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Molecular Biology of Cancer—Implications for Diagnosis and Treatment

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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 December 2023) | Viewed by 14723

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Dr. Stergios Boussios

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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, Kent, Gillingham ME7 5NY, UK
3. Kent Medway Medical School, University of Kent, Kent , Canterbury CT2 7LX, UK
4. AELIA Organization, 9(th)Km Thessaloniki-Thermi, 57001 Thessaloniki, Greece
Interests: prostate cancer; renal cancer; ovarian cancer; homologous recombination of DNA; PARP inhibitors; cervical cancer; carcinoma of unknown primary; colorectal cancer; cancer and autoimmune diseases; biomarkers
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Matin Sheriff

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Guest Editor

Department of Medical Oncology, Medway NHS Foundation Trust, Gillingham ME7 5NY, Kent, UK
Interests: prostate cancer; bladder cancer; renal cancer; DNA mismatch repair
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer has a genetic background. The expression of oncogenesis is an important event in the early stages of tumour formation. Most common cancers are caused by acquired mutations in somatic cells, whilst specific germline mutations account for rare hereditary cancer syndromes. Among the cancer-associated genes, oncogenes undergo activation and are phenotypically dominant, whereas tumour suppressor genes undergo inactivation and are phenotypically recessive. The biological behaviour of cancer can be considered in terms of eight specific hallmarks and two additional so-called enabling characteristics. The improvement of our knowledge about the molecular mechanisms by defining the pathways that influence cancer therapy is an ongoing effort. Through cutting-edge technologies, including genomics, computational biology, tumour imaging, and in vitro and in vivo functional models, it has become feasible to identify genes involved in the development of cancer. Furthermore, advances in genomics technology facilitating the routine DNA and RNA sequencing of tumours, single-cell transcriptomic profiling of cancer cells, and whole-genome CRISPR screens have contributed to the growing success of oncology-precision-medicine-targeted therapies directed against tumours and components of the tumour microenvironment.

Through this Special Issue, we aim to shed light on novel molecular diagnostic technologies, along with new therapeutic approaches, based on recent advances in cancer biology and molecular genetics.

Dr. Stergios Boussios
Prof. Dr. Matin Sheriff
Guest 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

genomics
epigenetics
translational research
oncology precision medicine

Published Papers (10 papers)

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Editorial

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7 pages, 216 KiB

Open AccessEditorial

Frontiers of Molecular Biology of Cancer

by Stergios Boussios, Elisabet Sanchez and Matin Sheriff

Int. J. Mol. Sci. 2023, 24(24), 17187; https://doi.org/10.3390/ijms242417187 - 06 Dec 2023

Viewed by 712

Abstract

Cancer is rooted in genetic background, with the expression of oncogenesis playing a pivotal role in the early stages of tumor formation [...] Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment)

Research

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13 pages, 1169 KiB

Open AccessCommunication

Breast Cancer Molecular Subtyping in Practice: A Real-World Study of the APIS Breast Cancer Subtyping Assay in a Consecutive Series of Breast Core Biopsies

by Silvana Di Palma, Panagiotis Koliou, Alex Simonovic, Daniela Costa, Catherine Faulkes, Brenda Kobutungi, Felicity Paterson, Jonathan David Horsnell, Farrokh Pakzad, Tracey Irvine, Polly Partlett, Elizabeth Clayton and Nadine Collins

Int. J. Mol. Sci. 2024, 25(5), 2616; https://doi.org/10.3390/ijms25052616 - 23 Feb 2024

Viewed by 734

Abstract

The APIS Breast Cancer Subtyping Kit is an mRNA-based assessment of the seven parameters including three biomarkers routinely assessed in all the newly diagnosed breast cancers (BC), oestrogen receptor (ER), progesterone receptor (PR) and HER-2 and an additional four genes that create a novel proliferation signature, MKI67, PCNA, CCNA2 and KIF23. Taken together, the data are used to produce a molecular subtype for every sample. The kit was evaluated against the current standard protocol of immunohistochemistry (IHC) and/or in situ hybridisation (ISH) in breast cancer patients. The data were presented at the weekly breast multidisciplinary team (MDT) meeting. A total of 98 consecutive cases of pre-operative breast cancer core biopsies and two core biopsies of nodal metastases yielding 100 cases were assessed. IHC and APIS results were available for 100 and 99 cases. ER was concordant in 97% cases, PR was concordant in 89% and HER-2 results were concordant with IHC/ISH in 100% of the cases. Ki-67 IHC was discordant in 3% of cases when compared with MK167 alone but discordant in 24% when compared with the four-gene proliferation signature. In conclusion, our study indicates that the APIS Breast Cancer Subtyping Kit is highly concordant when compared to the results produced for ER/PR/HER-2 by IHC and/or ISH. The assay could play a role in the routine assessment of newly diagnosed breast cancer (BC) specimens. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment)

