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Links between Fibrogenesis and Cancer: Mechanistic and Therapeutic Challenges 2.0
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Links between Fibrogenesis and Cancer: Mechanistic and Therapeutic Challenges 2.0

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 (1 September 2021) | Viewed by 52909

Special Issue Editor

Prof. Dr. Esteban C. Gabazza

E-Mail Website
Guest 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,

This Special Issue is a continuation of our previous Special Issue "Links between Fibrogenesis and Cancer: Mechanistic and Therapeutic Challenges" (https://www.mdpi.com/journal/ijms/special_issues/fibrogenesis).

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

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.

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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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Related Special Issue

Published Papers (8 papers)

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Editorial

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3 pages, 199 KiB  
Editorial
Chronic Fibrosis and Its Progression to Cancer
by Taro Yasuma and Esteban C. Gabazza
Int. J. Mol. Sci. 2022, 23(7), 3924; https://doi.org/10.3390/ijms23073924 - 1 Apr 2022
Viewed by 1735
Abstract
The terminal stage of many chronic inflammatory diseases is organ fibrosis [...] Full article
(This article belongs to the Special Issue Links between Fibrogenesis and Cancer: Mechanistic and Therapeutic Challenges 2.0)

Research

Jump to: Editorial, Review

23 pages, 5673 KiB  
Article
Phenotypic Plasticity of Fibroblasts during Mammary Carcinoma Development
by Eiman Elwakeel, Mirko Brüggemann, Annika F. Fink, Marcel H. Schulz, Tobias Schmid, Rajkumar Savai, Bernhard Brüne, Kathi Zarnack and Andreas Weigert
Int. J. Mol. Sci. 2019, 20(18), 4438; https://doi.org/10.3390/ijms20184438 - 9 Sep 2019
Cited by 15 | Viewed by 5543
Abstract
Cancer-associated fibroblasts (CAFs) in the tumor microenvironment contribute to all stages of tumorigenesis and are usually considered to be tumor-promoting cells. CAFs show a remarkable degree of heterogeneity, which is attributed to developmental origin or to local environmental niches, resulting in distinct CAF [...] Read more.
Cancer-associated fibroblasts (CAFs) in the tumor microenvironment contribute to all stages of tumorigenesis and are usually considered to be tumor-promoting cells. CAFs show a remarkable degree of heterogeneity, which is attributed to developmental origin or to local environmental niches, resulting in distinct CAF subsets within individual tumors. While CAF heterogeneity is frequently investigated in late-stage tumors, data on longitudinal CAF development in tumors are lacking. To this end, we used the transgenic polyoma middle T oncogene-induced mouse mammary carcinoma model and performed whole transcriptome analysis in FACS-sorted fibroblasts from early- and late-stage tumors. We observed a shift in fibroblast populations over time towards a subset previously shown to negatively correlate with patient survival, which was confirmed by multispectral immunofluorescence analysis. Moreover, we identified a transcriptomic signature distinguishing CAFs from early- and late-stage tumors. Importantly, the signature of early-stage CAFs correlated well with tumor stage and survival in human mammary carcinoma patients. A random forest analysis suggested predictive value of the complete set of differentially expressed genes between early- and late-stage CAFs on bulk tumor patient samples, supporting the clinical relevance of our findings. In conclusion, our data show transcriptome alterations in CAFs during tumorigenesis in the mammary gland, which suggest that CAFs are educated by the tumor over time to promote tumor development. Moreover, we show that murine CAF gene signatures can harbor predictive value for human cancer. Full article
(This article belongs to the Special Issue Links between Fibrogenesis and Cancer: Mechanistic and Therapeutic Challenges 2.0)
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Review

