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Cancers
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Fascin in Cancer, from Prognostic Marker to Molecular Target
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Fascin in Cancer, from Prognostic Marker to Molecular Target

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

Deadline for manuscript submissions: closed (15 September 2021) | Viewed by 22720

Special Issue Editor

Prof. Dr. Pablo Conesa-Zamora

E-Mail Website
Guest Editor
Molecular Pathology and Pharmacogenetic Group (Institute for Biomedicine Research from Murcia (IMIB)), Spain
Interests: molecular oncology; pharmacogenetics; drug design; colorectal cancer

Special Issue Information

Dear Colleagues,

Metastasis is the cause of over 90% of deaths due to cancer. In order for the tumor cell to acquire an invasive and metastatic phenotype, specific cytoskeleton rearrangements are needed which mainly involve actin. Fascin is the key protein in actin bundling, which a crucial process for generation of invasive structures such as lamellipodia and invadopodia. Moreover, fascin contributes to metastasis by altering mitochondrial function and metabolic stress resistance. Not surprisingly, fascin overexpression is associated with tumors with aggressive behavior, high metastatic potential, and resistance to chemotherapy, and in most cases, available targeted therapies are lacking. Recent X-ray crystal structures of fascin bound to chemical compounds have opened the possibility for specific drugs designed to target this protein which plays a causative role in tumor progression. This Special Issue will cover the different functions of fascin in tumor development and promotion, its value as prognostic marker in cancer, and promising advances in the design of chemical compounds targeting this actin-bundling protein.

Prof. Dr. Pablo Conesa-Zamora
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 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.

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). 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

  • invasion
  • metastasis
  • fascin
  • molecular target
  • drug design
  • cytoskeleton
  • actin

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Published Papers (7 papers)

