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Cancers
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Multicellular Effects of STAT3 in the Tumour Microenvironment
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Multicellular Effects of STAT3 in the Tumour Microenvironment

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

Deadline for manuscript submissions: closed (10 July 2022) | Viewed by 37029

Special Issue Editor

Dr. Ashwini L. Chand

E-Mail Website
Guest Editor
Cancer and Inflammation Program, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Heidelberg, VIC 3084, Australia
Interests: cancer biology; tumour microenvironment; cytokine signalling; tumour immunology; metastasis; cancer therapeutics

Special Issue Information

Dear Colleagues,

The signal transducer and activator of transcription 3 (STAT3) plays important roles during embryonic development as well as in the regulation of a range of homeostatic functions in adult tissues. The importance of STAT3 has been widely characterized in pluripotent stem cells and differentiated cellular lineages, including epithelial, fibroblast, endothelial and immune cells. The multicellular contribution of STAT3-dependent activity within the tumour microenvironment has been mainly shown to promote tumour development and metastasis. Conversely, there are distinct circumstances in which the activation of STAT3 has tumour-suppressive effects. Factors contributing to these contrasting effects of STAT3 either on tumour progression or suppression may likely include tumour type, cellular content, tumour molecular signature, stage of disease, as well as treatment exposure. In this Special Issue, we aim to showcase articles (original research and review manuscripts) that highlight the competing roles of STAT3 within the tumour microenvironment. A multitude of STAT3 inhibitors are now in preclinical development or under evaluation in clinical trials for their therapeutic efficacy in cancer. Hence, there is a distinct need for a better understanding of the diverse mechanisms associated with STAT3 activation, and how suppression of STAT3 activity could reduce or enhance tumour progression in different cancers.

Dr. Ashwini L. Chand
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.

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. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

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

  • STAT3
  • tumour microenvironment
  • cytokine signalling
  • immune evasion
  • metastasis
  • targeted treatments
  • chemoresistance
  • cancer stem cells
  • cell death
  • genetic instability and mutational signatures

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Published Papers (7 papers)

