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Links between Fibrogenesis and Cancer: Mechanistic and Therapeutic Challenges

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2019) | Viewed by 146794

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Special Issue Editor

Professor and Chairman, Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu city, Mie 514-8507, Japan
Interests: cancer; tissue fibrosis; microbiome
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Fibrosis is the end-stage of many chronic inflammatory diseases. It is associated with progressive scarring of an organ with reduction or loss of function. Scarring of parenchymal organs is characterized by abnormally-enhanced tissue deposition of extracellular matrix components, including several types of collagens, fibronectin and matricellular proteins, such as tenascin and periostin. The process is generally reversible at early stages, but it becomes irreversible with advanced disease. However, the point of no return is unknown. We address this question in this Special Issue with original research or reviews dealing with factors or biomarkers of fibrosis irreversibility.

Tissue fibrosis may be the consequence of different pathological states, including chronic inflammatory or infectious diseases, autoimmune disorders, graft rejection and malignancy; but in some diseases, such as idiopathic pulmonary fibrosis, the cause is unknown and the fibrotic process progresses despite the absence of conspicuous inflammation. Irrespective of the underlying pathological condition, tissue with ongoing fibrogenesis has a high content of matrix proteins and myofibroblasts activated by various pro-fibrotic factors among which transforming growth factor-β1 plays a critical role. However, the stimulus that perpetuates the secretion or increases the level and activation of transforming growth factor-β1 during fibrogenesis is unclear. Therefore, studies on genetic factors or environmental agents (e.g., microbiota) playing a role in the excessive and persistent growth factor activity during fibrotic processes will be part of this issue.

Disruption of organ parenchymal cells and of the normal organ structural scaffold during organ fibrogenesis causes loss of cell polarity that may promote uncontrolled cell proliferation leading eventually to cancer onset and progression. Tumors have been identified in fibrotic tissues decades ago and now it is well-recognized that fibrotic lesions enhance the risk of cancer in several organs such liver, lung and breast. The mechanism linking fibrosis and cancer is unknown. This Special Issue will address cellular and molecular abnormalities including aberrant expression of microRNAs, genetic and epigenetic alterations, evasion or delayed apoptosis, unregulated intracellular signal pathways, and dysregulation or defective intercellular communications that may provide insights to explain the pathological link between fibrogenesis and carcinogenesis.

The pathogenic role of myofibroblasts is common in both fibrosis and cancer. Myofibroblasts are the main source of matrix proteins and their enhanced activity is an important prognostic indicator in patients with either organ fibrosis or malignancy. Comparative studies evaluating the phenotypic, behavioral, biochemical and molecular alterations in myofibroblasts may help developing drugs equally effective for both disease conditions. For example, the multi-kinase inhibitor nintedanib was initially developed for use as an anti-cancer drug but was subsequently approved for treating lung fibrosis. This is because targeted receptors were also found to be abnormally activated in lung fibrosis. Research covering these topics will also be part of this Special Issue.

Topics for this Special Issue include, but are not limited to:

  1. Matricellular proteins
  2. Regulatory mechanism of secretion and activation of transforming growth factor-beta1 and other pro-fibrotic factors.
  3. Myofibroblasts from fibrotic tissue and cancerous tissues
  4. Epithelial or endothelial mesenchymal transition during fibrinogenesis and carcinogenesis
  5. Microbiome in fibrosis and cancer
  6. New therapeutic agents for organ fibrosis and cancer
  7. Interaction of myofibroblasts with extracellular matrix proteins
  8. Intracellular signal pathways controlling the expression of extracellular matrix proteins.
  9. Animal models of fibrosis and/or cancer
  10. Diagnostic approaches for lung fibrotic diseases and cancer.

Prof. Dr. Esteban C. Gabazza
Guest Editor

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Keywords

  • Fibrosis
  • Fibrosis-associated cancer
  • Endothelial mesenchymal transition
  • Carcinogenesis
  • Profibrotic cytokines
  • Microbiome
  • Cancer resistance to therapy
  • Experimental animal models

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Published Papers (17 papers)

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Editorial

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3 pages, 156 KiB  
Editorial
Links between Fibrogenesis and Cancer: Mechanistic and Therapeutic Challenges
by Liqiang Qin and Esteban C. Gabazza
Int. J. Mol. Sci. 2019, 20(17), 4313; https://doi.org/10.3390/ijms20174313 - 03 Sep 2019
Cited by 2 | Viewed by 2564
Abstract
Fibrosis is the end-stage of chronic inflammatory diseases and tissue damage resulting from a dysregulated wound-healing response [...] Full article

