxia (5% O₂) and normoxia (21% O₂) in 2D, 3D soft (60 Pa), and 3D stiff (4 kPa) collagen matrices. Physiological hypoxia was sufficient to trigger expression of markers of EMT in the HT-29 cells in 2D by day 7. This is in contrast to a control breast cancer cell line, MDA-MB-231, which expresses a mesenchymal phenotype regardless of the oxygen concentration. In 3D, HT-29 cells invaded more extensively in a stiff matrix environment with corresponding increases in the invasive genes MMP2 and RAE1. This demonstrates that the physiological environment can directly impact HT-29 cells in terms of EMT marker expression and invasion, compared to an established cell line, MDA-MB-231, which has already undergone EMT. This study highlights the importance of the biophysical microenvironment to cancer epithelial cells and how these factors can direct cell behaviour. In particular, that stiffness of the 3D matrix drives greater invasion in HT-29 cells regardless of hypoxia. It is also pertinent that some cell lines (already having undergone EMT) are not as sensitive to the biophysical features of their microenvironment. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in UK)

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Open AccessArticle

The Effects of GCSF Primary Prophylaxis on Survival Outcomes and Toxicity in Patients with Advanced Non-Small Cell Lung Cancer on First-Line Chemoimmunotherapy: A Sub-Analysis of the Spinnaker Study

Christian Ottensmeier

Fabio Gomes

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Giuseppe Luigi Banna

Int. J. Mol. Sci. 2023, 24(2), 1746; https://doi.org/10.3390/ijms24021746 - 16 Jan 2023

Viewed by 818

Abstract

GCSF prophylaxis is recommended in patients on chemotherapy with a >20% risk of febrile neutropenia and is to be considered if there is an intermediate risk of 10–20%. GCSF has been suggested as a possible adjunct to immunotherapy due to increased peripheral neutrophil recruitment and PD-L1 expression on neutrophils with GCSF use and greater tumour volume decrease with higher tumour GCSF expression. However, its potential to increase neutrophil counts and, thus, NLR values, could subsequently confer poorer prognoses on patients with advanced NSCLC. This analysis follows on from the retrospective multicentre observational cohort Spinnaker study on advanced NSCLC patients. The primary endpoints were OS and PFS. The secondary endpoints were the frequency and severity of AEs and irAEs. Patient information, including GCSF use and NLR values, was collected. A secondary comparison with matched follow-up duration was also undertaken. Three hundred and eight patients were included. Median OS was 13.4 months in patients given GCSF and 12.6 months in those not (p = 0.948). Median PFS was 7.3 months in patients given GCSF and 8.4 months in those not (p = 0.369). A total of 56% of patients receiving GCSF had Grade 1–2 AEs compared to 35% who did not receive GCSF (p = 0.004). Following an assessment with matched follow-up, 41% of patients given GCSF experienced Grade 1–2 irAEs compared to 23% of those not given GCSF (p = 0.023). GCSF prophylaxis use did not significantly affect overall or progression-free survival. Patients given GCSF prophylaxis were more likely to experience Grade 1–2 adverse effects and Grade 1–2 immunotherapy-related adverse effects. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in UK)

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Open AccessArticle

Activated Leukocyte Cell Adhesion Molecule (ALCAM), a Potential ‘Seed’ and ‘Soil’ Receptor in the Peritoneal Metastasis of Gastrointestinal Cancers

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Int. J. Mol. Sci. 2023, 24(1), 876; https://doi.org/10.3390/ijms24010876 - 03 Jan 2023

