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Inflammation and Cancer 2021

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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 May 2022) | Viewed by 38882

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Special Issue Editors

Dr. Michihiro Mutoh

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Guest Editor

1. Department of Molecular-Targeting Prevention, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
2. Epidemiology and Prevention Division, Center for Public Health Sciences, National Cancer Center, Tokyo 104-0045, Japan
Interests: cancer prevention; animal models; translational research
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Takuji Tanaka

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Guest Editor

Department of Diagnostic Pathology and Research Center of Diagnostic Pathology, Gifu Municipal Hospital, 7-1 Kashima-cho, Gifu 500-8513, Japan
Interests: colorectal carcinogenesis; cancer chemiprevention; inflammatory bowel disease; ulcerative colitis; Crohn’s disease; animal model
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Masahito Shimizu

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Guest Editor

First Department of Internal Medicine, Gifu University Hospital, Gifu 501-1194, Japan
Interests: liver carcinogenesis; cancer chemoprevention; chronic hepatitis; metabolic syndrome; retinoid; phytochemicals; clinical trial
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Based on the data that are now available in the GLOBOCAN series of the IARC, there were 14.1 million new cases of cancer and 8.2 million cancer deaths in 2012. Among epithelial malignancies, some cancers have strong links to chronic inflammation and develop in the background of uncontrolled chronic inflammation.

Recent scientific advances have greatly contributed to the dissection of the complex molecular and cellular pathways involved in the connection between cancer and inflammation. The decreased incidence of tumors in individuals who have used non-steroidal anti-inflammatory drugs is supportive of certain role for inflammation in cancer susceptibility. Inflammatory cells and mediators are essential components in the tumor microenvironment and play decisive roles in the initiation, promotion and progression of cancer, including epithelial-to-mesenchymal transition (EMT) and metastasis.

Activation of inflammasomes, which are large protein complexes, plays a critical role during inflammation by producing cytokines. The activation of inflammasomes plays diverse and sometimes contrasting roles in cancer promotion and therapy, depending on the specific context. Recent studies have shown that autophagy, an intracellular degradation system associated with maintenance of cellular homeostasis, plays a key role in inflammasome inactivation. Meanwhile, autophagy is induced upon progression of various human cancers to metastasis. Thus, major players in inflammation may be a double-edged sword for carcinogenesis. In this context, appropriate strategies will be required to prevent cancer.

In light of this, this Special Issue, entitled “Inflammation and Cancer 2021”, is well-timed to say the least, and provides a practical appreciation for the many biochemical, molecular, immunological, and cellular mechanisms shared by cancer and inflammatory processes.

Dr. Michihiro Mutoh
Prof. Dr. Takuji Tanaka
Prof. Dr. Masahito Shimizu
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

Inflammation
cytokines
gut microbiota
insulin resistance
molecular biology
autophagy
epithelial-to-mesenchymal transition (EMT)
tumor microenvironment

Related Special Issues

Inflammation and Cancer in International Journal of Molecular Sciences (15 articles)
Inflammation and Cancer 2018 in International Journal of Molecular Sciences (10 articles)
Inflammation and Cancer 2023 in International Journal of Molecular Sciences (5 articles)

Published Papers (11 papers)

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Research

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17 pages, 4111 KiB

Open AccessArticle

A Small Molecule That Promotes Cellular Senescence Prevents Fibrogenesis and Tumorigenesis

by Moon Kee Meang, Saesbyeol Kim, Ik-Hwan Kim, Han-Soo Kim and Byung-Soo Youn

Int. J. Mol. Sci. 2022, 23(12), 6852; https://doi.org/10.3390/ijms23126852 - 20 Jun 2022

Cited by 1 | Viewed by 2715

Abstract

Uncontrolled proliferative diseases, such as fibrosis or cancer, can be fatal. We previously found that a compound containing the chromone scaffold (CS), ONG41008, had potent antifibrogenic effects associated with EMT or cell-cycle control resembling tumorigenesis. We investigated the effects of ONG41008 on tumor cells and compared these effects with those in pathogenic myofibroblasts. Stimulation of A549 (lung carcinoma epithelial cells) or PANC1 (pancreatic ductal carcinoma cells) with ONG41008 resulted in robust cellular senescence, indicating that dysregulated cell proliferation is common to fibrotic cells and tumor cells. The senescence was followed by multinucleation, a manifestation of mitotic slippage. There was significant upregulation of expression and rapid nuclear translocation of p-TP53 and p16 in the treated cancer cells, which thereafter died after 72 h confirmed by 6 day live imaging. ONG41008 exhibited a comparable senogenic potential to that of dasatinib. Interestingly, ONG41008 was only able to activate caspase-3, 7 in comparison with quercetin and fisetin, also containing CS in PANC1. ONG41008 did not seem to be essentially toxic to normal human lung fibroblasts or primary prostate epithelial cells, suggesting ONG41008 can distinguish the intracellular microenvironment between normal cells and aged or diseased cells. This effect might occur as a result of the increased NAD/NADH ratio, because ONG41008 restored this important metabolic ratio in cancer cells. Taken together, this is the first study to demonstrate that a small molecule can arrest uncontrolled proliferation during fibrogenesis or tumorigenesis via both senogenic and senolytic potential. ONG41008 could be a potential drug for a broad range of fibrotic or tumorigenic diseases. Full article

