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Genes, Environment and Cancer

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 (15 January 2021) | Viewed by 22408

Special Issue Editors

Department of Biology, College of Science and Technology, Temple University, PA, USA 2. Department of Medical Biotechnologies, University of Siena, Italy
Interests: oncology; pathology; genetic epidemiology; cell cycle; epigenetics; bioinformatic and computational biology; mesothelioma; genomics
Special Issues, Collections and Topics in MDPI journals
Department of Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori‐IRCCS‐Fondazione G. Pascale, I‐80131, Napoli, Italy
Interests: mesothelioma; tumor-suppressor genes; environmental pollution; cancer therapy
Department of Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori‐IRCCS‐Fondazione G. Pascale, I‐80131, Napoli, Italy
Interests: mesothelioma; tumor-suppressor genes; oncolytic viruses; cancer therapy

Special Issue Information

Dear Colleagues,

Pollution is known to cause and exacerbate a number of chronic diseases, including cancer. In particular, the genetic and epigenetic susceptibility to cancer actually reinforce the concept of an environmental origin of many cancers. However, there is still a scientific debate as to whether cancer may be caused by the numerous polluting-activity-associated carcinogenic compounds. A clear example of this relationship is represented by malignant mesothelioma (MM). MM is a rare and highly fatal form of cancer of the pleura (or more rarely, peritoneum or pericardium) that is caused by the inhalation of asbestos and other mineral fibers. Most research efforts have focused on occupational exposure to asbestos and have demonstrated their carcinogenicity in animals and humans. However, the role of toxic environmental agents in the genesis of cancers affecting the general population, and the determination of the fraction of overall cancers attributable to pollution, remain issues worth investigation. Therefore, further research will need to explore this and provide a more comprehensive understanding of the problem.

Prof. Antonio Giordano
Dr. Iris Maria Forte
Dr. Antonella Iannuzzi Carmelina
Guest Editors

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Keywords

  • environmental pollution
  • cancer
  • mesothelioma
  • heavy metals
  • sentinel organisms
  • epidemiology
  • environmental factors
  • therapies

Published Papers (7 papers)