Research

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15 pages, 1462 KiB  
Article
Involvement of G-Protein-Coupled Receptor 40 in the Inhibitory Effects of Docosahexaenoic Acid on SREBP1-Mediated Lipogenic Enzyme Expression in Primary Hepatocytes
by Seungtae On, Hyun Young Kim, Hyo Seon Kim, Jeongwoo Park and Keon Wook Kang
Int. J. Mol. Sci. 2019, 20(11), 2625; https://doi.org/10.3390/ijms20112625 - 28 May 2019
Cited by 25 | Viewed by 3469
Abstract
Nonalcoholic fatty liver disease is a frequent liver malady, which can progress to cirrhosis, the end-stage liver disease if proper treatment is not applied. Omega-3 fatty acids, such as docosahexaenoic acid (DHA) and eicosapentaenoic acid, have been clinically proven to lower serum triglyceride [...] Read more.
Nonalcoholic fatty liver disease is a frequent liver malady, which can progress to cirrhosis, the end-stage liver disease if proper treatment is not applied. Omega-3 fatty acids, such as docosahexaenoic acid (DHA) and eicosapentaenoic acid, have been clinically proven to lower serum triglyceride levels. Various physiological activities of omega-3 fatty acids are due to their agonistic actions on G-protein-coupled receptor 40 (GPR40) and GPR120. Lipid droplets (LD) accumulation in hepatocytes confirmed that DHA treatment reduced the number of larger ( >10 μm2) LDs, as well as the total area of LDs. Moreover, DHA lowered protein and mRNA expression levels of lipogenic enzymes such as fatty acid synthase (FAS), acetyl-CoA carboxylase and stearoyl-CoA desaturase-1 (SCD-1) in primary hepatocytes incubated with liver X receptor (LXR) agonist T0901317 or high glucose and insulin. DHA also decreased protein expression of nuclear and precursor sterol response-element binding protein (SREBP)-1, a key lipogenesis transcription factor. We further found that exposure of murine primary hepatocytes to DHA for 12 h increased GPR40 and GPR120 mRNA levels. Specific agonists (Compound A for GPR120 and AMG-1638 for GPR40), hepatocytes from GPR120 knock-out mice and GPR40 selective antagonist (GW1100) were used to assess whether DHA’s antilipogenic effects are mediated through GPR120 or GPR40. Compound A did not decrease SREBP-1 and FAS protein expression in hepatocytes exposed to T0901317 or high glucose with insulin. Moreover, DHA downregulated lipogenesis enzyme expression in GPR120-null hepatocytes. In contrast, AMG-1638 lowered SREBP-1 and SCD-1 protein levels. Additionally, GW1100, a GPR40 antagonist, reversed the antilipogenic effects of DHA. Collectively, our data demonstrate that DHA downregulates the expression SREBP-1-mediated lipogenic enzymes via GPR40 in primary hepatocytes. Full article
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14 pages, 3288 KiB  
Article
Protein S is Protective in Acute Lung Injury by Inhibiting Cell Apoptosis
by Prince Baffour Tonto, Taro Yasuma, Tetsu Kobayashi, Corina N. D’Alessandro-Gabazza, Masaaki Toda, Haruko Saiki, Hajime Fujimoto, Kentaro Asayama, Kentaro Fujiwara, Kota Nishihama, Tomohito Okano, Atsuro Takeshita and Esteban C. Gabazza
Int. J. Mol. Sci. 2019, 20(5), 1082; https://doi.org/10.3390/ijms20051082 - 02 Mar 2019
Cited by 13 | Viewed by 3179
Abstract
Acute lung injury is a fatal disease characterized by inflammatory cell infiltration, alveolar-capillary barrier disruption, protein-rich edema, and impairment of gas exchange. Protein S is a vitamin K-dependent glycoprotein that exerts anticoagulant, immunomodulatory, anti-inflammatory, anti-apoptotic, and neuroprotective effects. The aim of this study [...] Read more.
Acute lung injury is a fatal disease characterized by inflammatory cell infiltration, alveolar-capillary barrier disruption, protein-rich edema, and impairment of gas exchange. Protein S is a vitamin K-dependent glycoprotein that exerts anticoagulant, immunomodulatory, anti-inflammatory, anti-apoptotic, and neuroprotective effects. The aim of this study was to evaluate whether human protein S inhibits cell apoptosis in acute lung injury. Acute lung injury in human protein S transgenic and wild-type mice was induced by intratracheal instillation of lipopolysaccharide. The effect of human protein S on apoptosis of lung tissue cells was evaluated by Western blotting. Inflammatory cell infiltration, alveolar wall thickening, myeloperoxidase activity, and the expression of inflammatory cytokines were reduced in human protein S transgenic mice compared to the wild-type mice after lipopolysaccharide instillation. Apoptotic cells and caspase-3 activity were reduced while phosphorylation of extracellular signal-regulated kinase was enhanced in the lung tissue from human protein S transgenic mice compared to wild-type mice after lipopolysaccharide instillation. The results of this study suggest that human protein S is protective in lipopolysaccharide-induced acute lung injury by inhibiting apoptosis of lung cells. Full article