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16 pages, 2907 KiB

Open AccessArticle

Unraveling the Angiogenic Puzzle: Pre-Treatment sVEGFR1 and sVEGFR2 Levels as Promising Prognostic Indicators in Early-Stage Breast Cancer Patients

by Elżbieta Zarychta, Kornel Bielawski, Katarzyna Wrzeszcz, Piotr Rhone and Barbara Ruszkowska-Ciastek

Int. J. Mol. Sci. 2023, 24(17), 13508; https://doi.org/10.3390/ijms241713508 - 31 Aug 2023

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Abstract

Despite the advancements in breast cancer (BrC) diagnosis and treatment, a considerable proportion of patients with early-stage disease still experience local recurrence or metastasis. This study aimed to assess the levels of specific angiogenic parameters in the EDTA plasma of BrC patients before and after treatment and to explore their clinical and prognostic significance. The levels of vascular endothelial growth factor A (VEGF-A), soluble form of vascular endothelial growth factor receptor type 1 (sVEGFR1), and soluble form of vascular endothelial growth factor receptor type 2 (sVEGFR2) were measured in 84 early BrC patients, both prior to surgery and within a median time of nine months post-treatment. Prognostic significance was evaluated using Kaplan-Meier survival and Cox regression analyses. Linear regression models were employed to examine the independent impact of selected angiogenic factors on DFS in breast cancer patients. The results of uni- and multivariate analyses indicated that a pre-treatment concentration of sVEGFR1 above 30.99 pg/mL was associated with improved disease-free survival (DFS) (p < 0.0001 for both analyses), while a pre-treatment concentration of sVEGFR2 above 9475.67 pg/mL was associated with an increased risk of BrC relapse (p < 0.0001 for both analyses). Additionally, a post-treatment concentration of sVEGFR2 above 7361.71 pg/mL was associated with better overall survival (OS) based on the Kaplan-Meier survival analysis (p = 0.0141). Furthermore, linear regression models revealed a significant inverse association between pre-treatment levels of sVEGFR1 and the risk of relapse (standardized β −0.2578, p = 0.0499) and a significant positive association of VEGF-A levels with the risk of recurrence (standardized β 0.2958, p = 0.0308). In conclusion, the findings suggest that both pre- and post-treatment levels of sVEGFR1 and sVEGFR2 may hold promise as potential prognostic markers for BrC patients. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment)

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24 pages, 8072 KiB

Open AccessArticle

Identification of Breast Cancer LCK Proto-Oncogene as a Master Regulator of TNBC Neutrophil Enrichment and Polarization

by Fatma Al Qutami, Walaa Al Halabi and Mahmood Y. Hachim

Int. J. Mol. Sci. 2023, 24(17), 13269; https://doi.org/10.3390/ijms241713269 - 26 Aug 2023

Viewed by 1104

Abstract

The role of neutrophils in breast cancer shows that the N1 proinflammatory subtype can suppress and attack the tumor. In contrast, the N2 pro-tumor subtype aids the tumor in its survival, progression, and metastasis. Recently, more focus has been directed to the role of innate myeloid cells, specifically neutrophils, in regulating the responses of lymphoid populations both in the progression of cancer and in response to therapy. However, the exact crosstalk between breast cancer cells and neutrophils is poorly understood. In this work, we used in-silico assays to investigate the role of the bidirectional effect of neutrophils on metastatic TNBC. Our reanalysis of publicly available data reveals that most TNBC’s classified within the CE2 subtype are leukocyte-poor and have four major cell types in their ecotypes: dendritic cells, macrophages, fibroblasts, and epithelial cells. Further immune deconvolution of these patients revealed that a few cells significantly differed between groups, including macrophages, neutrophils, and T cells. All BC showed lower infiltrating neutrophils compared to healthy surrounding tissue. Treated TNBCs improved the count of infiltrating neutrophils in TNBC. Most TNBC patients have a unique CE2 ecotype, characterized by more basal-like epithelial cells, more neutrophils, and fewer mononuclear lymphocytes (B cells, macrophages M1, T cell CD4+ (non-regulatory), and T cell CD8+ and T regs). This can be related to our finding that CE2 TNBCs are characterized by a lower LCK and higher ERBB2, and their top DEGs are related to leukocyte activation and NFKB pathway. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment)

