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Special Issue "Inflammation and Cancer 2018"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 December 2018).

Special Issue Editors

Dr. Michihiro Mutoh
Website
Guest Editor
Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan
Interests: cancer prevention; animal models; translational research
Special Issues and Collections in MDPI journals
Prof. Dr. Takuji Tanaka
Website
Guest Editor
Director, Department of Diagnostic Pathology (DDP) & Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, Gifu, Japan
Interests: colorectal carcinogenesis; inflammatory bowel disease; ulcerative colitis; Crohn’s disease; cancer chemiprevention; animal model
Special Issues and Collections in MDPI journals
Prof. Dr. Masahito Shimizu
Website
Guest Editor
Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
Interests: liver carcinogenesis; cancer chemoprevention; chronic hepatitis; metabolic syndrome; retinoid; phytochemicals; clinical trial
Special Issues and Collections 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 2018”, 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.

Prof. 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 papers will be 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

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Published Papers (10 papers)

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Research

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Open AccessArticle
Homeostatic Model Assessment of Insulin Resistance for Predicting the Recurrence of Hepatocellular Carcinoma after Curative Treatment
Int. J. Mol. Sci. 2019, 20(3), 605; https://doi.org/10.3390/ijms20030605 - 30 Jan 2019
Cited by 4
Abstract
Diabetes mellitus (DM) is a risk factor for hepatocellular carcinoma (HCC). The purpose of this study was to investigate the impact of the disorder of glucose metabolism on the recurrence of HCC after curative treatment. Two hundred and eleven patients with HCC who [...] Read more.
Diabetes mellitus (DM) is a risk factor for hepatocellular carcinoma (HCC). The purpose of this study was to investigate the impact of the disorder of glucose metabolism on the recurrence of HCC after curative treatment. Two hundred and eleven patients with HCC who received curative treatment in our hospital from 2006 to 2017 were enrolled in this study. Recurrence-free survival was estimated using the Kaplan–Meier method, and the differences between the groups partitioned by the presence or absence of DM and the values of hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), fasting immunoreactive insulin (FIRI), and homeostasis model assessment-insulin resistance (HOMA-IR) were evaluated using the log-rank test. There were no significant differences in the recurrence-free survival rate between the patients with and without DM (p = 0.144), higher and lower levels of HbA1c (≥6.5 and <6.5%, respectively; p = 0.509), FPG (≥126 and <126 mg/dL, respectively; p = 0.143), and FIRI (≥10 and <10 μU/mL, respectively; p = 0.248). However, the higher HOMA-IR group (≥2.3) had HCC recurrence significantly earlier than the lower HOMA-IR group (<2.3, p = 0.013). Moreover, there was a significant difference between the higher and lower HOMA-IR groups without DM (p = 0.009), and there was no significant difference between those groups with DM (p = 0.759). A higher HOMA-IR level, particularly in non-diabetic patients, was a significant predictor for HCC recurrence after curative treatment. Full article
(This article belongs to the Special Issue Inflammation and Cancer 2018)
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Open AccessArticle
IL-6 and IL-8 Serum Levels Predict Tumor Response and Overall Survival after TACE for Primary and Secondary Hepatic Malignancies
Int. J. Mol. Sci. 2018, 19(6), 1766; https://doi.org/10.3390/ijms19061766 - 14 Jun 2018
Cited by 13
Abstract
While surgical resection represents the standard potentially curative therapy for liver cancer, transarterial chemoembolization (TACE) has evolved as a standard therapy for intermediate-stage hepatocellular carcinoma (HCC) as well as liver metastases. However, it is still not fully understood which patients particularly benefit from [...] Read more.
While surgical resection represents the standard potentially curative therapy for liver cancer, transarterial chemoembolization (TACE) has evolved as a standard therapy for intermediate-stage hepatocellular carcinoma (HCC) as well as liver metastases. However, it is still not fully understood which patients particularly benefit from TACE. Cytokines represent a broad category of signaling molecules that might reflect concomitant inflammation as an adverse prognostic factor. Here, we evaluated the role of interleukin (IL)-6, IL-8, and CC-chemokine ligand (CCL)22 as biomarkers in the context of TACE treatment. Cytokine serum levels were analyzed by multiplex immunoassay in 54 patients (HCC: n = 44, liver metastases: n = 10) undergoing TACE as well as 51 healthy controls. Patients with primary and secondary liver cancer showed significantly elevated levels of IL-6 and IL-8 but not CCL22 compared to healthy controls. Interestingly, low pre-interventional levels of IL-6 and IL-8 were predictors for an objective response after TACE in binary logistic regression. In contrast, patients with high pre-interventional IL-6 and IL-8 serum levels not only poorly responded to TACE but had a significantly impaired overall survival. Serum levels of IL-6 and IL-8 represent promising biomarkers for patients undergoing TACE and might help to pre-interventionally identify patients who particularly benefit from TACE regarding objective treatment response and overall survival. Full article
(This article belongs to the Special Issue Inflammation and Cancer 2018)
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Open AccessArticle
Chrysin Attenuates Cell Viability of Human Colorectal Cancer Cells through Autophagy Induction Unlike 5-Fluorouracil/Oxaliplatin
Int. J. Mol. Sci. 2018, 19(6), 1763; https://doi.org/10.3390/ijms19061763 - 14 Jun 2018
Cited by 7
Abstract