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Research

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18 pages, 2452 KiB  
Article
Genetic Variations in Prostaglandin E2 Pathway Identified as Susceptibility Biomarkers for Gastric Cancer in an Intermediate Risk European Country
by Catarina Lopes, Carina Pereira, Mónica Farinha, Rui Medeiros and Mário Dinis-Ribeiro
Int. J. Mol. Sci. 2021, 22(2), 648; https://doi.org/10.3390/ijms22020648 - 11 Jan 2021
Cited by 4 | Viewed by 2391
Abstract
The cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway exerts deleterious pleiotropic effects in inflammation-induced gastric carcinogenesis. We aimed to assess the association of genetic variants in prostaglandin-endoperoxide synthase 2 (PTGS2), ATP binding cassette subfamily C member 4 (ABCC4), [...] Read more.
The cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway exerts deleterious pleiotropic effects in inflammation-induced gastric carcinogenesis. We aimed to assess the association of genetic variants in prostaglandin-endoperoxide synthase 2 (PTGS2), ATP binding cassette subfamily C member 4 (ABCC4), hydroxyprostaglandin dehydrogenase 15-(NAD) (HPGD), and solute carrier organic anion transporter family member 2A1 (SLCO2A1) PGE2 pathway-related genes with gastric cancer (GC) risk in a European Caucasian population. A hospital-based case-control study gathering 260 GC cases and 476 cancer-free controls was implemented. Using a tagSNP approach, 51 single nucleotide polymorphisms (SNPs) were genotyped through MassARRAY® iPLEX Gold Technology or allelic discrimination by real-time polymerase chain reaction (PCR). Homozygous carriers of the minor allele for both rs689466 and rs10935090 SNPs were associated with a 2.98 and 4.30-fold increased risk for GC, respectively (95% confidence interval (CI): 1.14–7.74, p = 0.027; 95% CI: 1.22–15.16, p = 0.026), with the latter also being associated with an anticipated diagnosis age. A multifactor dimensionality reduction analysis identified an overall three-factor best interactive model composed of age, rs689466, and rs1678374 that was associated with a 17.6-fold GC increased risk (95% CI: 11.67–26.48, p < 0.0001, (cross-validation) CV consistency of 8/10 and accuracy of 0.807). In this preliminary study, several tagSNPs in PGE2 pathway-related genes were identified as risk biomarkers for GC development. This approach may help to identify higher-risk individuals and may contribute to the tailoring screening of GC in intermediate-risk European countries. Full article
(This article belongs to the Special Issue Genes, Environment and Cancer)
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13 pages, 606 KiB  
Article
Associations of TIMP-3 Genetic Polymorphisms with EGFR Statuses and Cancer Clinicopathologic Development in Lung Adenocarcinoma Patients
by Jer-Hwa Chang, Tsung-Ching Lai, Po-Jen Yang, Pei-Chun Shih, Yi-Chieh Yang, Kai-Ling Lee, Tu-Chen Liu, Thomas Chang-Yao Tsao, Shun-Fa Yang and Ming-Hsien Chien
Int. J. Mol. Sci. 2020, 21(21), 8023; https://doi.org/10.3390/ijms21218023 - 28 Oct 2020
Cited by 9 | Viewed by 1888
Abstract
Lung adenocarcinoma (LADC) is a major subtype of lung cancer, particularly among populations of East Asia. The epidermal growth factor receptor (EGFR) is the most frequently mutated oncogene promoting LADC progression and can serve as a therapeutic target in LADC. The tissue inhibitor [...] Read more.
Lung adenocarcinoma (LADC) is a major subtype of lung cancer, particularly among populations of East Asia. The epidermal growth factor receptor (EGFR) is the most frequently mutated oncogene promoting LADC progression and can serve as a therapeutic target in LADC. The tissue inhibitor of metalloproteinases (TIMP)-3 is a major regulator of extracellular matrix turnover via targeting of matrix metalloproteinases (MMPs), and thus, plays a critical role in tumor development and progression. The purpose of this study was to investigate potential associations among TIMP-3 genetic polymorphisms, EGFR statuses, and cancer clinicopathologic development in patients with LADC. In this study, 277 LADC patients with different EGFR statuses were recruited to dissect the allelic discrimination of TIMP-3 -1296 T>C (rs9619311), TIMP3 249T>C (rs9862), and TIMP3 261C>T (rs11547635) polymorphisms using a TaqMan allelic discrimination assay. Our data showed that compared to those LADC patients with wild-type CC homozygotes of TIMP-3 rs9862, patients harboring TT homozygotes of rs9862 were at a higher risk of developing mutant EGFR (adjusted odds ratio (AOR) = 2.530; 95% confidence interval (CI): 1.230–5.205; p = 0.012), particularly the EGFR L858R point mutation (AOR = 2.975; 95% CI: 1.182–7.488; p = 0.021). Moreover, we observed that TIMP-3 TT homozygotes of rs9862 were correlated with the incidence of EGFR mutations in patients with a smoking habit (p = 0.045). Within male patients harboring a mutant EGFR, TIMP-3 rs9862 T (CT+TT) allele carriers were at higher risk of developing an advanced stage (p = 0.025) and lymph node metastasis (p = 0.043). Further analyses of clinical datasets revealed correlations of TIMP-3 expression with a favorable prognosis in patients with LADC. In conclusion, the data suggest that TIMP-3 rs9862 polymorphisms may contribute to identify subgroups of lung cancer patients at high risk for tumor progression, among carriers of LADC-bearing mutant EGFR. Full article