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Research

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19 pages, 4698 KiB  
Article
Inhibitors of the Actin-Bundling Protein Fascin-1 Developed for Tumor Therapy Attenuate the T-Cell Stimulatory Properties of Dendritic Cells
by Yanira Zeyn, Gregory Harms, Ingrid Tubbe, Evelyn Montermann, Nadine Röhrig, Maike Hartmann, Stephan Grabbe and Matthias Bros
Cancers 2022, 14(11), 2738; https://doi.org/10.3390/cancers14112738 - 31 May 2022
Cited by 2 | Viewed by 2629
Abstract
Background: Stimulated dendritic cells (DCs), which constitute the most potent population of antigen-presenting cells (APCs), express the actin-bundling protein Fascin-1 (Fscn1). In tumor cells, de novo expression of Fscn1 correlates with their invasive and metastatic properties. Therefore, Fscn1 inhibitors have been developed to [...] Read more.
Background: Stimulated dendritic cells (DCs), which constitute the most potent population of antigen-presenting cells (APCs), express the actin-bundling protein Fascin-1 (Fscn1). In tumor cells, de novo expression of Fscn1 correlates with their invasive and metastatic properties. Therefore, Fscn1 inhibitors have been developed to serve as antitumor agents. In this study, we were interested in better understanding the impact of Fscn1 inhibitors on DCs. Methods: In parallel settings, murine spleen cells and bone-marrow-derived DCs (BMDCs) were stimulated with lipopolysaccharide in the presence of Fscn1 inhibitors (NP-G2-044 and BDP-13176). An analysis of surface expression of costimulatory and coinhibitory receptors, as well as cytokine production, was performed by flow cytometry. Cytoskeletal alterations were assessed by confocal microscopy. The effects on the interactions of BMDCs with antigen-specific T cells were monitored by time lapse microscopy. The T-cell stimulatory and polarizing capacity of BMDCs were measured in proliferation assays and cytokine studies. Results: Administration of Fscn1 inhibitors diminished Fscn1 expression and the formation of dendritic processes by stimulated BMDCs and elevated CD273 (PD-L2) expression. Fscn1 inhibition attenuated the interaction of DCs with antigen-specific T cells and concomitant T-cell proliferation. Conclusions: Systemic administration of Fscn1 inhibitors for tumor therapy may also modulate DC-induced antitumor immune responses. Full article
(This article belongs to the Special Issue Fascin in Cancer, from Prognostic Marker to Molecular Target)
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26 pages, 5048 KiB  
Article
Alternative NF-κB Signaling Discriminates Induction of the Tumor Marker Fascin by the Viral Oncoproteins Tax-1 and Tax-2 of Human T-Cell Leukemia Viruses
by Stefanie Heym, Caroline F. Mohr, Hanna C. Engelbrecht, Bernhard Fleckenstein and Andrea K. Thoma-Kress
Cancers 2022, 14(3), 537; https://doi.org/10.3390/cancers14030537 - 21 Jan 2022
Cited by 1 | Viewed by 2234
Abstract
Transcriptional regulation of the actin-bundling protein and tumor marker Fascin is highly diverse depending on cell and tumor type. Previously, we discovered that the viral oncoprotein Tax-1 of human T-cell leukemia virus type 1 (HTLV-1) considerably enhances Fascin expression in T-cells, depending on [...] Read more.
Transcriptional regulation of the actin-bundling protein and tumor marker Fascin is highly diverse depending on cell and tumor type. Previously, we discovered that the viral oncoprotein Tax-1 of human T-cell leukemia virus type 1 (HTLV-1) considerably enhances Fascin expression in T-cells, depending on classical NF-κB signaling. In this study, we asked if the non-oncogenic Tax-2 of the related HTLV-2 is still able to induce Fascin by using luciferase assays, immunoblot, and qPCR. We found that Tax-2 only slightly induces Fascin expression compared to Tax-1; however, both Tax-1 and Tax-2 comparably activated a 1.6 kb fragment in the human Fascin promoter including Tax-responsive elements. Furthermore, we identified a link between Tax-induced activity of the alternative NF-κB pathway and Fascin induction. While treatment with the second mitochondria-derived activator of caspases (SMAC)-mimetic AZD5582, a compound known to robustly activate alternative NF-κB signaling, did not induce Fascin, combination of AZD5582 with activation of classical NF-κB signaling by Tax-2 significantly induced Fascin expression. In conclusion, our data demonstrate that both classical and alternative NF-κB activity are necessary for strong Fascin induction by the viral Tax oncoproteins, thus, shedding new light on the regulation of Fascin in T-cells and during viral transformation. Full article
(This article belongs to the Special Issue Fascin in Cancer, from Prognostic Marker to Molecular Target)
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12 pages, 2328 KiB  
Article
Fascin Inhibitors Decrease Cell Migration and Adhesion While Increase Overall Survival of Mice Bearing Bladder Cancers
by Zhankui Zhao, Yufeng Wang, J. Jillian Zhang and Xin-Yun Huang
Cancers 2021, 13(11), 2698; https://doi.org/10.3390/cancers13112698 - 30 May 2021
Cited by 13 | Viewed by 2554
Abstract
Bladder cancer is one of the most common cancers in the world. Early stage bladder tumors can be surgically removed, but these patients usually have relapses. When bladder cancer becomes metastatic, survival is very low. There is an urgent need for new treatments [...] Read more.
Bladder cancer is one of the most common cancers in the world. Early stage bladder tumors can be surgically removed, but these patients usually have relapses. When bladder cancer becomes metastatic, survival is very low. There is an urgent need for new treatments for metastatic bladder cancers. Here, we report that a new fascin inhibitor decreases the migration and adhesion of bladder cancer cells. Furthermore, this inhibitor decreases the primary tumor growth and increases the overall survival of mice bearing bladder cancers, alone, as well as in combination with the chemotherapy medication, cisplatin, or the immune checkpoint inhibitor, anti-PD-1 antibody. These data suggest that fascin inhibitors can be explored as a new treatment for bladder cancers. Full article
(This article belongs to the Special Issue Fascin in Cancer, from Prognostic Marker to Molecular Target)
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21 pages, 6592 KiB  
Article
The FDA-Approved Antiviral Raltegravir Inhibits Fascin1-Dependent Invasion of Colorectal Tumor Cells In Vitro and In Vivo
by Begoña Alburquerque-González, Ángel Bernabé-García, Manuel Bernabé-García, Javier Ruiz-Sanz, Fernando Feliciano López-Calderón, Leonardo Gonnelli, Lucia Banci, Jorge Peña-García, Irene Luque, Francisco José Nicolás, María Luisa Cayuela-Fuentes, Enrico Luchinat, Horacio Pérez-Sánchez, Silvia Montoro-García and Pablo Conesa-Zamora
Cancers 2021, 13(4), 861; https://doi.org/10.3390/cancers13040861 - 18 Feb 2021
Cited by 26 | Viewed by 4232
Abstract
Background: Fascin1 is the key actin-bundling protein involved in cancer invasion and metastasis whose expression is associated with bad prognosis in tumor from different origins. Methods: In the present study, virtual screening (VS) was performed for the search of Fascin1 inhibitors and RAL, [...] Read more.
Background: Fascin1 is the key actin-bundling protein involved in cancer invasion and metastasis whose expression is associated with bad prognosis in tumor from different origins. Methods: In the present study, virtual screening (VS) was performed for the search of Fascin1 inhibitors and RAL, an FDA-approved inhibitor of human immunodeficiency virus-1 (HIV-1) integrase, was identified as a potential Fascin1 inhibitor. Biophysical techniques including nuclear magnetic resonance (NMR) and differential scanning fluorimetry (DSF) were carried out in order to confirm RAL as a Fascin1 blocker. The effect of RAL on actin-bundling activity Fascin1 was assessed by transmission electron microscopy (TEM), immunofluorescence, migration, and invasion assays on two human colorectal adenocarcinoma cell lines: HCT-116 and DLD-1. In addition, the anti-metastatic potential of RAL was in vivo evaluated by using the zebrafish animal model. Results: NMR and DSF confirmed in silico predictions and TEM demonstrated the RAL-induced disorganization of the actin structure compared to control conditions. The protrusion of lamellipodia in cancer cell line overexpressing Fascin1 (HCT-116) was abolished in the presence of this drug. By following the addition of RAL, migration of HCT-116 and DLD-1 cell lines was significantly inhibited. Finally, using endogenous and exogenous models of Fascin1 expression, the invasive capacity of colorectal tumor cells was notably impaired in the presence of RAL in vivo assays; without undesirable cytotoxic effects. Conclusion: The current data show the in vitro and in vivo efficacy of the antiretroviral drug RAL in inhibiting human colorectal cancer cells invasion and metastasis in a Fascin1-dependent manner. Full article
(This article belongs to the Special Issue Fascin in Cancer, from Prognostic Marker to Molecular Target)
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Graphical abstract