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12 pages, 1791 KiB

Open AccessArticle

Tumor Suppressor Properties of Small C-Terminal Domain Phosphatases in Clear Cell Renal Cell Carcinoma

by George S. Krasnov, Grigory A. Puzanov, Erdem B. Dashinimaev, Khava S. Vishnyakova, Tatiana T. Kondratieva, Yegor S. Chegodaev, Anton Y. Postnov, Vera N. Senchenko and Yegor E. Yegorov

Int. J. Mol. Sci. 2023, 24(16), 12986; https://doi.org/10.3390/ijms241612986 - 19 Aug 2023

Cited by 1 | Viewed by 1204

Abstract

Clear cell renal cell carcinoma (ccRCC) accounts for 80–90% of kidney cancers worldwide. Small C-terminal domain phosphatases CTDSP1, CTDSP2, and CTDSPL (also known as SCP1, 2, 3) are involved in the regulation of several important pathways associated with carcinogenesis. In various cancer types, these phosphatases may demonstrate either antitumor or oncogenic activity. Tumor-suppressive activity of these phosphatases in kidney cancer has been shown previously, but in general case, the antitumor activity may be dependent on the choice of cell line. In the present work, transfection of the Caki-1 cell line (ccRCC morphologic phenotype) with expression constructs containing the coding regions of these genes resulted in inhibition of cell growth in vitro in the case of CTDSP1 (p < 0.001) and CTDSPL (p < 0.05) but not CTDSP2. The analysis of The Cancer Genome Atlas (TCGA) data showed differential expression of some of CTDSP genes and of their target, RB1. These results were confirmed by quantitative RT-PCR using an independent sample of primary ccRCC tumors (n = 52). We observed CTDSPL downregulation and found a positive correlation of expression for two gene pairs: CTDSP1 and CTDSP2 (r_s = 0.76; p < 0.001) and CTDSPL and RB1 (r_s = 0.38; p < 0.05). Survival analysis based on TCGA data demonstrated a strong association of lower expression of CTDSP1, CTDSP2, CTDSPL, and RB1 with poor survival of ccRCC patients (p < 0.001). In addition, according to TCGA, CTDSP1, CTDSP2, and RB1 were differently expressed in two subtypes of ccRCC—ccA and ccB, characterized by different survival rates. These results confirm that CTDSP1 and CTDSPL have tumor suppressor properties in ccRCC and reflect their association with the more aggressive ccRCC phenotype. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment)

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19 pages, 12319 KiB

Open AccessArticle

OLR1 Is a Pan-Cancer Prognostic and Immunotherapeutic Predictor Associated with EMT and Cuproptosis in HNSCC

by Lei Wu, Yuantong Liu, Weiwei Deng, Tianfu Wu, Linlin Bu and Lei Chen

Int. J. Mol. Sci. 2023, 24(16), 12904; https://doi.org/10.3390/ijms241612904 - 17 Aug 2023

