Optimisation of Therapeutic Targets in Obesity, Inflammation, and Cancers

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 28313

Special Issue Editor

Lecturer in Health Sciences, College of Nursing and Health Sciences, Flinders University of South Australia, Adelaide 5001, Australia
Interests: breast cancer; oesophageal adenocarcinoma; oestrogen receptors; sphingolipids; breast cancer stem cells
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Inflammation is not only the key defence mechanism for the elimination of harmful microorganisms and particles, but also a regulatory process for maintaining internal homeostasis, initiation of differentiation and healing, and anticancer surveillance. Dysbalanced immune responses are linked to obesity and cancer progression. Obesity and other metabolic abnormalities are characterised by a low level of persistent inflammation which can facilitate cancer initiation and support tumorigenesis. Elevated levels of pro-inflammatory markers in elderly patients have also been detected and defined as “inflammageing”, the condition which is associated with increased cancer morbidity and mortality. Therefore, priming of patients’ immune responses against cancer pathogenesis is a promising strategy in ageing and/or obese populations. Furthermore, the convergence of intracellular mechanisms of cancer progression, inflammation, and metabolic transformation has been detected, suggesting that novel anticancer strategies should target key effectors responsible for regulation of both metabolism and immune system responses.

This Special Issue of Cancers focuses on novel anticancer methodologies, including nanomedicine, designed for multifactorial targeting of tumorigenesis, inhibiting obesity- and inflammation-related targets. Original research papers, idea-provoking reviews, case reports, and opinion papers that discuss identification and optimisation of both cancer-linked inflammatory and metabolic targets are invited.

Dr. Olga Sukocheva
Guest Editor

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Keywords

  • inflammation
  • cancer
  • immune surveillance
  • immunoageing
  • obesity
  • metabolic transformation
  • tumour microenvironment
  • cytokine
  • cell plasticity
  • tumour progression
  • TNFalpha

Published Papers (10 papers)