(This article belongs to the Special Issue Inflammation and Cancer 2021)

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12 pages, 4467 KiB

Open AccessArticle

γH2AX, a DNA Double-Strand Break Marker, Correlates with PD-L1 Expression in Smoking-Related Lung Adenocarcinoma

by Eiko Sakurai, Hisato Ishizawa, Yuka Kiriyama, Ayano Michiba, Yasushi Hoshikawa and Tetsuya Tsukamoto

Int. J. Mol. Sci. 2022, 23(12), 6679; https://doi.org/10.3390/ijms23126679 - 15 Jun 2022

Cited by 4 | Viewed by 1603

Abstract

In recent years, the choice of immune checkpoint inhibitors (ICIs) as a treatment based on high expression of programmed death-ligand 1 (PD-L1) in lung cancers has been increasing in prevalence. The high expression of PD-L1 could be a predictor of ICI efficacy as well as high tumor mutation burden (TMB), which is determined using next-generation sequencing (NGS). However, a great deal of effort is required to perform NGS to determine TMB. The present study focused on γH2AX, a double-strand DNA break marker, and the suspected positive relation between TMB and γH2AX was investigated. We assessed the possibility of γH2AX being an alternative marker of TMB or PD-L1. One hundred formalin-fixed, paraffin-embedded specimens of lung cancer were examined. All of the patients in the study received thoracic surgery, having been diagnosed with lung adenocarcinoma or squamous cell carcinoma. The expressions of γH2AX and PD-L1 (clone: SP142) were evaluated immunohistochemically. Other immunohistochemical indicators, p53 and Ki-67, were also used to estimate the relationships of γH2AX. Positive relationships between γH2AX and PD-L1 were proven, especially in lung adenocarcinoma. Tobacco consumption was associated with higher expression of γH2AX, PD-L1, Ki-67, and p53. In conclusion, the immunoexpression of γH2AX could be a predictor for the adaptation of ICIs as well of as PD-L1 and TMB. Full article

(This article belongs to the Special Issue Inflammation and Cancer 2021)

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17 pages, 6084 KiB

Open AccessArticle

Fucoxanthin Prevents Pancreatic Tumorigenesis in C57BL/6J Mice That Received Allogenic and Orthotopic Transplants of Cancer Cells

by Wataru Murase, Yukino Kamakura, Serina Kawakami, Ayaka Yasuda, Momoka Wagatsuma, Atsuhito Kubota, Hiroyuki Kojima, Tohru Ohta, Mami Takahashi, Michihiro Mutoh, Takuji Tanaka, Hayato Maeda, Kazuo Miyashita and Masaru Terasaki

Int. J. Mol. Sci. 2021, 22(24), 13620; https://doi.org/10.3390/ijms222413620 - 19 Dec 2021

Cited by 7 | Viewed by 3037

Abstract

Fucoxanthin (Fx) is a marine carotenoid with anti-inflammatory and anti-cancer properties in various animal models of carcinogenesis. However, there is currently no information on the effects of Fx in animal models of pancreatic cancer. We investigated the chemopreventive effects of Fx in C57BL/6J mice that received allogenic and orthotopic transplantations of cancer cells (KMPC44) derived from a pancreatic cancer murine model (Ptf1a^Cre/+; LSL-kras^G12D/+). Using microarray, immunofluorescence, western blot, and siRNA analyses, alterations in cancer-related genes and protein expression were evaluated in pancreatic tumors of Fx-administered mice. Fx administration prevented the adenocarcinoma (ADC) development of pancreatic and parietal peritoneum tissues in a pancreatic cancer murine model, but not the incidence of ADC. Gene and protein expressions showed that the suppression of chemokine (C-C motif) ligand 21 (CCL21)/chemokine receptor 7 (CCR7) axis, its downstream of Rho A, B- and T-lymphocyte attenuator (BTLA), N-cadherin, αSMA, pFAK(Tyr³⁹⁷), and pPaxillin(Tyr³¹) were significantly suppressed in the pancreatic tumors of mice treated with Fx. In addition, Ccr7 knockdown significantly attenuated the growth of KMPC44 cells. These results suggest that Fx is a promising candidate for pancreatic cancer chemoprevention that mediates the suppression of the CCL21/CCR7 axis, BTLA, tumor microenvironment, epithelial mesenchymal transition, and adhesion. Full article