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15 pages, 6866 KiB  
Article
Non-Canonical Regulation of Type I Collagen through Promoter Binding of SOX2 and Its Contribution to Ameliorating Pulmonary Fibrosis by Butylidenephthalide
by Hong-Meng Chuang, Li-Ing Ho, Mao-Hsuan Huang, Kun-Lun Huang, Tzyy-Wen Chiou, Shinn-Zong Lin, Hong-Lin Su and Horng-Jyh Harn
Int. J. Mol. Sci. 2018, 19(10), 3024; https://doi.org/10.3390/ijms19103024 - 04 Oct 2018
Cited by 8 | Viewed by 4112
Abstract
Pulmonary fibrosis is a fatal respiratory disease that gradually leads to dyspnea, mainly accompanied by excessive collagen production in the fibroblast and myofibroblast through mechanisms such as abnormal alveolar epithelial cells remodeling and stimulation of the extracellular matrix (ECM). Our results show that [...] Read more.
Pulmonary fibrosis is a fatal respiratory disease that gradually leads to dyspnea, mainly accompanied by excessive collagen production in the fibroblast and myofibroblast through mechanisms such as abnormal alveolar epithelial cells remodeling and stimulation of the extracellular matrix (ECM). Our results show that a small molecule, butylidenephthalide (BP), reduces type I collagen (COL1) expression in Transforming Growth Factor beta (TGF-β)-induced lung fibroblast without altering downstream pathways of TGF-β, such as Smad phosphorylation. Treatment of BP also reduces the expression of transcription factor Sex Determining Region Y-box 2 (SOX2), and the ectopic expression of SOX2 overcomes the inhibitory actions of BP on COL1 expression. We also found that serial deletion of the SOX2 binding site on 3′COL1 promoter results in a marked reduction in luciferase activity. Moreover, chromatin immunoprecipitation, which was found on the SOX2 binding site of the COL1 promoter, decreases in BP-treated cells. In an in vivo study using a bleomycin-induced pulmonary fibrosis C57BL/6 mice model, mice treated with BP displayed reduced lung fibrosis and collagen deposition, recovering in their pulmonary ventilation function. The reduction of SOX2 expression in BP-treated lung tissues is consistent with our findings in the fibroblast. This is the first report that reveals a non-canonical regulation of COL1 promoter via SOX2 binding, and contributes to the amelioration of pulmonary fibrosis by BP treatment. Full article
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11 pages, 1918 KiB  
Communication
Renal Injury during Long-Term Crizotinib Therapy
by Taro Yasuma, Tetsu Kobayashi, Corina N. D’Alessandro-Gabazza, Hajime Fujimoto, Kentaro Ito, Yoichi Nishii, Kota Nishihama, Prince Baffour Tonto, Atsuro Takeshita, Masaaki Toda, Esteban C. Gabazza, Osamu Taguchi, Shigenori Yonemura and Osamu Hataji
Int. J. Mol. Sci. 2018, 19(10), 2902; https://doi.org/10.3390/ijms19102902 - 25 Sep 2018
Cited by 10 | Viewed by 3095
Abstract
Crizotinib is highly effective against anaplastic lymphoma kinase-positive and c-ros oncogen1-positive non-small cell lung cancer. Renal dysfunction is associated with crizotinib therapy but the mechanism is unknown. Here, we report a case of anaplastic lymphoma kinase positive non-small cell lung cancer showing multiple [...] Read more.
Crizotinib is highly effective against anaplastic lymphoma kinase-positive and c-ros oncogen1-positive non-small cell lung cancer. Renal dysfunction is associated with crizotinib therapy but the mechanism is unknown. Here, we report a case of anaplastic lymphoma kinase positive non-small cell lung cancer showing multiple cysts and dysfunction of the kidneys during crizotinib administration. We also present results demonstrating that long-term crizotinib treatment induces fibrosis and dysfunction of the kidneys by activating the tumor necrosis factor-α/nuclear factor-κB signaling pathway. In conclusion, this study shows the renal detrimental effects of crizotinib, suggesting the need of careful monitoring of renal function during crizotinib therapy. Full article
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Review