Viewed by 670

Abstract

Activated Leukocyte Cell Adhesion Molecule (ALCAM/CD166) is a cell–cell adhesion protein conferring heterotypic and homotypic interactions between cells of the same type and different types. It is aberrantly expressed in various cancer types and has been shown to be a regulator of cancer metastasis. In the present study, we investigated potential roles of ALCAM in the peritoneal transcoelomic metastasis in gastrointestinal cancers, a metastatic type commonly occurred in gastro-intestinal and gynaecological malignancies and resulting in poor clinical outcomes. Specifically, we studied whether ALCAM acts as both a ‘seed’ receptor in these tumour cells and a ‘soil’ receptor in peritoneal mesothelial cells during cancer metastasis. Gastric cancer and pancreatic cancer tissues with or without peritoneal metastasis were compared for their levels of ALCAM expression. The impact of ALCAM expression in these tumours was also correlated to the patients’ clinical outcomes, namely peritoneal metastasis-free survival. In addition, cancer cells of gastric and pancreatic origins were used to create cell models with decreased or increased levels of ALCAM expression by genetic knocking down or overexpression, respectively. Human peritoneal mesothelial cells were also genetically transfected to generate cell models with different profiles of ALCAM expression. These cell models were used in the tumour-mesothelial interaction assay to assess if and how the interaction was influenced by ALCAM. Both gastric and pancreatic tumour tissues from patients who developed peritoneal metastases had higher levels of ALCAM transcript than those without. Patients who had tumours with high levels of ALCAM had a much shorter peritoneal metastasis free survival compared with those who had low ALCAM expression (p = 0.006). ALCAM knockdown of the mesothelial cell line MET5A rendered the cells with reduced interaction with both gastric cancer cells and pancreatic cancer cells. Likewise, levels of ALCAM in both human gastric and pancreatic cancer cells were also a determining factor for their adhesiveness to mesothelial cells, a process that was likely to be triggered the phosphorylation of the SRC kinase. A soluble ALCAM (sALCAM) was found to be able to inhibit the adhesiveness between cancer cells and mesothelial cells, mechanistically behaving like a SRC kinase inhibitor. ALCAM is an indicator of peritoneal metastasis in both gastric and pancreatic cancer patients. It acts as not only a potential peritoneal ‘soil’ receptor of tumour seeding but also a ‘soil’ receptor in peritoneal mesothelial cells during cancer metastasis. These findings have an important therapeutic implication for treating peritoneal transcoelomic metastases. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in UK)

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Open AccessArticle

EPLIN, a Putative Tumour Suppressor in Colorectal Cancer, Implications in Drug Resistance

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Int. J. Mol. Sci. 2022, 23(23), 15232; https://doi.org/10.3390/ijms232315232 - 03 Dec 2022

Viewed by 566

Abstract

Colorectal cancer is a serious threat to human health. Poor prognosis and frequently reported drug resistance urges research into novel biomarkers and mechanisms to aid in the understanding of the development and progression of colorectal cancer and to optimise therapeutic strategies. In the current study, we investigated the roles of a putative tumour suppressor, EPLIN, in colorectal cancer. Our clinical colorectal cancer cohort and online databases revealed a downregulation of EPLIN in colorectal cancer tissues compared with normal tissues. The reduced expression of EPLIN was associated with poor clinical outcomes of patients. In vitro cellular function assays showed that EPLIN elicited an inhibitory effect on cellular growth, adhesion, migration and invasion. Utilising a protein microarray on protein samples from normal and tumour patient tissues suggested HSP60, Her2 and other signalling events were novel potential interacting partners of EPLIN. It was further revealed that EPLIN and HSP60 were negative regulators of Her2 in colorectal cancer cells. The clinical cohort also demonstrated that expression of HSP60 and Her2 affected clinical outcomes, but most interestingly the combination of EPLIN, HSP60 and Her2 was able to identify patients with the most unfavourable clinical outcome by independently predicting patient overall survival and disease free survival. Furthermore, EPLIN and HSP60 exhibited potential to regulate cellular response to chemotherapeutic and EGFR/Her2 targeted therapeutic agents. In conclusion, EPLIN is an important prognostic factor for patients with colon cancer and reduced EPLIN in CRC contributes to aggressive traits of CRC cells and their responses to chemotherapeutic drugs. Collectively, EPLIN is a pivotal factor for the development and progression of colorectal cancer and has important clinical and therapeutic values in this cancer type. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in UK)

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Open AccessArticle

Computational Biology Dynamics of Mps1 Kinase Molecular Interactions with Isoflavones Reveals a Chemical Scaffold with Potential to Develop New Therapeutics for the Treatment of Cancer

Lauren Pugh

Alisha Pancholi

Priscila Celeste Purat

Sandra Agudo-Alvarez

Raúl Benito-Arenas

Agatha Bastida

and

Victor M. Bolanos-Garcia

Int. J. Mol. Sci. 2022, 23(22), 14228; https://doi.org/10.3390/ijms232214228 - 17 Nov 2022