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16 pages, 706 KiB  
Review
Molecular Mechanisms of Malignant Transformation of Oral Submucous Fibrosis by Different Betel Quid Constituents—Does Fibroblast Senescence Play a Role?
by Pangzhen Zhang, Nathaniel Quan En Chua, Simon Dang, Ashleigh Davis, Kah Wee Chong, Stephen S. Prime and Nicola Cirillo
Int. J. Mol. Sci. 2022, 23(3), 1637; https://doi.org/10.3390/ijms23031637 - 31 Jan 2022
Cited by 29 | Viewed by 5230
Abstract
Betel quid (BQ) is a package of mixed constituents that is chewed by more than 600 million people worldwide, particularly in Asia. The formulation of BQ depends on a variety of factors but typically includes areca nut, betel leaf, and slaked lime and [...] Read more.
Betel quid (BQ) is a package of mixed constituents that is chewed by more than 600 million people worldwide, particularly in Asia. The formulation of BQ depends on a variety of factors but typically includes areca nut, betel leaf, and slaked lime and may or may not contain tobacco. BQ chewing is strongly associated with the development of potentially malignant and malignant diseases of the mouth such as oral submucous fibrosis (OSMF) and oral squamous cell carcinoma (OSCC), respectively. We have shown recently that the constituents of BQ vary geographically and that the capacity to induce disease reflects the distinct chemical composition of the BQ. In this review, we examined the diverse chemical constituents of BQ and their putative role in oral carcinogenesis. Four major areca alkaloids—arecoline, arecaidine, guvacoline and guvacine—together with the polyphenols, were identified as being potentially involved in oral carcinogenesis. Further, we propose that fibroblast senescence, which is induced by certain BQ components, may be a key driver of tumour progression in OSMF and OSCC. Our study emphasizes that the characterization of the detrimental or protective effects of specific BQ ingredients may facilitate the development of targeted BQ formulations to prevent and/or treat potentially malignant oral disorders and oral cancer in BQ users. Full article
(This article belongs to the Special Issue Links between Fibrogenesis and Cancer: Mechanistic and Therapeutic Challenges 2.0)
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28 pages, 1188 KiB  
Review
Molecular Mechanisms and Cellular Contribution from Lung Fibrosis to Lung Cancer Development
by Anna Valeria Samarelli, Valentina Masciale, Beatrice Aramini, Georgina Pamela Coló, Roberto Tonelli, Alessandro Marchioni, Giulia Bruzzi, Filippo Gozzi, Dario Andrisani, Ivana Castaniere, Linda Manicardi, Antonio Moretti, Luca Tabbì, Giorgia Guaitoli, Stefania Cerri, Massimo Dominici and Enrico Clini
Int. J. Mol. Sci. 2021, 22(22), 12179; https://doi.org/10.3390/ijms222212179 - 10 Nov 2021
Cited by 53 | Viewed by 7488
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung disease (ILD) of unknown aetiology, with a median survival of 2–4 years from the time of diagnosis. Although IPF has unknown aetiology by definition, there have been identified several risks factors increasing [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung disease (ILD) of unknown aetiology, with a median survival of 2–4 years from the time of diagnosis. Although IPF has unknown aetiology by definition, there have been identified several risks factors increasing the probability of the onset and progression of the disease in IPF patients such as cigarette smoking and environmental risk factors associated with domestic and occupational exposure. Among them, cigarette smoking together with concomitant emphysema might predispose IPF patients to lung cancer (LC), mostly to non-small cell lung cancer (NSCLC), increasing the risk of lung cancer development. To this purpose, IPF and LC share several cellular and molecular processes driving the progression of both pathologies such as fibroblast transition proliferation and activation, endoplasmic reticulum stress, oxidative stress, and many genetic and epigenetic markers that predispose IPF patients to LC development. Nintedanib, a tyrosine–kinase inhibitor, was firstly developed as an anticancer drug and then recognized as an anti-fibrotic agent based on the common target molecular pathway. In this review our aim is to describe the updated studies on common cellular and molecular mechanisms between IPF and lung cancer, knowledge of which might help to find novel therapeutic targets for this disease combination. Full article
(This article belongs to the Special Issue Links between Fibrogenesis and Cancer: Mechanistic and Therapeutic Challenges 2.0)
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15 pages, 1216 KiB  
Review
Impact of Dietary Fat on the Progression of Liver Fibrosis: Lessons from Animal and Cell Studies
by Fangping Jia, Xiao Hu, Takefumi Kimura and Naoki Tanaka
Int. J. Mol. Sci. 2021, 22(19), 10303; https://doi.org/10.3390/ijms221910303 - 24 Sep 2021
Cited by 15 | Viewed by 3439
Abstract
Previous studies have revealed that a high-fat diet is one of the key contributors to the progression of liver fibrosis, and increasing studies are devoted to analyzing the different influences of diverse fat sources on the progression of non-alcoholic steatohepatitis. When we treated [...] Read more.
Previous studies have revealed that a high-fat diet is one of the key contributors to the progression of liver fibrosis, and increasing studies are devoted to analyzing the different influences of diverse fat sources on the progression of non-alcoholic steatohepatitis. When we treated three types of isocaloric diets that are rich in cholesterol, saturated fatty acid (SFA) and trans fatty acid (TFA) with hepatitis C virus core gene transgenic mice that spontaneously developed hepatic steatosis without apparent fibrosis, TFA and cholesterol-rich diet, but not SFA-rich diet, displayed distinct hepatic fibrosis. This review summarizes the recent advances in animal and cell studies regarding the effects of these three types of fat on liver fibrogenesis. Full article
(This article belongs to the Special Issue Links between Fibrogenesis and Cancer: Mechanistic and Therapeutic Challenges 2.0)