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34 pages, 3101 KiB  
Review
TGF-β-Mediated Epithelial-Mesenchymal Transition and Cancer Metastasis
by Yang Hao, David Baker and Peter ten Dijke
Int. J. Mol. Sci. 2019, 20(11), 2767; https://doi.org/10.3390/ijms20112767 - 05 Jun 2019
Cited by 626 | Viewed by 25619
Abstract
Transforming growth factor β (TGF-β) is a secreted cytokine that regulates cell proliferation, migration, and the differentiation of a plethora of different cell types. Consistent with these findings, TGF-β plays a key role in controlling embryogenic development, inflammation, and tissue repair, as well [...] Read more.
Transforming growth factor β (TGF-β) is a secreted cytokine that regulates cell proliferation, migration, and the differentiation of a plethora of different cell types. Consistent with these findings, TGF-β plays a key role in controlling embryogenic development, inflammation, and tissue repair, as well as in maintaining adult tissue homeostasis. TGF-β elicits a broad range of context-dependent cellular responses, and consequently, alterations in TGF-β signaling have been implicated in many diseases, including cancer. During the early stages of tumorigenesis, TGF-β acts as a tumor suppressor by inducing cytostasis and the apoptosis of normal and premalignant cells. However, at later stages, when cancer cells have acquired oncogenic mutations and/or have lost tumor suppressor gene function, cells are resistant to TGF-β-induced growth arrest, and TGF-β functions as a tumor promotor by stimulating tumor cells to undergo the so-called epithelial-mesenchymal transition (EMT). The latter leads to metastasis and chemotherapy resistance. TGF-β further supports cancer growth and progression by activating tumor angiogenesis and cancer-associated fibroblasts and enabling the tumor to evade inhibitory immune responses. In this review, we will consider the role of TGF-β signaling in cell cycle arrest, apoptosis, EMT and cancer cell metastasis. In particular, we will highlight recent insights into the multistep and dynamically controlled process of TGF-β-induced EMT and the functions of miRNAs and long noncoding RNAs in this process. Finally, we will discuss how these new mechanistic insights might be exploited to develop novel therapeutic interventions. Full article
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30 pages, 2332 KiB  
Review
Activated Fibroblast Program Orchestrates Tumor Initiation and Progression; Molecular Mechanisms and the Associated Therapeutic Strategies
by Go J. Yoshida, Arata Azuma, Yukiko Miura and Akira Orimo
Int. J. Mol. Sci. 2019, 20(9), 2256; https://doi.org/10.3390/ijms20092256 - 07 May 2019
Cited by 95 | Viewed by 8721
Abstract
Neoplastic epithelial cells coexist in carcinomas with various non-neoplastic stromal cells, together creating the tumor microenvironment. There is a growing interest in the cross-talk between tumor cells and stromal fibroblasts referred to as carcinoma-associated fibroblasts (CAFs), which are frequently present in human carcinomas. [...] Read more.
Neoplastic epithelial cells coexist in carcinomas with various non-neoplastic stromal cells, together creating the tumor microenvironment. There is a growing interest in the cross-talk between tumor cells and stromal fibroblasts referred to as carcinoma-associated fibroblasts (CAFs), which are frequently present in human carcinomas. CAF populations extracted from different human carcinomas have been shown to possess the ability to influence the hallmarks of cancer. Indeed, several mechanisms underlying CAF-promoted tumorigenesis are elucidated. Activated fibroblasts in CAFs are characterized as alpha-smooth muscle actin-positive myofibroblasts and actin-negative fibroblasts, both of which are competent to support tumor growth and progression. There are, however, heterogeneous CAF populations presumably due to the diverse sources of their progenitors in the tumor-associated stroma. Thus, molecular markers allowing identification of bona fide CAF populations with tumor-promoting traits remain under investigation. CAFs and myofibroblasts in wound healing and fibrosis share biological properties and support epithelial cell growth, not only by remodeling the extracellular matrix, but also by producing numerous growth factors and inflammatory cytokines. Notably, accumulating evidence strongly suggests that anti-fibrosis agents suppress tumor development and progression. In this review, we highlight important tumor-promoting roles of CAFs based on their analogies with wound-derived myofibroblasts and discuss the potential therapeutic strategy targeting CAFs. Full article