20 pages, 5285 KiB  
Article
Anti-Metastasis Fascin Inhibitors Decrease the Growth of Specific Subtypes of Cancers
by Yufeng Wang, J. Jillian Zhang and Xin-Yun Huang
Cancers 2020, 12(8), 2287; https://doi.org/10.3390/cancers12082287 - 14 Aug 2020
Cited by 18 | Viewed by 3121
Abstract
Fascin is an actin-bundling protein that is critical for filopodial formation and other cellular cytoskeletal structures. An elevated expression of fascin has been observed in tumor cells and is correlated with a shorter survival of cancer patients. Given its roles in tumor cell [...] Read more.
Fascin is an actin-bundling protein that is critical for filopodial formation and other cellular cytoskeletal structures. An elevated expression of fascin has been observed in tumor cells and is correlated with a shorter survival of cancer patients. Given its roles in tumor cell migration and invasion, we have developed small-molecule fascin inhibitors to prevent and delay tumor metastasis. Here we report the characterization of a new fascin inhibitor in mice. In addition to its inhibitory effects on tumor metastasis, we also report that fascin inhibitors can decrease the growth of specific subtypes of cancers, including epidermal growth factor receptor (EGFR)-high triple-negative breast cancer, and activated B-cell subtypes of diffuse large B-cell lymphoma. Hence, fascin inhibitors can be used to not only inhibit tumor metastasis, but also decrease the tumor growth of specific cancer types. Full article
(This article belongs to the Special Issue Fascin in Cancer, from Prognostic Marker to Molecular Target)
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Review