(This article belongs to the Special Issue Genes, Environment and Cancer)
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17 pages, 1042 KiB  
Article
An Analysis of Clinical, Surgical, Pathological and Molecular Characteristics of Endometrial Cancer According to Mismatch Repair Status. A Multidisciplinary Approach
by Giulia Dondi, Sara Coluccelli, Antonio De Leo, Simona Ferrari, Elisa Gruppioni, Alessandro Bovicelli, Lea Godino, Camelia Alexandra Coadă, Alessio Giuseppe Morganti, Antonio Giordano, Donatella Santini, Claudio Ceccarelli, Daniela Turchetti, Pierandrea De Iaco and Anna Myriam Perrone
Int. J. Mol. Sci. 2020, 21(19), 7188; https://doi.org/10.3390/ijms21197188 - 29 Sep 2020
Cited by 17 | Viewed by 2784
Abstract
Since 2016, our hospital has applied tumor testing with immunohistochemistry (IHC) in endometrial cancer in order to detect mutations of mismatch repair genes (MMR). All cases with MMR deficiency proteins expression are sent for genetic testing, except those with MLH1 protein deficiency, in [...] Read more.
Since 2016, our hospital has applied tumor testing with immunohistochemistry (IHC) in endometrial cancer in order to detect mutations of mismatch repair genes (MMR). All cases with MMR deficiency proteins expression are sent for genetic testing, except those with MLH1 protein deficiency, in which case genetic testing is performed if negative for promoter hypermethylation. The primary aim of this study was to investigate the ability of our algorithm to identify Lynch syndrome (LS). The Secondary aims were to investigate the relationship between MMR status and clinicopathological features and prognosis of primary endometrial cancer (EC). From January 2016 to December 2018, 239 patients with EC were retrospectively analyzed and subdivided according to MMR status. Patients were divided in three groups: MMR proficient, LS and Lynch-like cancer (LLC). LS was characterized by a lower age and BMI, more use of contraceptive and less use of hormonal replacement therapy, nulliparity and a trend versus a better prognosis. LLC appeared more related to MMR proficient than LS and exhibited a more aggressive behavior. Our multidisciplinary approach permitted a correct diagnosis of germline mutation in patients with newly diagnosis EC and it confirmed clinicopathologic and prognostic characteristics of LS. Full article
(This article belongs to the Special Issue Genes, Environment and Cancer)
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11 pages, 10089 KiB  
Article
Definition of a Novel Plasmid-Based Gene Transfection Protocol of Mammalian Skeletal Muscles by Means of In Vivo Electroporation
by Enrico P. Spugnini, Manuel Scimeca, Bruno Amadio, Giancarlo Cortese, Maurizio Fanciulli, Bruno Vincenzi, Antonio De Luca and Alfonso Baldi
Int. J. Mol. Sci. 2020, 21(18), 6494; https://doi.org/10.3390/ijms21186494 - 05 Sep 2020
Cited by 4 | Viewed by 2883
Abstract
We describe an original electroporation protocol for in vivo plasmid DNA transfection. The right hind limbs of C57 mice are exposed to a specifically designed train of permeabilizing electric pulses by transcutaneous application of tailored needle electrodes, immediately after the injection of pEGFP-C1 [...] Read more.
We describe an original electroporation protocol for in vivo plasmid DNA transfection. The right hind limbs of C57 mice are exposed to a specifically designed train of permeabilizing electric pulses by transcutaneous application of tailored needle electrodes, immediately after the injection of pEGFP-C1 plasmid encoding GFP (Green Fluorescente Protein). The electroporated rodents show a greater GFP expression than the controls at three different time points (4, 10, and 15 days). The electroporated muscles display only mild interstitial myositis, with a significant increase in inflammatory cell infiltrates. Finally, mild gait abnormalities are registered in electroporated mice only in the first 48 h after the treatment. This protocol has proven to be highly efficient in terms of expression levels of the construct, is easy to apply since it does not require surgical exposure of the muscle and is well tolerated by the animals because it does not cause evident morphological and functional damage to the electroporated muscle. Full article
(This article belongs to the Special Issue Genes, Environment and Cancer)
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Review