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19 pages, 618 KiB  
Review
Recent Insight into the Role of Fibrosis in Nonalcoholic Steatohepatitis-Related Hepatocellular Carcinoma
by Antonio Sircana, Elena Paschetta, Francesca Saba, Federica Molinaro and Giovanni Musso
Int. J. Mol. Sci. 2019, 20(7), 1745; https://doi.org/10.3390/ijms20071745 - 09 Apr 2019
Cited by 35 | Viewed by 5908
Abstract
Hepatocellular carcinoma (HCC) is one of the most widespread tumors in the world and its prognosis is poor because of lack of effective treatments. Epidemiological studies show that non-alcoholic steatohepatitis (NASH) and advanced fibrosis represent a relevant risk factors to the HCC development. [...] Read more.
Hepatocellular carcinoma (HCC) is one of the most widespread tumors in the world and its prognosis is poor because of lack of effective treatments. Epidemiological studies show that non-alcoholic steatohepatitis (NASH) and advanced fibrosis represent a relevant risk factors to the HCC development. However little is known of pathophysiological mechanisms linking liver fibrogenesis to HCC in NASH. Recent advances in scientific research allowed to discover some mechanisms that may represent potential therapeutic targets. These include the integrin signaling, hepatic stellate cells (HSCs) activation, Hedgehog signaling and alteration of immune system. In the near future, knowledge of fibrosis-dependent carcinogenic mechanisms, will help optimize antifibrotic therapies as an approach to prevent and treat HCC in patients with NASH and advanced fibrosis. Full article
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19 pages, 1750 KiB  
Review
The Role of Fibrosis and Liver-Associated Fibroblasts in the Pathogenesis of Hepatocellular Carcinoma
by Jacopo Baglieri, David A. Brenner and Tatiana Kisseleva
Int. J. Mol. Sci. 2019, 20(7), 1723; https://doi.org/10.3390/ijms20071723 - 07 Apr 2019
Cited by 187 | Viewed by 11087
Abstract
Hepatocellular carcinoma (HCC) is one of the most aggressive types of cancer and lacks effective therapeutic approaches. Most HCC develops in the setting of chronic liver injury, hepatic inflammation, and fibrosis. Hepatic stellate cells (HSCs) and cancer-associated fibroblasts (CAFs) are key players in [...] Read more.
Hepatocellular carcinoma (HCC) is one of the most aggressive types of cancer and lacks effective therapeutic approaches. Most HCC develops in the setting of chronic liver injury, hepatic inflammation, and fibrosis. Hepatic stellate cells (HSCs) and cancer-associated fibroblasts (CAFs) are key players in liver fibrogenesis and hepatocarcinogenesis, respectively. CAFs, which probably derive from HSCs, activate into extracellular matrix (ECM)-producing myofibroblasts and crosstalk with cancer cells to affect tumor growth and invasion. In this review, we describe the different components which form the HCC premalignant microenvironment (PME) and the tumor microenvironment (TME), focusing on the liver fibrosis process and the biology of CAFs. We will describe the CAF-dependent mechanisms which have been suggested to promote hepatocarcinogenesis, such as the alteration of ECM, CAF-dependent production of cytokines and angiogenic factors, CAF-dependent reduction of immuno-surveillance, and CAF-dependent promotion of epithelial-mesenchymal transition (EMT). New knowledge of the fibrosis process and the role of CAFs in HCC may pave the way for new therapeutic strategies for liver cancer. Full article
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16 pages, 479 KiB  
Review
Molecular Mechanisms of Pulmonary Fibrogenesis and Its Progression to Lung Cancer: A Review
by Tomonari Kinoshita and Taichiro Goto
Int. J. Mol. Sci. 2019, 20(6), 1461; https://doi.org/10.3390/ijms20061461 - 22 Mar 2019
Cited by 100 | Viewed by 8919
Abstract
Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, and limited to the lungs. Despite the increasing research interest in the pathogenesis of IPF, unfavorable survival rates remain [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, and limited to the lungs. Despite the increasing research interest in the pathogenesis of IPF, unfavorable survival rates remain associated with this condition. Recently, novel therapeutic agents have been shown to control the progression of IPF. However, these drugs do not improve lung function and have not been tested prospectively in patients with IPF and coexisting lung cancer, which is a common comorbidity of IPF. Optimal management of patients with IPF and lung cancer requires understanding of pathogenic mechanisms and molecular pathways that are common to both diseases. This review article reflects the current state of knowledge regarding the pathogenesis of pulmonary fibrosis and summarizes the pathways that are common to IPF and lung cancer by focusing on the molecular mechanisms. Full article