(This article belongs to the Special Issue Inflammation and Cancer 2021)

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15 pages, 2727 KiB

Open AccessArticle

The Combination of Cigarette Smoking and Alcohol Consumption Synergistically Increases Reactive Carbonyl Species in Human Male Plasma

by Kanae Mure, Susumu Tomono, Minae Mure, Mano Horinaka, Michihiro Mutoh, Toshiyuki Sakai, Hideki Ishikawa and Keiji Wakabayashi

Int. J. Mol. Sci. 2021, 22(16), 9043; https://doi.org/10.3390/ijms22169043 - 22 Aug 2021

Cited by 2 | Viewed by 2236

Abstract

Cigarette smoking and alcohol consumption are major risk factors for lifestyle-related diseases. Although it has been reported that the combination of these habits worsens risks, the underlying mechanism remains elusive. Reactive carbonyl species (RCS) cause chemical modifications of biological molecules, leading to alterations in cellular signaling pathways, and total RCS levels have been used as a lipid peroxidation marker linked to lifestyle-related diseases. In this study, at least 41 types of RCS were identified in the lipophilic fraction of plasma samples from 40 subjects using liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS). Higher levels of 10 alkanals, 5 trans-2-alkenals, 1 cis-4-alkenal, and 3 alkadienals were detected in the smoking/drinking group (N = 10) as compared to those with either habit (N = 10 each) or without both habits (N = 10) in the analysis of covariances adjusted for age and BMI. The levels of 3 alkanals, 1 trans-2-alkenal, 1 alkadienal, and 1 4-hydroxy-2-alkenal in the smoking/drinking group were significantly higher than those in the no-smoking/drinking and no-smoking/no-drinking groups. These results strongly indicate that the combination of cigarette smoking and alcohol drinking synergistically increases the level and variety of RCS in the circulating blood, and may further jeopardize cellular function. Full article

(This article belongs to the Special Issue Inflammation and Cancer 2021)

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16 pages, 2054 KiB

Open AccessArticle

Obesity Has a Systemic Effect on Immune Cells in Naïve and Cancer-Bearing Mice

by Silke Neumann, Katrin Campbell, Matthew J. Woodall, Meghan Evans, Andrew N. Clarkson and Sarah L. Young

Int. J. Mol. Sci. 2021, 22(16), 8803; https://doi.org/10.3390/ijms22168803 - 16 Aug 2021

Cited by 4 | Viewed by 2574

Abstract

Obesity is a major risk factor for developing cancer, with obesity-induced immune changes and inflammation in breast (BC) and colorectal cancer (CRC) providing a potential link between the two. This study investigates systemic effects of obesity on adaptive and innate immune cells in healthy and tumour-bearing mice. Immune cells from lean and obese mice were phenotyped prior to implantation of either BC (C57mg and EO771.LMB) or CRC (MC38) cells as tumour models. Tumour growth rate, tumour-infiltrating lymphocytes (TIL) and peripheral blood immune cell populations were compared between obese and lean mice. In vitro studies showed that naïve obese mice had higher levels of myeloid cells in the bone marrow and bone marrow-derived dendritic cells expressed lower levels of activation markers compared to cells from their lean counterparts. In the tumour setting, BC tumours grew faster in obese mice than in lean mice and lower numbers of TILs as well as higher frequency of exhausted T cells were observed. Data from peripheral blood showed lower levels of myeloid cells in tumour-bearing obese mice. This study highlights that systemic changes to the immune system are relevant for tumour burden and provides a potential mechanism behind the effects of obesity on cancer development and progression in patients. Full article

(This article belongs to the Special Issue Inflammation and Cancer 2021)

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Review

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24 pages, 1312 KiB

Open AccessReview

Inflammation in Urological Malignancies: The Silent Killer

by Martina Catalano, Giandomenico Roviello, Raffaella Santi, Donata Villari, Pietro Spatafora, Ilaria Camilla Galli, Francesco Sessa, Francesco Lupo Conte, Enrico Mini, Tommaso Cai and Gabriella Nesi