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22 pages, 844 KiB  
Review
The Urokinase Receptor: A Multifunctional Receptor in Cancer Cell Biology. Therapeutic Implications
by Anna Li Santi, Filomena Napolitano, Nunzia Montuori and Pia Ragno
Int. J. Mol. Sci. 2021, 22(8), 4111; https://doi.org/10.3390/ijms22084111 - 16 Apr 2021
Cited by 35 | Viewed by 3088
Abstract
Proteolysis is a key event in several biological processes; proteolysis must be tightly controlled because its improper activation leads to dramatic consequences. Deregulation of proteolytic activity characterizes many pathological conditions, including cancer. The plasminogen activation (PA) system plays a key role in cancer; [...] Read more.
Proteolysis is a key event in several biological processes; proteolysis must be tightly controlled because its improper activation leads to dramatic consequences. Deregulation of proteolytic activity characterizes many pathological conditions, including cancer. The plasminogen activation (PA) system plays a key role in cancer; it includes the serine-protease urokinase-type plasminogen activator (uPA). uPA binds to a specific cellular receptor (uPAR), which concentrates proteolytic activity at the cell surface, thus supporting cell migration. However, a large body of evidence clearly showed uPAR involvement in the biology of cancer cell independently of the proteolytic activity of its ligand. In this review we will first describe this multifunctional molecule and then we will discuss how uPAR can sustain most of cancer hallmarks, which represent the biological capabilities acquired during the multistep cancer development. Finally, we will illustrate the main data available in the literature on uPAR as a cancer biomarker and a molecular target in anti-cancer therapy. Full article
(This article belongs to the Special Issue Genes, Environment and Cancer)
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15 pages, 1338 KiB  
Review
Tumor Hypoxia and Circulating Tumor Cells
by Walter Tinganelli and Marco Durante
Int. J. Mol. Sci. 2020, 21(24), 9592; https://doi.org/10.3390/ijms21249592 - 16 Dec 2020
Cited by 16 | Viewed by 3019
Abstract
Circulating tumor cells (CTCs) are a rare tumor cell subpopulation induced and selected by the tumor microenvironment’s extreme conditions. Under hypoxia and starvation, these aggressive and invasive cells are able to invade the lymphatic and circulatory systems. Escaping from the primary tumor, CTCs [...] Read more.
Circulating tumor cells (CTCs) are a rare tumor cell subpopulation induced and selected by the tumor microenvironment’s extreme conditions. Under hypoxia and starvation, these aggressive and invasive cells are able to invade the lymphatic and circulatory systems. Escaping from the primary tumor, CTCs enter into the bloodstream to form metastatic deposits or re-establish themselves in cancer’s primary site. Although radiotherapy is widely used to cure solid malignancies, it can promote metastasis. Radiation can disrupt the primary tumor vasculature, increasing the dissemination of CTCs. Radiation also induces epithelial–mesenchymal transition (EMT) and eliminates suppressive signaling, causing the proliferation of existent, but previously dormant, disseminated tumor cells (DTCs). In this review, we collect the results and evidence underlying the molecular mechanisms of CTCs and DTCs and the effects of radiation and hypoxia in developing these cells. Full article
(This article belongs to the Special Issue Genes, Environment and Cancer)
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17 pages, 2689 KiB  
Review
Progression-Free Survival and Overall Survival of CDK 4/6 Inhibitors Plus Endocrine Therapy in Metastatic Breast Cancer: A Systematic Review and Meta-Analysis
by Michela Piezzo, Paolo Chiodini, Maria Riemma, Stefania Cocco, Roberta Caputo, Daniela Cianniello, Germira Di Gioia, Vincenzo Di Lauro, Francesca Di Rella, Giuseppina Fusco, Giovanni Iodice, Francesco Nuzzo, Carmen Pacilio, Matilde Pensabene and Michelino De Laurentiis
Int. J. Mol. Sci. 2020, 21(17), 6400; https://doi.org/10.3390/ijms21176400 - 03 Sep 2020
Cited by 50 | Viewed by 5513
Abstract
The introduction of CDK4/6 inhibitors in combination with endocrine therapy (ET) represents the most relevant advance in the management of hormone receptor (HR) positive, HER2-negative metastatic breast cancer over the last few years. This meta-analysis of randomized controlled trials (RCTs) is aimed to [...] Read more.
The introduction of CDK4/6 inhibitors in combination with endocrine therapy (ET) represents the most relevant advance in the management of hormone receptor (HR) positive, HER2-negative metastatic breast cancer over the last few years. This meta-analysis of randomized controlled trials (RCTs) is aimed to better characterize the efficacy of CDK4/6 inhibitors in some relevant subgroups and to test heterogeneity between different compounds with a particular focus on their ability to improve overall survival (OS). Pooled estimates of hazard ratios (HRs) were computed for progression-free survival (PFS), OS, and objective response rate (ORR) analysis in predefined subgroups to better understand treatment effect concerning specific patients’ characteristics. To estimate the absolute benefit in terms of PFS, pooled survival curves were generated by pooling the data of all trials. A total of eight RCTs were included. Adding a CDK4/6 inhibitor to ET is beneficial in terms of PFS, irrespective of the presence or not of visceral metastases, the number of metastatic sites, and the length of the treatment-free interval (TFI). The addition of CDK4/6 inhibitors produces a significant OS improvement, both in aromatase inhibitor (AI)-sensitive (HR 0.75, 95% CI) and AI-resistant patients (HR 0.77, 95% CI [0.67–0.89]). Pooled data from each single drug show that palbociclib remains the only class member not showing a statistically significant HR for OS (HR 0.83, 95% CI [0.68–1.02]). Full article
(This article belongs to the Special Issue Genes, Environment and Cancer)
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