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24 pages, 1244 KiB  
Review
Molecular Mechanisms Driving Progression of Liver Cirrhosis towards Hepatocellular Carcinoma in Chronic Hepatitis B and C Infections: A Review
by Tatsuo Kanda, Taichiro Goto, Yosuke Hirotsu, Mitsuhiko Moriyama and Masao Omata
Int. J. Mol. Sci. 2019, 20(6), 1358; https://doi.org/10.3390/ijms20061358 - 18 Mar 2019
Cited by 182 | Viewed by 12779
Abstract
Almost all patients with hepatocellular carcinoma (HCC), a major type of primary liver cancer, also have liver cirrhosis, the severity of which hampers effective treatment for HCC despite recent progress in the efficacy of anticancer drugs for advanced stages of HCC. Here, we [...] Read more.
Almost all patients with hepatocellular carcinoma (HCC), a major type of primary liver cancer, also have liver cirrhosis, the severity of which hampers effective treatment for HCC despite recent progress in the efficacy of anticancer drugs for advanced stages of HCC. Here, we review recent knowledge concerning the molecular mechanisms of liver cirrhosis and its progression to HCC from genetic and epigenomic points of view. Because ~70% of patients with HCC have hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection, we focused on HBV- and HCV-associated HCC. The literature suggests that genetic and epigenetic factors, such as microRNAs, play a role in liver cirrhosis and its progression to HCC, and that HBV- and HCV-encoded proteins appear to be involved in hepatocarcinogenesis. Further studies are needed to elucidate the mechanisms, including immune checkpoints and molecular targets of kinase inhibitors, associated with liver cirrhosis and its progression to HCC. Full article
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18 pages, 763 KiB  
Review
Nano-Strategies to Target Breast Cancer-Associated Fibroblasts: Rearranging the Tumor Microenvironment to Achieve Antitumor Efficacy
by Marta Truffi, Serena Mazzucchelli, Arianna Bonizzi, Luca Sorrentino, Raffaele Allevi, Renzo Vanna, Carlo Morasso and Fabio Corsi
Int. J. Mol. Sci. 2019, 20(6), 1263; https://doi.org/10.3390/ijms20061263 - 13 Mar 2019
Cited by 74 | Viewed by 7126
Abstract
Cancer-associated fibroblasts (CAF) are the most abundant cells of the tumor stroma and they critically influence cancer growth through control of the surrounding tumor microenvironment (TME). CAF-orchestrated reactive stroma, composed of pro-tumorigenic cytokines and growth factors, matrix components, neovessels, and deregulated immune cells, [...] Read more.
Cancer-associated fibroblasts (CAF) are the most abundant cells of the tumor stroma and they critically influence cancer growth through control of the surrounding tumor microenvironment (TME). CAF-orchestrated reactive stroma, composed of pro-tumorigenic cytokines and growth factors, matrix components, neovessels, and deregulated immune cells, is associated with poor prognosis in multiple carcinomas, including breast cancer. Therefore, beyond cancer cells killing, researchers are currently focusing on TME as strategy to fight breast cancer. In recent years, nanomedicine has provided a number of smart delivery systems based on active targeting of breast CAF and immune-mediated overcome of chemoresistance. Many efforts have been made both to eradicate breast CAF and to reshape their identity and function. Nano-strategies for CAF targeting profoundly contribute to enhance chemosensitivity of breast tumors, enabling access of cytotoxic T-cells and reducing immunosuppressive signals. TME rearrangement also includes reorganization of the extracellular matrix to enhance permeability to chemotherapeutics, and nano-systems for smart coupling of chemo- and immune-therapy, by increasing immunogenicity and stimulating antitumor immunity. The present paper reviews the current state-of-the-art on nano-strategies to target breast CAF and TME. Finally, we consider and discuss future translational perspectives of proposed nano-strategies for clinical application in breast cancer. Full article
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23 pages, 2721 KiB  
Review
The Usefulness of Immunohistochemistry in the Differential Diagnosis of Lesions Originating from the Myometrium
by Piotr Rubisz, Michał Ciebiera, Lidia Hirnle, Magdalena Zgliczyńska, Tomasz Łoziński, Piotr Dzięgiel and Christopher Kobierzycki
Int. J. Mol. Sci. 2019, 20(5), 1136; https://doi.org/10.3390/ijms20051136 - 06 Mar 2019
Cited by 28 | Viewed by 8451
Abstract