Chemotherapeutic 5-fluorouracil (5-FU) combined with oxaliplatin is often used as the standard treatment for colorectal cancer (CRC). The disturbing side effects and drug resistance commonly observed in chemotherapy motivate us to develop alternative optimal therapeutic options for CRC treatment. Chrysin, a natural and [...] Read more.
Chemotherapeutic 5-fluorouracil (5-FU) combined with oxaliplatin is often used as the standard treatment for colorectal cancer (CRC). The disturbing side effects and drug resistance commonly observed in chemotherapy motivate us to develop alternative optimal therapeutic options for CRC treatment. Chrysin, a natural and biologically active flavonoid abundant in propolis, is reported to have antitumor effects on a few CRCs. However, whether and how chrysin achieves similar effectiveness to the 5-FU combination is not clear. In this study, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), western blotting, fluorescence microscopy, and reactive oxygen species (ROS) production were assayed. We found that chrysin exhibited similar inhibition of cell viability as the 5-FU combination in a panel of human CRC cells. Furthermore, the results showed that chrysin significantly increased the levels of LC3-II, an autophagy-related marker, in CRC cells, which was not observed with the 5-FU combination. More importantly, blockage of autophagy induction restored chrysin-attenuated CRC cell viability. Further mechanistic analysis revealed that chrysin, not the 5-FU combination, induced ROS generation, and in turn, inhibited the phosphorylation of protein kinase B (Akt) and mammalian target of rapamycin (mTOR). Collectively, these results imply that chrysin may be a potential replacement for the 5-FU and oxaliplatin combination to achieve antitumor activity through autophagy for CRC treatment in the future. Full article
(This article belongs to the Special Issue Inflammation and Cancer 2018)
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Open AccessArticle
Downregulation of BTLA on NKT Cells Promotes Tumor Immune Control in a Mouse Model of Mammary Carcinoma
Int. J. Mol. Sci. 2018, 19(3), 752; https://doi.org/10.3390/ijms19030752 - 07 Mar 2018
Cited by 11
Abstract
Natural Killer T cells (NKT cells) are emerging as critical regulators of pro- and anti-tumor immunity, both at baseline and in therapeutic settings. While type I NKT cells can promote anti-tumor immunity, their activity in the tumor microenvironment may be limited by negative [...] Read more.
Natural Killer T cells (NKT cells) are emerging as critical regulators of pro- and anti-tumor immunity, both at baseline and in therapeutic settings. While type I NKT cells can promote anti-tumor immunity, their activity in the tumor microenvironment may be limited by negative regulators such as inhibitory immune checkpoints. We observed dominant expression of B- and T-lymphocyte attenuator (BTLA) on type I NKT cells in polyoma middle T oncogene-driven (PyMT) murine autochthonous mammary tumors. Other immune checkpoint receptors, such as programmed cell death 1 (PD-1) were equally distributed among T cell populations. Interference with BTLA using neutralizing antibodies limited tumor growth and pulmonary metastasis in the PyMT model in a therapeutic setting, correlating with an increase in type I NKT cells and expression of cytotoxic marker genes. While therapeutic application of an anti-PD-1 antibody increased the number of CD8+ cytotoxic T cells and elevated IL-12 expression, tumor control was not established. Expression of ZBTB16, the lineage-determining transcription factor of type I NKT cells, was correlated with a favorable patient prognosis in the METABRIC dataset, and BTLA levels were instrumental to further distinguish prognosis in patents with high ZBTB16 expression. Taken together, these data support a role of BTLA on type I NKT cells in limiting anti-tumor immunity. Full article
(This article belongs to the Special Issue Inflammation and Cancer 2018)
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Open AccessArticle
Peretinoin, an Acyclic Retinoid, Inhibits Hepatitis B Virus Replication by Suppressing Sphingosine Metabolic Pathway In Vitro
Int. J. Mol. Sci. 2018, 19(2), 108; https://doi.org/10.3390/ijms19020108 - 23 Jan 2018
Cited by 3
Abstract
Hepatocellular carcinoma (HCC) frequently develops from hepatitis C virus (HCV) and hepatitis B virus (HBV) infection. We previously reported that peretinoin, an acyclic retinoid, inhibits HCV replication. This study aimed to examine the influence of peretinoin on the HBV lifecycle. HBV-DNA and covalently [...] Read more.
Hepatocellular carcinoma (HCC) frequently develops from hepatitis C virus (HCV) and hepatitis B virus (HBV) infection. We previously reported that peretinoin, an acyclic retinoid, inhibits HCV replication. This study aimed to examine the influence of peretinoin on the HBV lifecycle. HBV-DNA and covalently closed circular DNA (cccDNA) were evaluated by a qPCR method in HepG2.2.15 cells. Peretinoin significantly reduced the levels of intracellular HBV-DNA, nuclear cccDNA, and HBV transcript at a concentration that did not induce cytotoxicity. Conversely, other retinoids, such as 9-cis, 13-cis retinoic acid (RA), and all-trans-retinoic acid (ATRA), had no effect or rather increased HBV replication. Mechanistically, although peretinoin increased the expression of HBV-related transcription factors, as observed for other retinoids, peretinoin enhanced the binding of histone deacetylase 1 (HDAC1) to cccDNA in the nucleus and negatively regulated HBV transcription. Moreover, peretinoin significantly inhibited the expression of SPHK1, a potential inhibitor of HDAC activity, and might be involved in hepatic inflammation, fibrosis, and HCC. SPHK1 overexpression in cells cancelled the inhibition of HBV replication induced by peretinoin. This indicates that peretinoin activates HDAC1 and thereby suppresses HBV replication by inhibiting the sphingosine metabolic pathway. Therefore, peretinoin may be a novel therapeutic agent for HBV replication and chemoprevention against HCC. Full article
(This article belongs to the Special Issue Inflammation and Cancer 2018)
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Review