Cited by 1 | Viewed by 1850

Abstract

Metabolism plays a critical role in cancer. OLR1 has been implicated in cardiovascular and metabolic disorders, while its association with tumorigenesis and tumor immunity remains poorly defined in the literature. We conducted comprehensive pan-cancer analyses based on the TCGA database to examine OLR1 expression and its prognostic implications. Correlations between OLR1 expression level and tumor immunity and immunotherapy were investigated by immune infiltration, enrichment, and TIDE analysis methods. Immunohistochemistry detected OLR1 expression in HNSCC. We used the GSEA method to explore the potential signaling pathways in which OLR1 is involved, and a correlation analysis to investigate the relationships between OLR1 and epithelial–mesenchymal transition (EMT) and cuproptosis. In addition, the effects of OLR1 knockdown on the EMT process, invasion, stemness, and cuproptosis of HNSCC cells were examined by scratch, Transwell, CCK8, sphere formation, and flow cytometry, while changes in related proteins were detected using the immunoblotting method. OLR1 is highly expressed in most cancers, and it is associated with patient prognosis. OLR1 expression positively correlates with immunosuppressive cell infiltration and immune checkpoint molecules, while being negatively associated with effector T cells. Moreover, significant correlations are observed between OLR1 expression and tumor mutation burden (TMB) and microsatellite instability (MSI) in some cancers. In HNSCC, OLR1 expression is related to advanced clinicopathological factors and unfavorable outcomes. Patients with high OLR1 expression levels are prone to experience immune escape and benefit less from immune checkpoint inhibitor (ICI) therapy. Moreover, OLR1 expression may affect EMT, stemness, and cuproptosis resistance outcomes. OLR1 is an immune-related prognostic biomarker with potential as a prognostic indicator for immunotherapy, and it may also be involved in regulating the EMT process and cuproptosis in HNSCC. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment)

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24 pages, 4601 KiB

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Plasmatic MicroRNAs and Treatment Outcomes of Patients with Metastatic Castration-Resistant Prostate Cancer: A Hospital-Based Cohort Study and In Silico Analysis

by Jani Silva, Valéria Tavares, Ana Afonso, Juliana Garcia, Fátima Cerqueira and Rui Medeiros

Int. J. Mol. Sci. 2023, 24(10), 9101; https://doi.org/10.3390/ijms24109101 - 22 May 2023

Cited by 3 | Viewed by 1720

Abstract

Prostate cancer (PCa) is one of the most common malignancies among men worldwide. Inevitably, all advanced PCa patients develop metastatic castration-resistant prostate cancer (mCRPC), an aggressive phase of the disease. Treating mCRPC is challenging, and prognostic tools are needed for disease management. MicroRNA (miRNA) deregulation has been reported in PCa, constituting potential non-invasive prognostic biomarkers. As such, this study aimed to evaluate the prognostic potential of nine miRNAs in the liquid biopsies (plasma) of mCRPC patients treated with second-generation androgen receptor axis-targeted (ARAT) agents, abiraterone acetate (AbA) and enzalutamide (ENZ). Low expression levels of miR-16-5p and miR-145-5p in mCRPC patients treated with AbA were significantly associated with lower progression-free survival (PFS). The two miRNAs were the only predictors of the risk of disease progression in AbA-stratified analyses. Low miR-20a-5p levels in mCRPC patients with Gleason scores of <8 were associated with worse overall survival (OS). The transcript seems to predict the risk of death regardless of the ARAT agent. According to the in silico analyses, miR-16-5p, miR-145-5p, and miR-20a-5p seem to be implicated in several processes, namely, cell cycle, proliferation, migration, survival, metabolism, and angiogenesis, suggesting an epigenetic mechanism related to treatment outcome. These miRNAs may represent attractive prognostic tools to be used in mCRPC management, as well as a step further in the identification of new potential therapeutic targets, to use in combination with ARAT for an improved treatment outcome. Despite the promising results, real-world validation is necessary. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment)

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Review

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35 pages, 2427 KiB

Open AccessReview

Circulating microRNAs as Potential Biomarkers in Pancreatic Cancer—Advances and Challenges

by Attila A. Seyhan

Int. J. Mol. Sci. 2023, 24(17), 13340; https://doi.org/10.3390/ijms241713340 - 28 Aug 2023