Uterine leiomyomas (LMs), currently the most common gynecological complaint around the world, are a serious medical, social and economic problem. Accurate diagnosis is the necessary prerequisite of the diagnostic-therapeutic process. Statistically, mistakes may occur more often in case of disease entities with high [...] Read more.
Uterine leiomyomas (LMs), currently the most common gynecological complaint around the world, are a serious medical, social and economic problem. Accurate diagnosis is the necessary prerequisite of the diagnostic-therapeutic process. Statistically, mistakes may occur more often in case of disease entities with high prevalence rates. Histopathology, based on increasingly advanced immunohistochemistry methods, is routinely used in the diagnosis of neoplastic diseases. Markers of the highest sensitivity and specificity profiles are used in the process. As far as LMs are concerned, the crux of the matter is to identify patients with seemingly benign lesions which turn out to be suspicious (e.g., atypical LM) or malignant (e.g., leiomyosarcoma (LMS)), which is not uncommon. In this study, we present the current state of knowledge about the use of immunohistochemical markers in the differential diagnosis of LM, atypical LM, smooth muscle tumors of uncertain malignant potential (STUMP), and LMS, as well as their clinical predictive value. Full article
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28 pages, 1145 KiB  
Review
Idiopathic Pulmonary Fibrosis and Lung Cancer: Mechanisms and Molecular Targets
by Beatriz Ballester, Javier Milara and Julio Cortijo
Int. J. Mol. Sci. 2019, 20(3), 593; https://doi.org/10.3390/ijms20030593 - 30 Jan 2019
Cited by 172 | Viewed by 12207
Abstract
Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pulmonary disease with a median survival of 2–4 years after diagnosis. A significant number of IPF patients have risk factors, such as a history of smoking or concomitant emphysema, both of which can [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pulmonary disease with a median survival of 2–4 years after diagnosis. A significant number of IPF patients have risk factors, such as a history of smoking or concomitant emphysema, both of which can predispose the patient to lung cancer (LC) (mostly non-small cell lung cancer (NSCLC)). In fact, IPF itself increases the risk of LC development by 7% to 20%. In this regard, there are multiple common genetic, molecular, and cellular processes that connect lung fibrosis with LC, such as myofibroblast/mesenchymal transition, myofibroblast activation and uncontrolled proliferation, endoplasmic reticulum stress, alterations of growth factors expression, oxidative stress, and large genetic and epigenetic variations that can predispose the patient to develop IPF and LC. The current approved IPF therapies, pirfenidone and nintedanib, are also active in LC. In fact, nintedanib is approved as a second line treatment in NSCLC, and pirfenidone has shown anti-neoplastic effects in preclinical studies. In this review, we focus on the current knowledge on the mechanisms implicated in the development of LC in patients with IPF as well as in current IPF and LC-IPF candidate therapies based on novel molecular advances. Full article
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20 pages, 1136 KiB  
Review
High Risk of Hepatocellular Carcinoma Development in Fibrotic Liver: Role of the Hippo-YAP/TAZ Signaling Pathway
by Hyuk Moon, Kyungjoo Cho, Sunyeong Shin, Do Young Kim, Kwang-Hyub Han and Simon Weonsang Ro
Int. J. Mol. Sci. 2019, 20(3), 581; https://doi.org/10.3390/ijms20030581 - 29 Jan 2019
Cited by 30 | Viewed by 7198
Abstract
Liver cancer is the fourth leading cause of cancer-related death globally, accounting for approximately 800,000 deaths annually. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, making up about 80% of cases. Liver fibrosis and its end-stage disease, cirrhosis, are major [...] Read more.
Liver cancer is the fourth leading cause of cancer-related death globally, accounting for approximately 800,000 deaths annually. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, making up about 80% of cases. Liver fibrosis and its end-stage disease, cirrhosis, are major risk factors for HCC. A fibrotic liver typically shows persistent hepatocyte death and compensatory regeneration, chronic inflammation, and an increase in reactive oxygen species, which collaboratively create a tumor-promoting microenvironment via inducing genetic alterations and chromosomal instability, and activating various oncogenic molecular signaling pathways. In this article, we review recent advances in fields of liver fibrosis and carcinogenesis, and consider several molecular signaling pathways that promote hepato-carcinogenesis under the microenvironment of liver fibrosis. In particular, we pay attention to emerging roles of the Hippo-YAP/TAZ signaling pathway in stromal activation, hepatic fibrosis, and liver cancer. Full article