Viewed by 645

Abstract

The protein kinase Mps1 (monopolar spindle 1) is an important regulator of the Spindle Assembly Checkpoint (SAC), the evolutionary conserved checkpoint system of higher organisms that monitors the proper bipolar attachment of all chromosomes to the mitotic spindle during cell division. Defects in the catalytic activity and the transcription regulation of Mps1 are associated with genome instability, aneuploidy, and cancer. Moreover, multiple Mps1 missense and frameshift mutations have been reported in a wide range of types of cancer of different tissue origin. Due to these features, Mps1 arises as one promising drug target for cancer therapy. In this contribution, we developed a computational biology approach to study the dynamics of human Mps1 kinase interaction with isoflavones, a class of natural flavonoids, and compared their predicted mode of binding with that observed in the crystal structure of Mps1 in complex with reversine, a small-sized inhibitor of Mps1 and Aurora B kinases. We concluded that isoflavones define a chemical scaffold that can be used to develop new Mps1 inhibitors for the treatment of cancer associated with Mps1 amplification and aberrant chromosome segregation. In a broader context, the present report illustrates how modern chemoinformatics approaches can accelerate drug development in oncology. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in UK)

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Review

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Open AccessReview

Ran GTPase and Its Importance in Cellular Signaling and Malignant Phenotype

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Int. J. Mol. Sci. 2023, 24(4), 3065; https://doi.org/10.3390/ijms24043065 - 04 Feb 2023

Viewed by 705

Abstract

Ran is a member of the Ras superfamily of proteins, which primarily regulates nucleocytoplasmic trafficking and mediates mitosis by regulating spindle formation and nuclear envelope (NE) reassembly. Therefore, Ran is an integral cell fate determinant. It has been demonstrated that aberrant Ran expression in cancer is a result of upstream dysregulation of the expression of various factors, such as osteopontin (OPN), and aberrant activation of various signaling pathways, including the extracellular-regulated kinase/mitogen-activated protein kinase (ERK/MEK) and phosphatidylinositol 3-kinase/Protein kinase B (PI3K/Akt) pathways. In vitro, Ran overexpression has severe effects on the cell phenotype, altering proliferation, adhesion, colony density, and invasion. Therefore, Ran overexpression has been identified in numerous types of cancer and has been shown to correlate with tumor grade and the degree of metastasis present in various cancers. The increased malignancy and invasiveness have been attributed to multiple mechanisms. Increased dependence on Ran for spindle formation and mitosis is a consequence of the upregulation of these pathways and the ensuing overexpression of Ran, which increases cellular dependence on Ran for survival. This increases the sensitivity of cells to changes in Ran concentration, with ablation being associated with aneuploidy, cell cycle arrest, and ultimately, cell death. It has also been demonstrated that Ran dysregulation influences nucleocytoplasmic transport, leading to transcription factor misallocation. Consequently, patients with tumors that overexpress Ran have been shown to have a higher malignancy rate and a shorter survival time compared to their counterparts. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in UK)

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Open AccessReview

Therapeutic Antibodies in Cancer Treatment in the UK

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Int. J. Mol. Sci. 2022, 23(23), 14589; https://doi.org/10.3390/ijms232314589 - 23 Nov 2022

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Abstract

The growing understanding of the molecular mechanisms of carcinogenesis accelerated the development of monoclonal therapeutic antibodies to specifically target multiple cancer pathways. Recombinant protein therapeutics now constitute a large proportion of yearly approved medicines. Oncology, autoimmune diseases and to a smaller degree the prophylaxis of organ transplant rejection are their main application areas. As of the date of this review, 37 monoclonal antibody products are approved for use in cancer treatments in the United Kingdom. Currently, the antibody therapeutics market is dominated by monoclonal immunoglobulins (IgGs). New types of recombinant antibody therapeutics developed more recently include bispecific recombinant antibodies and other recombinantly produced functional proteins. This review focuses on the approved therapeutic antibodies used in cancer treatment in the UK today and describes their antigen targets and molecular mechanisms involved. We provide convenient links to the relevant databases and other relevant resources for all antigens and antibodies mentioned. This review provides a comprehensive summary of the different monoclonal antibodies that are currently in clinical use primarily in malignancy, including their function, which is of importance to those in the medical field and allied specialties. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in UK)

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