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21 pages, 1124 KiB  
Review
Fascin in Gynecological Cancers: An Update of the Literature
by Ishita Gupta, Semir Vranic, Hamda Al-Thawadi and Ala-Eddin Al Moustafa
Cancers 2021, 13(22), 5760; https://doi.org/10.3390/cancers13225760 - 17 Nov 2021
Cited by 8 | Viewed by 2913
Abstract
Fascin is an actin-binding protein that is encoded by the FSCN1 gene (located on chromosome 7). It triggers membrane projections and stimulates cell motility in cancer cells. Fascin overexpression has been described in different types of human cancers in which its expression correlated [...] Read more.
Fascin is an actin-binding protein that is encoded by the FSCN1 gene (located on chromosome 7). It triggers membrane projections and stimulates cell motility in cancer cells. Fascin overexpression has been described in different types of human cancers in which its expression correlated with tumor growth, migration, invasion, and metastasis. Moreover, overexpression of fascin was found in oncovirus-infected cells, such as human papillomaviruses (HPVs) and Epstein-Barr virus (EBV), disrupting the cell–cell adhesion and enhancing cancer progression. Based on these findings, several studies reported fascin as a potential biomarker and a therapeutic target in various cancers. This review provides a brief overview of the FSCN1 role in various cancers with emphasis on gynecological malignancies. We also discuss fascin interactions with other genes and oncoviruses through which it might induce cancer development and progression. Full article
(This article belongs to the Special Issue Fascin in Cancer, from Prognostic Marker to Molecular Target)
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22 pages, 2103 KiB  
Review
Emerging Role of Fascin-1 in the Pathogenesis, Diagnosis, and Treatment of the Gastrointestinal Cancers
by Bojana Ristic, Jonathan Kopel, Syed A. A. Sherazi, Shweta Gupta, Sonali Sachdeva, Pardeep Bansal, Aman Ali, Abhilash Perisetti and Hemant Goyal
Cancers 2021, 13(11), 2536; https://doi.org/10.3390/cancers13112536 - 21 May 2021
Cited by 15 | Viewed by 3548
Abstract
Gastrointestinal (GI) cancers, including esophageal, gastric, colorectal, liver, and pancreatic cancers, remain as one of the leading causes of death worldwide, with a large proportion accounting for fatalities related to metastatic disease. Invasion of primary cancer occurs by the actin cytoskeleton remodeling, including [...] Read more.
Gastrointestinal (GI) cancers, including esophageal, gastric, colorectal, liver, and pancreatic cancers, remain as one of the leading causes of death worldwide, with a large proportion accounting for fatalities related to metastatic disease. Invasion of primary cancer occurs by the actin cytoskeleton remodeling, including the formation of the filopodia, stereocilia, and other finger-like membrane protrusions. The crucial step of actin remodeling in the malignant cells is mediated by the fascin protein family, with fascin-1 being the most active. Fascin-1 is an actin-binding protein that cross-links filamentous actin into tightly packed parallel bundles, giving rise to finger-like cell protrusions, thus equipping the cell with the machinery necessary for adhesion, motility, and invasion. Thus, fascin-1 has been noted to be a key component for determining patient diagnosis and treatment plan. Indeed, the overexpression of fascin-1 in GI tract cancers has been associated with a poor clinical prognosis and metastatic progression. Moreover, fascin-1 has received attention as a potential therapeutic target for metastatic GI tract cancers. In this review, we provide an up-to-date literature review of the role of fascin-1 in the initiation of GI tract cancers, metastatic progression, and patients’ clinical outcomes. Full article
(This article belongs to the Special Issue Fascin in Cancer, from Prognostic Marker to Molecular Target)
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