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26 pages, 3157 KiB  
Review
The Role of Tumor Necrosis Factor α in the Biology of Uterine Fibroids and the Related Symptoms
by Michał Ciebiera, Marta Włodarczyk, Magdalena Zgliczyńska, Krzysztof Łukaszuk, Błażej Męczekalski, Christopher Kobierzycki, Tomasz Łoziński and Grzegorz Jakiel
Int. J. Mol. Sci. 2018, 19(12), 3869; https://doi.org/10.3390/ijms19123869 - 04 Dec 2018
Cited by 49 | Viewed by 7668
Abstract
Uterine fibroids (UFs) are the most common benign tumors of the female genital tract. The incidence of UFs has been estimated at 25–80% depending on selected population. The pathophysiology of UFs remains poorly understood. The transformation of smooth muscle cells of the uterus [...] Read more.
Uterine fibroids (UFs) are the most common benign tumors of the female genital tract. The incidence of UFs has been estimated at 25–80% depending on selected population. The pathophysiology of UFs remains poorly understood. The transformation of smooth muscle cells of the uterus into abnormal, immortal cells, capable of clonal division, is the main component of all pathways leading to UF tumor formation and tumor necrosis factor α (TNF-α) is believed to be one of the key factors in this field. TNF-α is a cell signaling protein involved in systemic inflammation and is one of the cytokines responsible for the acute phase reaction. This publication presents current data about the role of tumor necrosis factor α in the biology of UFs and the related symptoms. TNF-α is an extremely important cytokine associated with the biology of UFs, UF-related symptoms and complaints. Its concentration has been proven to be elevated in women with clinically symptomatic UFs. The presented data suggest the presence of an “inflammation-like” state in women with UFs where TNF-α is a potent inflammation inducer. The origin of numerous symptoms reported by women with UFs can be traced back to the TNF-α influence. Nevertheless, our knowledge on this subject remains limited and TNF-α dependent pathways in UF pathophysiology should be investigated further. Full article
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23 pages, 835 KiB  
Review
YAP/TAZ Signaling as a Molecular Link between Fibrosis and Cancer
by Satoshi Noguchi, Akira Saito and Takahide Nagase
Int. J. Mol. Sci. 2018, 19(11), 3674; https://doi.org/10.3390/ijms19113674 - 20 Nov 2018
Cited by 163 | Viewed by 13560
Abstract
Tissue fibrosis is a pathological condition that is associated with impaired epithelial repair and excessive deposition of extracellular matrix (ECM). Fibrotic lesions increase the risk of cancer in various tissues, but the mechanism linking fibrosis and cancer is unclear. Yes-associated protein (YAP) and [...] Read more.
Tissue fibrosis is a pathological condition that is associated with impaired epithelial repair and excessive deposition of extracellular matrix (ECM). Fibrotic lesions increase the risk of cancer in various tissues, but the mechanism linking fibrosis and cancer is unclear. Yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ) are core components of the Hippo pathway, which have multiple biological functions in the development, homeostasis, and regeneration of tissues and organs. YAP/TAZ act as sensors of the structural and mechanical features of the cell microenvironment. Recent studies have shown aberrant YAP/TAZ activation in both fibrosis and cancer in animal models and human tissues. In fibroblasts, ECM stiffness mechanoactivates YAP/TAZ, which promote the production of profibrotic mediators and ECM proteins. This results in tissue stiffness, thus establishing a feed-forward loop of fibroblast activation and tissue fibrosis. In contrast, in epithelial cells, YAP/TAZ are activated by the disruption of cell polarity and increased ECM stiffness in fibrotic tissues, which promotes the proliferation and survival of epithelial cells. YAP/TAZ are also involved in the epithelial–mesenchymal transition (EMT), which contributes to tumor progression and cancer stemness. Importantly, the crosstalk with transforming growth factor (TGF)-β signaling and Wnt signaling is essential for the profibrotic and tumorigenic roles of YAP/TAZ. In this article, we review the latest advances in the pathobiological roles of YAP/TAZ signaling and their function as a molecular link between fibrosis and cancer. Full article
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