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Research

Jump to: Review, Other

26 pages, 7620 KiB  
Article
Vitamin D3 Inhibits the Viability of Breast Cancer Cells In Vitro and Ehrlich Ascites Carcinomas in Mice by Promoting Apoptosis and Cell Cycle Arrest and by Impeding Tumor Angiogenesis
by Prashanth Kumar M. Veeresh, Chaithanya G. Basavaraju, Siva Dallavalasa, Preethi G. Anantharaju, Suma M. Natraj, Olga A. Sukocheva and SubbaRao V. Madhunapantula
Cancers 2023, 15(19), 4833; https://doi.org/10.3390/cancers15194833 - 2 Oct 2023
Cited by 2 | Viewed by 2405
Abstract
The incidence of aggressive and resistant breast cancers is growing at alarming rates, indicating a necessity to develop better treatment strategies. Recent epidemiological and preclinical studies detected low serum levels of vitamin D in cancer patients, suggesting that vitamin D may be effective [...] Read more.
The incidence of aggressive and resistant breast cancers is growing at alarming rates, indicating a necessity to develop better treatment strategies. Recent epidemiological and preclinical studies detected low serum levels of vitamin D in cancer patients, suggesting that vitamin D may be effective in mitigating the cancer burden. However, the molecular mechanisms of vitamin D3 (cholecalciferol, vit-D3)-induced cancer cell death are not fully elucidated. The vit-D3 efficacy of cell death activation was assessed using breast carcinoma cell lines in vitro and a widely used Ehrlich ascites carcinoma (EAC) breast cancer model in vivo in Swiss albino mice. Both estrogen receptor-positive (ER+, MCF-7) and -negative (ER-, MDA-MB-231, and MDA-MB-468) cell lines absorbed about 50% of vit-D3 in vitro over 48 h of incubation. The absorbed vit-D3 retarded the breast cancer cell proliferation in a dose-dependent manner with IC50 values ranging from 0.10 to 0.35 mM. Prolonged treatment (up to 72 h) did not enhance vit-D3 anti-proliferative efficacy. Vit-D3-induced cell growth arrest was mediated by the upregulation of p53 and the downregulation of cyclin-D1 and Bcl2 expression levels. Vit-D3 retarded cell migration and inhibited blood vessel growth in vitro as well as in a chorioallantoic membrane (CAM) assay. The intraperitoneal administration of vit-D3 inhibited solid tumor growth and reduced body weight gain, as assessed in mice using a liquid tumor model. In summary, vit-D3 cytotoxic effects in breast cancer cell lines in vitro and an EAC model in vivo were associated with growth inhibition, the induction of apoptosis, cell cycle arrest, and the impediment of angiogenic processes. The generated data warrant further studies on vit-D3 anti-cancer therapeutic applications. Full article
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11 pages, 2807 KiB  
Article
Cardiovascular Effects of Cumulative Doses of Radioiodine in Differentiated Thyroid Cancer Patients with Type 2 Diabetes Mellitus
by Adina Elena Stanciu, Marcel Marian Stanciu, Anca Zamfirescu and Dan Cristian Gheorghe
Cancers 2022, 14(10), 2359; https://doi.org/10.3390/cancers14102359 - 10 May 2022
Cited by 2 | Viewed by 1494
Abstract
Radioiodine (131I) therapy for differentiated thyroid cancer (DTC) involves exposure of the whole body, including the heart, to ionizing radiation. This exposure to the subsequent risk of heart disease is uncertain, especially in patients with DTC associated with type 2 diabetes [...] Read more.
Radioiodine (131I) therapy for differentiated thyroid cancer (DTC) involves exposure of the whole body, including the heart, to ionizing radiation. This exposure to the subsequent risk of heart disease is uncertain, especially in patients with DTC associated with type 2 diabetes mellitus (DTC/+T2DM). The current study aimed to assess the relationship between left ventricular ejection fraction (LVEF), high cumulative 131I dose, and peripheral blood parameters in patients with DTC/−T2DM and DTC/+T2DM. The study enrolled 72 female patients with DTC/−T2DM and 24 with DTC/+T2DM who received cumulative 131I doses above 150 mCi (5.55 GBq). LVEF was lower in patients with concomitant T2DM than those without (p < 0.001). The cumulative 131I dosage was inversely correlated with LVEF only in DTC/−T2DM patients (r = −0.57, p < 0.001). In the DTC/+T2DM group, LVEF was negatively associated with absolute platelet count (r = −0.67, p < 0.001) and platelet-to-lymphocyte ratio (r = −0.76, p < 0.001). Our results demonstrate that exposure to high cumulative 131I doses has different cardiovascular effects in DTC/−T2DM and DTC/+T2DM. Full article
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16 pages, 2978 KiB  
Article
Oestrogen Receptor Isoforms May Represent a Therapeutic Target in Oesophageal Adenocarcinoma
by Steven L. Due, David I. Watson, Isabell Bastian, Ann-Kathrin Eichelmann and Damian J. Hussey
Cancers 2022, 14(8), 1891; https://doi.org/10.3390/cancers14081891 - 8 Apr 2022
Viewed by 1511
Abstract
Oesophageal adenocarcinoma is a rapidly increasing problem in which treatment options are limited. Previous studies have shown that oesophageal adenocarcinoma cells and tissues express oestrogen receptors (ERs) and show growth suppression and apoptosis in response to ER modulator agents such as tamoxifen. ERs [...] Read more.