Int. J. Mol. Sci. 2023, 24(1), 866; https://doi.org/10.3390/ijms24010866 - 03 Jan 2023

Cited by 6 | Viewed by 2136

Abstract

Several studies have investigated the role of inflammation in promoting tumorigenesis and cancer progression. Neoplastic as well as surrounding stromal and inflammatory cells engage in well-orchestrated reciprocal interactions to establish an inflammatory tumor microenvironment. The tumor-associated inflammatory tissue is highly plastic, capable of continuously modifying its phenotypic and functional characteristics. Accumulating evidence suggests that chronic inflammation plays a critical role in the development of urological cancers. Here, we review the origins of inflammation in urothelial, prostatic, renal, testicular, and penile cancers, focusing on the mechanisms that drive tumor initiation, growth, progression, and metastasis. We also discuss how tumor-associated inflammatory tissue may be a diagnostic marker of clinically significant tumor progression risk and the target for future anti-cancer therapies. Full article

(This article belongs to the Special Issue Inflammation and Cancer 2021)

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16 pages, 1376 KiB

Open AccessReview

Hepatocellular Carcinoma: Understanding the Inflammatory Implications of the Microbiome

by Ahamed A. Khalyfa, Shil Punatar and Alex Yarbrough

Int. J. Mol. Sci. 2022, 23(15), 8164; https://doi.org/10.3390/ijms23158164 - 25 Jul 2022

Cited by 8 | Viewed by 2230

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. It is well known that repeated inflammatory insults in the liver can cause hepatic cellular injury that lead to cirrhosis and, ultimately, hepatocellular carcinoma. Furthermore, the microbiome has been implicated in multiple inflammatory conditions which predispose patients to malignancy. With this in mind, we explore the inflammatory implications of the microbiome on pathways that lead to HCC. We also focus on how an understanding of these underlying inflammatory principles lead to a more wholistic understanding of this deadly disease, as well as potential therapeutic implications. Full article

(This article belongs to the Special Issue Inflammation and Cancer 2021)

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21 pages, 1873 KiB

Open AccessReview

CXCR2 Receptor: Regulation of Expression, Signal Transduction, and Involvement in Cancer

by Jan Korbecki, Patrycja Kupnicka, Mikołaj Chlubek, Jarosław Gorący, Izabela Gutowska and Irena Baranowska-Bosiacka

Int. J. Mol. Sci. 2022, 23(4), 2168; https://doi.org/10.3390/ijms23042168 - 16 Feb 2022

Cited by 39 | Viewed by 7616

Abstract

Chemokines are a group of about 50 chemotactic cytokines crucial for the migration of immune system cells and tumor cells, as well as for metastasis. One of the 20 chemokine receptors identified to date is CXCR2, a G-protein-coupled receptor (GPCR) whose most known ligands are CXCL8 (IL-8) and CXCL1 (GRO-α). In this article we present a comprehensive review of literature concerning the role of CXCR2 in cancer. We start with regulation of its expression at the transcriptional level and how this regulation involves microRNAs. We show the mechanism of CXCR2 signal transduction, in particular the action of heterotrimeric G proteins, phosphorylation, internalization, intracellular trafficking, sequestration, recycling, and degradation of CXCR2. We discuss in detail the mechanism of the effects of activated CXCR2 on the actin cytoskeleton. Finally, we describe the involvement of CXCR2 in cancer. We focused on the importance of CXCR2 in tumor processes such as proliferation, migration, and invasion of tumor cells as well as the effects of CXCR2 activation on angiogenesis, lymphangiogenesis, and cellular senescence. We also discuss the importance of CXCR2 in cell recruitment to the tumor niche including tumor-associated neutrophils (TAN), tumor-associated macrophages (TAM), myeloid-derived suppressor cells (MDSC), and regulatory T (T_reg) cells. Full article

(This article belongs to the Special Issue Inflammation and Cancer 2021)

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25 pages, 1340 KiB

Open AccessReview

CXCL1: Gene, Promoter, Regulation of Expression, mRNA Stability, Regulation of Activity in the Intercellular Space

by Jan Korbecki, Katarzyna Barczak, Izabela Gutowska, Dariusz Chlubek and Irena Baranowska-Bosiacka

Int. J. Mol. Sci. 2022, 23(2), 792; https://doi.org/10.3390/ijms23020792 - 12 Jan 2022