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25 pages, 1082 KiB  
Review
Dendritic Cell and T Cell Crosstalk in Liver Fibrogenesis and Hepatocarcinogenesis: Implications for Prevention and Therapy of Liver Cancer
by Isabella Lurje, Linda Hammerich and Frank Tacke
Int. J. Mol. Sci. 2020, 21(19), 7378; https://doi.org/10.3390/ijms21197378 - 6 Oct 2020
Cited by 71 | Viewed by 7722
Abstract
Liver fibrosis is a chronic, highly prevalent disease that may progress to cirrhosis and substantially increases the risk for development of hepatocellular carcinoma (HCC). Fibrotic livers are characterized by an inflammatory microenvironment that is composed of various immunologically active cells, including liver-resident populations [...] Read more.
Liver fibrosis is a chronic, highly prevalent disease that may progress to cirrhosis and substantially increases the risk for development of hepatocellular carcinoma (HCC). Fibrotic livers are characterized by an inflammatory microenvironment that is composed of various immunologically active cells, including liver-resident populations (e.g., Kupffer cells, hepatic stellate cells and sinusoidal endothelium) and infiltrating leukocytes (e.g., monocytes, monocyte-derived macrophages, neutrophils and lymphocytes). While inflammatory injury drives both fibrogenesis and carcinogenesis, the tolerogenic microenvironment of the liver conveys immunosuppressive effects that encourage tumor growth. An insufficient crosstalk between dendritic cells (DCs), the professional antigen presenting cells, and T cells, the efficient anti-tumor effector cells, is one of the main mechanisms of HCC tumor tolerance. The meticulous analysis of patient samples and mouse models of fibrosis-HCC provided in-depth insights into molecular mechanisms of immune interactions in liver cancer. The therapeutic modulation of this multifaceted immunological response, e.g., by inhibiting immune checkpoint molecules, in situ vaccination, oncolytic viruses or combinations thereof, is a rapidly evolving field that holds the potential to improve the outcome of patients with HCC. This review aims to highlight the current understanding of DC–T cell interactions in fibrogenesis and hepatocarcinogenesis and to illustrate the potentials and pitfalls of therapeutic clinical translation. Full article
(This article belongs to the Special Issue Links between Fibrogenesis and Cancer: Mechanistic and Therapeutic Challenges 2.0)
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19 pages, 278 KiB  
Review
Oral Submucous Fibrosis: A Review on Biomarkers, Pathogenic Mechanisms, and Treatments
by Yen-Wen Shen, Yin-Hwa Shih, Lih-Jyh Fuh and Tzong-Ming Shieh
Int. J. Mol. Sci. 2020, 21(19), 7231; https://doi.org/10.3390/ijms21197231 - 30 Sep 2020
Cited by 77 | Viewed by 11918
Abstract
Oral submucous fibrosis (OSF) is a collagen deposition disorder that affects a patient’s oral function and quality of life. It may also potentially transform into malignancy. This review summarizes the risk factors, pathogenic mechanisms, and treatments of OSF based on clinical and bio-molecular [...] Read more.
Oral submucous fibrosis (OSF) is a collagen deposition disorder that affects a patient’s oral function and quality of life. It may also potentially transform into malignancy. This review summarizes the risk factors, pathogenic mechanisms, and treatments of OSF based on clinical and bio-molecular evidence. Betel nut chewing is a major risk factor that causes OSF in Asia. However, no direct evidence of arecoline-induced carcinogenesis has been found in animal models. Despite identification of numerous biomarkers of OSF lesions and conducting trials with different drug combinations, clinicians still adopt conservative treatments that primarily focus on relieving the symptoms of OSF. Treatments focus on reducing inflammation and improving mouth opening to improve a patient’s quality of life. In conclusion, high-quality clinical studies are needed to aid clinicians in developing and applying molecular biomarkers as well as standard treatment guidelines. Full article
(This article belongs to the Special Issue Links between Fibrogenesis and Cancer: Mechanistic and Therapeutic Challenges 2.0)
17 pages, 714 KiB  
Review
Molecular Mechanisms: Connections between Nonalcoholic Fatty Liver Disease, Steatohepatitis and Hepatocellular Carcinoma
by Tatsuo Kanda, Taichiro Goto, Yosuke Hirotsu, Ryota Masuzaki, Mitsuhiko Moriyama and Masao Omata
Int. J. Mol. Sci. 2020, 21(4), 1525; https://doi.org/10.3390/ijms21041525 - 23 Feb 2020
Cited by 71 | Viewed by 8922
Abstract
Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), causes hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The patatin-like phospholipase-3 (PNPLA3) I148M sequence variant is one of the strongest genetic determinants of NAFLD/NASH. PNPLA3 is an independent risk factor for HCC among patients [...] Read more.
Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), causes hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The patatin-like phospholipase-3 (PNPLA3) I148M sequence variant is one of the strongest genetic determinants of NAFLD/NASH. PNPLA3 is an independent risk factor for HCC among patients with NASH. The obesity epidemic is closely associated with the rising prevalence and severity of NAFLD/NASH. Furthermore, metabolic syndrome exacerbates the course of NAFLD/NASH. These factors are able to induce apoptosis and activate immune and inflammatory pathways, resulting in the development of hepatic fibrosis and NASH, leading to progression toward HCC. Small intestinal bacterial overgrowth (SIBO), destruction of the intestinal mucosa barrier function and a high-fat diet all seem to exacerbate the development of hepatic fibrosis and NASH, leading to HCC in patients with NAFLD/NASH. Thus, the intestinal microbiota may play a role in the development of NAFLD/NASH. In this review, we describe recent advances in our knowledge of the molecular mechanisms contributing to the development of hepatic fibrosis and HCC in patients with NAFLD/NASH. Full article
(This article belongs to the Special Issue Links between Fibrogenesis and Cancer: Mechanistic and Therapeutic Challenges 2.0)
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