Oesophageal adenocarcinoma is a rapidly increasing problem in which treatment options are limited. Previous studies have shown that oesophageal adenocarcinoma cells and tissues express oestrogen receptors (ERs) and show growth suppression and apoptosis in response to ER modulator agents such as tamoxifen. ERs are known to be expressed in a number of isoforms that act together to regulate cell growth and cell death. In this study, we used western blotting to profile the expression of ERα and ERβ isoforms, and expression of the oncologically related molecules p53, HER2, and EGFR, in a panel of oesophageal adenocarcinoma cell lines. The cytotoxicity of tamoxifen in the cell lines was determined with Annexin V-FITC flow cytometry, and correlations between cytotoxicity and receptor expression were assessed using Spearman’s rank-order correlation. Oesophageal adenocarcinoma cell lines showed varying cytotoxicity in response to tamoxifen. The ER species ERα90, ERα50, and ERα46, as well as p53, were positively associated with a cytotoxic response. Conversely, ERα74, ERα70, and ERβ54 were associated with a lack of cytotoxic response. The ER species detected in oesophageal adenocarcinoma cells may work together to confer sensitivity to ER modulators in this disease, which could open up a new avenue for therapy in selected patients. Full article
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16 pages, 2593 KiB  
Article
Increased Sensitivity of Detection of RASSF1A and GSTP1 DNA Fragments in Serum of Prostate Cancer Patients: Optimisation of Diagnostics Using OBBPA-ddPCR
by Markus Friedemann, Friederike Horn, Katharina Gutewort, Lars Tautz, Carsten Jandeck, Nicole Bechmann, Olga Sukocheva, Manfred P. Wirth, Susanne Fuessel and Mario Menschikowski
Cancers 2021, 13(17), 4459; https://doi.org/10.3390/cancers13174459 - 4 Sep 2021
Cited by 6 | Viewed by 2552
Abstract
Identification of aberrant DNA methylation is a promising tool in prostate cancer (PCa) diagnosis and treatment. In this study, we evaluated a two-step method named optimised bias-based preamplification followed by digital PCR (OBBPA-dPCR). The method was used to identify promoter hypermethylation of 2 [...] Read more.
Identification of aberrant DNA methylation is a promising tool in prostate cancer (PCa) diagnosis and treatment. In this study, we evaluated a two-step method named optimised bias-based preamplification followed by digital PCR (OBBPA-dPCR). The method was used to identify promoter hypermethylation of 2 tumour suppressor genes RASSF1A and GSTP1 in the circulating cell-free DNA (cfDNA) from serum samples of PCa patients (n = 75), benign prostatic hyperplasia (BPH, n = 58), and healthy individuals (controls, n = 155). The PCa cohort was further subdivided into subgroups comprising (I) patients with Gleason Scores (GS) ≤ 7 (n = 55), (II) GS ≥ 8 (n = 10), and (III) patients with metastatic PCa diagnosis (n = 10). We found that RASSF1A methylation levels were significantly increased in all 3 PCa subgroups compared to the controls and BPH cohorts (p < 0.01 for all comparisons). Fractional abundances of methylated GSTP1 DNA fragments were significantly increased in subgroup III of metastatic PCa patients (p < 0.001). RASSF1A methylation analysis was found to be beneficial as a complementary biomarker where further diagnostic validation is most crucial. In combination with free PSA, RASSF1A methylation status helps to identify PCa patients with GS ≥ 8 and grey-zone total PSA values between 2–10 ng/mL. In our study, PCR biases between 80–90% were sufficient to detect minute amounts of tumour DNA with high signal-to-noise ratios as well as high analytical sensitivity and specificity. Both RASSF1A and GSTP1 exhibited strongly increased DNA methylation levels in all metastatic PCa patients. Our data indicates a superior sensitivity of epigenetic biomarker analyses in early detection of PCa metastases that should also help to improve PCa therapy. Full article
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22 pages, 30545 KiB  
Article
Control of Skeletal Muscle Atrophy Associated to Cancer or Corticosteroids by Ceramide Kinase
by Federica Pierucci, Alessia Frati, Chiara Battistini, Fabio Penna, Paola Costelli and Elisabetta Meacci
Cancers 2021, 13(13), 3285; https://doi.org/10.3390/cancers13133285 - 30 Jun 2021
Cited by 11 | Viewed by 3210
Abstract
Apart from cytokines and chemokines, sphingolipid mediators, particularly sphingosine-1-phosphate (S1P) and ceramide 1-phosphate (C1P), contribute to cancer and inflammation. Cancer, as well as other inflammatory conditions, are associated with skeletal muscle (SkM) atrophy, which is characterized by the unbalance between protein synthesis and [...] Read more.
Apart from cytokines and chemokines, sphingolipid mediators, particularly sphingosine-1-phosphate (S1P) and ceramide 1-phosphate (C1P), contribute to cancer and inflammation. Cancer, as well as other inflammatory conditions, are associated with skeletal muscle (SkM) atrophy, which is characterized by the unbalance between protein synthesis and degradation. Although the signaling pathways involved in SkM mass wasting are multiple, the regulatory role of simple sphingolipids is limited. Here, we report the impairment of ceramide kinase (CerK), the enzyme responsible for the phosphorylation of ceramide to C1P, associated with the accomplishment of atrophic phenotype in various experimental models of SkM atrophy: in vivo animal model bearing the C26 adenocarcinoma or Lewis lung carcinoma tumors, in human and murine SkM cells treated with the conditioned medium obtained from cancer cells or with the glucocorticoid dexamethasone. Notably, we demonstrate in all the three experimental approaches a drastic decrease of CerK expression. Gene silencing of CerK promotes the up-regulation of atrogin-1/MAFbx expression, which was also observed after cell treatment with C8-ceramide, a biologically active ceramide analogue. Conversely, C1P treatment significantly reduced the corticosteroid’s effects. Altogether, these findings provide evidence that CerK, acting as a molecular modulator, may be a new possible target for SkM mass regulation associated with cancer or corticosteroids. Full article
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Review