Cited by 44 | Viewed by 6574

Abstract

CXCL1 is one of the most important chemokines, part of a group of chemotactic cytokines involved in the development of many inflammatory diseases. It activates CXCR2 and, at high levels, CXCR1. The expression of CXCL1 is elevated in inflammatory reactions and also has important functions in physiology, including the induction of angiogenesis and recruitment of neutrophils. Due to a lack of reviews that precisely describe the regulation of CXCL1 expression and function, in this paper, we present the mechanisms of CXCL1 expression regulation with a special focus on cancer. We concentrate on the regulation of CXCL1 expression through the regulation of CXCL1 transcription and mRNA stability, including the involvement of NF-κB, p53, the effect of miRNAs and cytokines such as IFN-γ, IL-1β, IL-17, TGF-β and TNF-α. We also describe the mechanisms regulating CXCL1 activity in the extracellular space, including proteolytic processing, CXCL1 dimerization and the influence of the ACKR1/DARC receptor on CXCL1 localization. Finally, we explain the role of CXCL1 in cancer and possible therapeutic approaches directed against this chemokine. Full article

(This article belongs to the Special Issue Inflammation and Cancer 2021)

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27 pages, 6916 KiB

Open AccessReview

Anti-Hepatocellular Carcinoma Biomolecules: Molecular Targets Insights

by Nouf Juaid, Amr Amin, Ali Abdalla, Kevin Reese, Zaenah Alamri, Mohamed Moulay, Suzan Abdu and Nabil Miled

Int. J. Mol. Sci. 2021, 22(19), 10774; https://doi.org/10.3390/ijms221910774 - 06 Oct 2021

Cited by 63 | Viewed by 4489

Abstract

This report explores the available curative molecules directed against hepatocellular carcinoma (HCC). Limited efficiency as well as other drawbacks of existing molecules led to the search for promising potential alternatives. Understanding of the cell signaling mechanisms propelling carcinogenesis and driven by cell proliferation, invasion, and angiogenesis can offer valuable information for the investigation of efficient treatment strategies. The complexity of the mechanisms behind carcinogenesis inspires researchers to explore the ability of various biomolecules to target specific pathways. Natural components occurring mainly in food and medicinal plants, are considered an essential resource for discovering new and promising therapeutic molecules. Novel biomolecules normally have an advantage in terms of biosafety. They are also widely diverse and often possess potent antioxidant, anti-inflammatory, and anti-cancer properties. Based on quantitative structure–activity relationship studies, biomolecules can be used as templates for chemical modifications that improve efficiency, safety, and bioavailability. In this review, we focus on anti-HCC biomolecules that have their molecular targets partially or completely characterized as well as having anti-cancer molecular mechanisms that are fairly described. Full article

(This article belongs to the Special Issue Inflammation and Cancer 2021)

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12 pages, 306 KiB

Open AccessPerspective

Skin Inflammation Modulation via TNF-α, IL-17, and IL-12 Family Inhibitors Therapy and Cancer Control in Patients with Psoriasis

by Daniel Octavian Costache, Oana Feroiu, Adelina Ghilencea, Mihaela Georgescu, Ana Căruntu, Constantin Căruntu, Sorin George Țiplica, Mariana Jinga and Raluca Simona Costache

Int. J. Mol. Sci. 2022, 23(9), 5198; https://doi.org/10.3390/ijms23095198 - 06 May 2022

Cited by 6 | Viewed by 2183

Abstract

The systemic inflammatory syndrome concept is one of the foundations that stand at the basis of revolutionary modern and future therapies, based on the in-depth understanding of the delicate mechanisms that govern the collaboration between the systems and organs of the human body and, at the same time, the fine balance that ensures a reproach-free operation. An interesting concept that we propose is that of the environment-inadequacy status, a concept that non-specifically incorporates all the situations of the organism’s response disorders in the face of imprecisely defined situations of the environment. The correlation between these two concepts will define the future of modern medicine, along with the gene-adjustment mechanisms. Psoriasis is a clear example of an inadequate body response as a result of exposure to as of yet undefined triggers with an excessive systemic inflammatory reaction and hitherto insufficiently controllable. Modern biological therapies, such as TNF-α, IL-12 family, and IL-17 inhibitors, are intended to profoundly reshape the cytokine configuration of patients with inflammatory diseases such as psoriasis, with tremendous success in disease control. Yet, because of the important roles of cytokines in cancer promotion and control, concern was raised about the fact that the use of biologicals may alter immune surveillance and promote cancer progression. Both theoretical and practical data nevertheless showed that the treatment-induced control of cytokines may be beneficial for reducing the inflammatory milieu that promotes cancer and such have a beneficial role in maintaining health. We briefly present the intricate roles of those cytokine families on cancer control, with some debates on if their inhibition might or might not promote additional tumoral development. Full article

(This article belongs to the Special Issue Inflammation and Cancer 2021)

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