Cited by 7 | Viewed by 2086

Abstract

There is an urgent unmet need for robust and reliable biomarkers for early diagnosis, prognosis, and prediction of response to specific treatments of many aggressive and deadly cancers, such as pancreatic cancer, and liquid biopsy-based miRNA profiling has the potential for this. MiRNAs are a subset of non-coding RNAs that regulate the expression of a multitude of genes post-transcriptionally and thus are potential diagnostic, prognostic, and predictive biomarkers and have also emerged as potential therapeutics. Because miRNAs are involved in the post-transcriptional regulation of their target mRNAs via repressing gene expression, defects in miRNA biogenesis pathway and miRNA expression perturb the expression of a multitude of oncogenic or tumor-suppressive genes that are involved in the pathogenesis of various cancers. As such, numerous miRNAs have been identified to be downregulated or upregulated in many cancers, functioning as either oncomes or oncosuppressor miRs. Moreover, dysregulation of miRNA biogenesis pathways can also change miRNA expression and function in cancer. Profiling of dysregulated miRNAs in pancreatic cancer has been shown to correlate with disease diagnosis, indicate optimal treatment options and predict response to a specific therapy. Specific miRNA signatures can track the stages of pancreatic cancer and hold potential as diagnostic, prognostic, and predictive markers, as well as therapeutics such as miRNA mimics and miRNA inhibitors (antagomirs). Furthermore, identified specific miRNAs and genes they regulate in pancreatic cancer along with downstream pathways can be used as potential therapeutic targets. However, a limited understanding and validation of the specific roles of miRNAs, lack of tissue specificity, methodological, technical, or analytical reproducibility, harmonization of miRNA isolation and quantification methods, the use of standard operating procedures, and the availability of automated and standardized assays to improve reproducibility between independent studies limit bench-to-bedside translation of the miRNA biomarkers for clinical applications. Here I review recent findings on miRNAs in pancreatic cancer pathogenesis and their potential as diagnostic, prognostic, and predictive markers. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment)

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20 pages, 340 KiB

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A Functional Genomics Review of Non-Small-Cell Lung Cancer in Never Smokers

by Mohammad Hamouz, Raneem Y. Hammouz, Muhammad Ahmed Bajwa, Abdelrahman Waleed Alsayed, Magdalena Orzechowska and Andrzej K. Bednarek

Int. J. Mol. Sci. 2023, 24(17), 13314; https://doi.org/10.3390/ijms241713314 - 28 Aug 2023

Cited by 1 | Viewed by 1391

Abstract

There is currently a dearth of information regarding lung cancer in never smokers (LCINS). Additionally, there is a difference in somatic mutations, tumour mutational burden, and chromosomal aberrations between smokers and never smokers (NS), insinuating a different disease entity in LCINS. A better understanding of actionable driver alterations prevalent in LCINS and the genomic landscape will contribute to identifying new molecular targets of relevance for NS that will drastically improve outcomes. Differences in treatment outcomes between NS and smokers, as well as sexes, with NSCLC suggest unique tumour characteristics. Epidermal growth factor receptor (EGFR) tyrosine kinase mutations and echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) gene rearrangements are more common in NS and have been associated with chemotherapy resistance. Moreover, NS are less likely to benefit from immune mediators including PD-L1. Unravelling the genomic and epigenomic underpinnings of LCINS will aid in the development of not only novel targeted therapies but also more refined approaches. This review encompasses driver genes and pathways involved in the pathogenesis of LCINS and a deeper exploration of the genomic landscape and tumour microenvironment. We highlight the dire need to define the genetic and environmental aspects entailing the development of lung cancer in NS. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment)

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17 pages, 1440 KiB

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Hallmarks of the Tumour Microenvironment of Gliomas and Its Interaction with Emerging Immunotherapy Modalities

by Christian A. Linares, Anjana Varghese, Aruni Ghose, Sayali D. Shinde, Sola Adeleke, Elisabet Sanchez, Matin Sheriff, Cyrus Chargari, Elie Rassy and Stergios Boussios

Int. J. Mol. Sci. 2023, 24(17), 13215; https://doi.org/10.3390/ijms241713215 - 25 Aug 2023

Cited by 1 | Viewed by 2064

Abstract

Gliomas are aggressive, primary central nervous system tumours arising from glial cells. Glioblastomas are the most malignant. They are known for their poor prognosis or median overall survival. The current standard of care is overwhelmed by the heterogeneous, immunosuppressive tumour microenvironment promoting immune evasion and tumour proliferation. The advent of immunotherapy with its various modalities—immune checkpoint inhibitors, cancer vaccines, oncolytic viruses and chimeric antigen receptor T cells and NK cells—has shown promise. Clinical trials incorporating combination immunotherapies have overcome the microenvironment resistance and yielded promising survival and prognostic benefits. Rolling these new therapies out in the real-world scenario in a low-cost, high-throughput manner is the unmet need of the hour. These will have practice-changing implications to the glioma treatment landscape. Here, we review the immunobiological hallmarks of the TME of gliomas, how the TME evades immunotherapies and the work that is being conducted to overcome this interplay. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment)

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