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25 pages, 1188 KiB  
Review
Targeting Chronic Inflammation of the Digestive System in Cancer Prevention: Modulators of the Bioactive Sphingolipid Sphingosine-1-Phosphate Pathway
by Eileen M. McGowan, Yiguang Lin and Size Chen
Cancers 2022, 14(3), 535; https://doi.org/10.3390/cancers14030535 - 21 Jan 2022
Cited by 10 | Viewed by 2639
Abstract
Incidence of gastrointestinal (GI) cancers is increasing, and late-stage diagnosis makes these cancers difficult to treat. Chronic and low-grade inflammation are recognized risks for most GI cancers. The GI mucosal immune system maintains healthy homeostasis and signalling molecules made from saturated fats, bioactive [...] Read more.
Incidence of gastrointestinal (GI) cancers is increasing, and late-stage diagnosis makes these cancers difficult to treat. Chronic and low-grade inflammation are recognized risks for most GI cancers. The GI mucosal immune system maintains healthy homeostasis and signalling molecules made from saturated fats, bioactive sphingolipids, play essential roles in healthy GI immunity. Sphingosine-1-phosphate (S1P), a bioactive sphingolipid, is a key mediator in a balanced GI immune response. Disruption in the S1P pathway underlies systemic chronic metabolic inflammatory disorders, including diabetes and GI cancers, providing a strong rationale for using modulators of the S1P pathway to treat pathological inflammation. Here, we discuss the effects of bioactive sphingolipids in immune homeostasis with a focus on S1P in chronic low-grade inflammation associated with increased risk of GI carcinogenesis. Contemporary information on S1P signalling involvement in cancers of the digestive system, from top to bottom, is reviewed. Further, we discuss the use of novel S1P receptor modulators currently in clinical trials and their potential as first-line drugs in the clinic for chronic inflammatory diseases. Recently, ozanimod (ZeposiaTM) and etrasimod have been approved for clinical use to treat ulcerative colitis and eosinophilic oesophagitis, respectively, which may have longer term benefits in reducing risk of GI cancers. Full article
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41 pages, 4153 KiB  
Review
Therapeutic Influence on Important Targets Associated with Chronic Inflammation and Oxidative Stress in Cancer Treatment
by Margarita Neganova, Junqi Liu, Yulia Aleksandrova, Sergey Klochkov and Ruitai Fan
Cancers 2021, 13(23), 6062; https://doi.org/10.3390/cancers13236062 - 1 Dec 2021
Cited by 34 | Viewed by 4469
Abstract
Chronic inflammation and oxidative stress are the interconnected pathological processes, which lead to cancer initiation and progression. The growing level of oxidative and inflammatory damage was shown to increase cancer severity and contribute to tumor spread. The overproduction of reactive oxygen species (ROS), [...] Read more.
Chronic inflammation and oxidative stress are the interconnected pathological processes, which lead to cancer initiation and progression. The growing level of oxidative and inflammatory damage was shown to increase cancer severity and contribute to tumor spread. The overproduction of reactive oxygen species (ROS), which is associated with the reduced capacity of the endogenous cell defense mechanisms and/or metabolic imbalance, is the main contributor to oxidative stress. An abnormal level of ROS was defined as a predisposing factor for the cell transformation that could trigger pro-oncogenic signaling pathways, induce changes in gene expression, and facilitate accumulation of mutations, DNA damage, and genomic instability. Additionally, the activation of transcription factors caused by a prolonged oxidative stress, including NF-κB, p53, HIF1α, etc., leads to the expression of several genes responsible for inflammation. The resulting hyperactivation of inflammatory mediators, including TNFα, TGF-β, interleukins, and prostaglandins can contribute to the development of neoplasia. Pro-inflammatory cytokines were shown to trigger adaptive reactions and the acquisition of resistance by tumor cells to apoptosis, while promoting proliferation, invasion, and angiogenesis. Moreover, the chronic inflammatory response leads to the excessive production of free radicals, which further aggravate the initiated reactions. This review summarizes the recent data and progress in the discovery of mechanisms that associate oxidative stress and chronic inflammation with cancer onset and metastasis. In addition, the review provides insights for the development of therapeutic approaches and the discovery of natural substances that will be able to simultaneously inhibit several key oncological and inflammation-related targets. Full article
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16 pages, 287 KiB  
Review
Dosimetry, Efficacy, Safety, and Cost-Effectiveness of Proton Therapy for Non-Small Cell Lung Cancer
by Bin Qiu, Yu Men, Junjie Wang and Zhouguang Hui