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Open AccessReview
Current Knowledge of the Potential Links between Inflammation and Prostate Cancer
Int. J. Mol. Sci. 2019, 20(15), 3833; https://doi.org/10.3390/ijms20153833 - 06 Aug 2019
Cited by 11
Abstract
Inflammation is inherent in prostatic diseases and it is now accepted that it may facilitate cellular proliferation in both benign and malignant conditions. The strong relationship between prostatic inflammation and pathogenesis of benign prostatic hyperplasia (BPH) is supported by epidemiologic, histopathologic and molecular [...] Read more.
Inflammation is inherent in prostatic diseases and it is now accepted that it may facilitate cellular proliferation in both benign and malignant conditions. The strong relationship between prostatic inflammation and pathogenesis of benign prostatic hyperplasia (BPH) is supported by epidemiologic, histopathologic and molecular evidence. Contrariwise, the role of inflammation in prostate carcinogenesis is still controversial, although current data indicate that the inflammatory microenvironment can regulate prostate cancer (PCa) growth and progression. Knowledge of the complex molecular landscape associated with chronic inflammation in the context of PCa may lead to the introduction and optimization of novel targeted therapies. In this perspective, evaluation of the inflammatory component in prostate specimens could be included in routine pathology reports. Full article
(This article belongs to the Special Issue Inflammation and Cancer 2018)
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Open AccessReview
The Role of TGF-β Signaling in Lung Cancer Associated with Idiopathic Pulmonary Fibrosis
Int. J. Mol. Sci. 2018, 19(11), 3611; https://doi.org/10.3390/ijms19113611 - 15 Nov 2018
Cited by 15
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease of unknown etiology and dismal prognosis. IPF patients are known to have an increased risk of lung cancer and careful decision-making is required for the treatment of lung cancer associated with IPF. Transforming [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease of unknown etiology and dismal prognosis. IPF patients are known to have an increased risk of lung cancer and careful decision-making is required for the treatment of lung cancer associated with IPF. Transforming growth factor (TGF)-β signaling plays a central role in tissue fibrosis and tumorigenesis. TGF-β-mediated pathological changes that occur in IPF lung tissue may promote the process of field cancerization and provide the microenvironment favorable to cancer initiation and progression. This review summarizes the current knowledge related to IPF pathogenesis and explores the molecular mechanisms that underlie the occurrence of lung cancer in the background of IPF, with an emphasis on the multifaceted effects of TGF-β signaling. Full article
(This article belongs to the Special Issue Inflammation and Cancer 2018)
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Open AccessReview
Molecular Signatures of the Insulin-Like Growth Factor 1-Mediated Epithelial-Mesenchymal Transition in Breast, Lung and Gastric Cancers
Int. J. Mol. Sci. 2018, 19(8), 2411; https://doi.org/10.3390/ijms19082411 - 15 Aug 2018
Cited by 20
Abstract
The insulin-like growth factor (IGF) system, which is constituted by the IGF-1 and IGF-2 peptide hormones, their corresponding receptors and several IGF binding proteins, is involved in physiological and pathophysiological processes. The IGF system promotes cancer proliferation/survival and its signaling induces the epithelial-mesenchymal [...] Read more.
The insulin-like growth factor (IGF) system, which is constituted by the IGF-1 and IGF-2 peptide hormones, their corresponding receptors and several IGF binding proteins, is involved in physiological and pathophysiological processes. The IGF system promotes cancer proliferation/survival and its signaling induces the epithelial-mesenchymal transition (EMT) phenotype, which contributes to the migration, invasiveness, and metastasis of epithelial tumors. These cancers share two major IGF-1R signaling transduction pathways, PI3K/AKT and RAS/MEK/ERK. However, as far as we could review at this time, each type of cancer cell undergoes EMT through tumor-specific routes. Here, we review the tumor-specific molecular signatures of IGF-1-mediated EMT in breast, lung, and gastric cancers. Full article