Cancers 2021, 13(18), 4545; https://doi.org/10.3390/cancers13184545 - 10 Sep 2021
Cited by 1 | Viewed by 2138
Abstract
Non-small cell lung cancer (NSCLC) is the most common malignancy which requires radiotherapy (RT) as an important part of its multimodality treatment. With the advent of the novel irradiation technique, the clinical outcome of NSCLC patients who receive RT has been dramatically improved. [...] Read more.
Non-small cell lung cancer (NSCLC) is the most common malignancy which requires radiotherapy (RT) as an important part of its multimodality treatment. With the advent of the novel irradiation technique, the clinical outcome of NSCLC patients who receive RT has been dramatically improved. The emergence of proton therapy, which allows for a sharper dose of build-up and drop-off compared to photon therapy, has potentially improved clinical outcomes of NSCLC. Dosimetry studies have indicated that proton therapy can significantly reduce the doses for normal organs, especially the lung, heart, and esophagus while maintaining similar robust target volume coverage in both early and advanced NSCLC compared with photon therapy. However, to date, most studies have been single-arm and concluded no significant changes in the efficacy for early-stage NSCLC by proton therapy over stereotactic body radiation therapy (SBRT). The results of proton therapy for advanced NSCLC in these studies were promising, with improved clinical outcomes and reduced toxicities compared with historical photon therapy data. However, these studies were also mainly single-arm and lacked a direct comparison between the two therapies. Currently, there is much emerging evidence focusing on dosimetry, efficacy, safety, and cost-effectiveness of proton therapy for NSCLC that has been published, however, a comprehensive review comparing these therapies is, to date, lacking. Thus, this review focuses on these aspects of proton therapy for NSCLC. Full article
16 pages, 21180 KiB  
Review
Stereotactic Ablative Brachytherapy: Recent Advances in Optimization of Radiobiological Cancer Therapy
by Hui Xue, Bin Qiu, Hao Wang, Ping Jiang, Olga Sukocheva, Ruitai Fan, Lixiang Xue and Junjie Wang
Cancers 2021, 13(14), 3493; https://doi.org/10.3390/cancers13143493 - 12 Jul 2021
Cited by 6 | Viewed by 3619
Abstract
Brachytherapy (BT), a type of focal anti-cancer radiotherapy, delivers a highly focused radiation dose to localized tumors, sparing surrounding normal tissues. Recent technological advances have helped to increase the accuracy of BT and, thus, improve BT-based cancer treatment. Stereotactic ablative brachytherapy (SABT) was [...] Read more.
Brachytherapy (BT), a type of focal anti-cancer radiotherapy, delivers a highly focused radiation dose to localized tumors, sparing surrounding normal tissues. Recent technological advances have helped to increase the accuracy of BT and, thus, improve BT-based cancer treatment. Stereotactic ablative brachytherapy (SABT) was designed to improve the ablative effect of radiation, which was achieved via improved image guidance, and calculation of ablative dose, shorter treatment duration, and better organ preservation. Recently collected data characterized SABT as having the potential to cure various early-stage cancers. The method provides higher tumor control rate levels that were previously achievable only by surgical resection. Notably, SABT is suitable for application with unresectable malignancies. However, the pathological assessment of SABT irradiated tumors is limited due to difficulties in specimen acquisition. Prostate, lung, liver, and gynecological cancers are the most commonly reported SABT-treated malignancies. This study will give an overview of SABT, focusing on the advances in SABT optimization, and provide insights on the future benefits of the combined application of SABT with cancer immunotherapies. Full article
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Other

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10 pages, 865 KiB  
Obituary
Health Science Community Will Miss This Bright and Uniting Star: In Memory of Professor Gjumrakch Aliev, M.D, Ph.D.
by Vladimir N. Chubarev, Narasimha M. Beeraka, Mikhail Y. Sinelnikov, Kirill V. Bulygin, Vladimir N. Nikolenko, Elizaveta Mihaylenko, Vadim V. Tarasov, Liudmila M. Mikhaleva, Palmiro Poltronieri, Vijaya Padma Viswanadha, Siva G. Somasundaram, Cecil E. Kirkland, Kuo Chen, Junqi Liu, Ruitai Fan, Mohammad Amjad Kamal, Alexander A. Mironov, SubbaRao V. Madhunapantula, Etheresia Pretorius, Sergey V. Dindyaev, Cristian Muresanu and Olga A. Sukochevaadd Show full author list remove Hide full author list
Cancers 2021, 13(8), 1965; https://doi.org/10.3390/cancers13081965 - 19 Apr 2021
Cited by 2 | Viewed by 2825
Abstract
It is with deep sadness that we offer our memorial on the unexpected demise of our dear colleague, Professor Gjumrakch Aliev [...] Full article
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