(This article belongs to the Special Issue Inflammation and Cancer 2018)
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Open AccessReview
Clinically Relevant Anti-Inflammatory Agents for Chemoprevention of Colorectal Cancer: New Perspectives
Int. J. Mol. Sci. 2018, 19(8), 2332; https://doi.org/10.3390/ijms19082332 - 08 Aug 2018
Cited by 20
Abstract
Substantial efforts are underway for prevention of early stages or recurrence of colorectal cancers (CRC) or new polyp formation by chemoprevention strategies. Several epidemiological, clinical and preclinical studies to date have supported the chemopreventive potentials of several targeted drug classes including non-steroidal anti-inflammatory [...] Read more.
Substantial efforts are underway for prevention of early stages or recurrence of colorectal cancers (CRC) or new polyp formation by chemoprevention strategies. Several epidemiological, clinical and preclinical studies to date have supported the chemopreventive potentials of several targeted drug classes including non-steroidal anti-inflammatory drugs (NSAIDs) (aspirin, naproxen, sulindac, celecoxib, and licofelone), statins and other natural agents—both individually, and in combinations. Most preclinical trials although were efficacious, only few agents entered clinical trials and have been proven to be potential chemopreventive agents for colon cancer. However, there are limitations for these agents that hinder their approval by the food and drug administration for chemoprevention use in high-risk individuals and in patients with early stages of CRC. In this review, we update the recent advancement in pre-clinical and clinical development of selected anti-inflammatory agents (aspirin, naproxen, sulindac, celecoxib, and licofelone) and their combinations for further development as novel colon cancer chemopreventive drugs. We provide further new perspectives from this old research, and insights into precision medicine strategies to overcome unwanted side-effects and overcoming strategies for colon cancer chemoprevention. Full article
(This article belongs to the Special Issue Inflammation and Cancer 2018)
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Open AccessReview
Regulation and Sensing of Inflammasomes and Their Impact on Intestinal Health
Int. J. Mol. Sci. 2017, 18(11), 2379; https://doi.org/10.3390/ijms18112379 - 09 Nov 2017
Cited by 10
Abstract
Pattern recognition receptors such as nucleotide-binding oligomerization domain (NOD)-containing protein receptors (NLRs) and the pyrin and hematopoitic interferon-inducible nuclear protein (HIN) domain (PYHIN) receptors initiate the inflammatory response following cell stress or pathogenic challenge. When activated, some of these receptors oligomerize to form [...] Read more.
Pattern recognition receptors such as nucleotide-binding oligomerization domain (NOD)-containing protein receptors (NLRs) and the pyrin and hematopoitic interferon-inducible nuclear protein (HIN) domain (PYHIN) receptors initiate the inflammatory response following cell stress or pathogenic challenge. When activated, some of these receptors oligomerize to form the structural backbone of a signalling platform known as an inflammasome. Inflammasomes promote the activation of caspase-1 and the maturation of the proinflammatory cytokines, interleukin (IL)-1β and IL-18. The gut dysregulation of the inflammasome complex is thought to be a contributing factor in the development of inflammatory bowel diseases (IBD), such as ulcerative colitis (UC) and Crohn’s disease (CD). The importance of inflammasomes to intestinal health has been emphasized by various inflammasome-deficient mice in dextran sulphate sodium (DSS) models of intestinal inflammation and by the identification of novel potential candidate genes in population-based human studies. In this review, we summarise the most recent findings with regard to the formation, sensing, and regulation of the inflammasome complex and highlight their importance in maintaining intestinal health. Full article
(This article belongs to the Special Issue Inflammation and Cancer 2018)
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