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Research

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17 pages, 1500 KiB  
Article
Paracrine IL-6 Signaling Confers Proliferation between Heterogeneous Inflammatory Breast Cancer Sub-Clones
by Riley J. Morrow, Amr H. Allam, Belinda Yeo, Siddhartha Deb, Carmel Murone, Elgene Lim, Cameron N. Johnstone and Matthias Ernst
Cancers 2022, 14(9), 2292; https://doi.org/10.3390/cancers14092292 - 4 May 2022
Cited by 8 | Viewed by 2990
Abstract
Inflammatory breast cancer (IBC) describes a highly aggressive form of breast cancer of diverse molecular subtypes and clonal heterogeneity across individual tumors. Accordingly, IBC is recognized by its clinical signs of inflammation, associated with expression of interleukin (IL)-6 and other inflammatory cytokines. Here, [...] Read more.
Inflammatory breast cancer (IBC) describes a highly aggressive form of breast cancer of diverse molecular subtypes and clonal heterogeneity across individual tumors. Accordingly, IBC is recognized by its clinical signs of inflammation, associated with expression of interleukin (IL)-6 and other inflammatory cytokines. Here, we investigate whether sub-clonal differences between expression of components of the IL-6 signaling cascade reveal a novel role for IL-6 to mediate a proliferative response in trans using two prototypical IBC cell lines. We find that SUM149 and SUM 190 cells faithfully replicate differential expression observed in a subset of human IBC specimens between IL-6, the activated form of the key downstream transcription factor STAT3, and of the HER2 receptor. Surprisingly, the high level of IL-6 produced by SUM149 cells activates STAT3 and stimulates proliferation in SUM190 cells, but not in SUM149 cells with low IL-6R expression. Importantly, SUM149 conditioned medium or co-culture with SUM149 cells induced growth of SUM190 cells, and this effect was abrogated by the IL-6R neutralizing antibody Tocilizumab. The results suggest a novel function for inter-clonal IL-6 signaling in IBC, whereby IL-6 promotes in trans proliferation of IL-6R and HER2-expressing responsive sub-clones and, therefore, may provide a vulnerability that can be exploited therapeutically by repurposing of a clinically approved antibody. Full article
(This article belongs to the Special Issue Multicellular Effects of STAT3 in the Tumour Microenvironment)
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18 pages, 6388 KiB  
Article
Targeting STAT3 Signaling in COL1+ Fibroblasts Controls Colitis-Associated Cancer in Mice
by Christina Heichler, Anabel Schmied, Karin Enderle, Kristina Scheibe, Marta Murawska, Benjamin Schmid, Maximilian J. Waldner, Markus F. Neurath and Clemens Neufert
Cancers 2022, 14(6), 1472; https://doi.org/10.3390/cancers14061472 - 14 Mar 2022
Cited by 6 | Viewed by 4051
Abstract
Colorectal cancer (CRC) is a common disease and has limited treatment options. The importance of cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) in CRC has been increasingly recognized. However, the role of CAF subsets in CRC is hardly understood and opposing functions [...] Read more.
Colorectal cancer (CRC) is a common disease and has limited treatment options. The importance of cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) in CRC has been increasingly recognized. However, the role of CAF subsets in CRC is hardly understood and opposing functions of type I (COL1+) vs. type VI (COL6+) collagen-expressing subsets were reported before with respect to NFκB-related signaling. Here, we have focused on COL1+ fibroblasts, which represent a frequent CAF population in CRC and studied their role upon STAT3 activation in vivo. Using a dual strategy with a conditional gain-of-function and a conditional loss-of-function approach in an in vivo model of colitis-associated cancer, tumor development was evaluated by different readouts, including advanced imaging methodologies, e.g., light sheet microscopy and CT-scan. Our data demonstrate that the inhibition of STAT3 activation in COL1+ fibroblasts reduces tumor burden, whereas the constitutive activation of STAT3 promotes the development of inflammation-driven CRC. In addition, our work characterizes the co-expression and distribution of type I and type VI collagen by CAFs in inflammation-associated colorectal cancer using reporter mice. This work indicates a critical contribution of STAT3 signaling in COL1+ CAFs, suggesting that the blockade of STAT3 activation in type I collagen-expressing fibroblasts could serve as promising therapeutic targets in colitis-associated CRC. In combination with previous work by others and us, our current findings highlight the context-dependent roles of COL1+ CAFs and COL6+ CAFs that might be variable according to the specific pathway activated. Full article
(This article belongs to the Special Issue Multicellular Effects of STAT3 in the Tumour Microenvironment)
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16 pages, 3406 KiB  
Article
STAT1 and STAT3 Exhibit a Crosstalk and Are Associated with Increased Inflammation in Hepatocellular Carcinoma
by Carolin Ploeger, Johannes Schreck, Thorben Huth, Angelika Fraas, Thomas Albrecht, Alphonse Charbel, Junfang Ji, Stephan Singer, Kai Breuhahn, Stefan Pusch, Bruno Christian Köhler, Christoph Springfeld, Peter Schirmacher, Arianeb Mehrabi, Benjamin Goeppert and Stephanie Roessler
Cancers 2022, 14(5), 1154; https://doi.org/10.3390/cancers14051154 - 23 Feb 2022
Cited by 14 | Viewed by 4073
Abstract
Liver cancers, which are mostly hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are very aggressive tumors with poor prognosis. Therapeutic options with curative intent are largely limited to surgery and available systemic therapies show limited benefit. Signal transducer and activator of transcription 1 (STAT1) [...] Read more.
Liver cancers, which are mostly hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are very aggressive tumors with poor prognosis. Therapeutic options with curative intent are largely limited to surgery and available systemic therapies show limited benefit. Signal transducer and activator of transcription 1 (STAT1) and 3 (STAT3) are key transcription factors activated by pro-inflammatory cytokines such as interferon-γ (IFN-γ) and interleukin-6 (IL-6). In this study, we combined in vitro cell culture experiments and immunohistochemical analyses of human HCC (N = 124) and CCA (N = 138) specimens. We observed that in the absence of STAT3, IL-6 induced the activation of STAT1 and its target genes suggesting that IL-6 derived from the tumor microenvironment may activate both STAT1 and STAT3 target genes in HCC tumor cells. In addition, STAT1 and STAT3 were highly activated in a subset of HCC, which exhibited a high degree of infiltrating CD8- and FOXP3-positive immune cells and PD-L1 expression. Our results demonstrate that STAT1 and STAT3 are expressed and activated in HCC and tumor infiltrating immune cells. In addition, HCC cases with high STAT1 and STAT3 expression also exhibited a high degree of immune cell infiltration, suggesting increased immunological tolerance. Full article
(This article belongs to the Special Issue Multicellular Effects of STAT3 in the Tumour Microenvironment)
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22 pages, 7485 KiB  
Article
Onco-miR-21 Promotes Stat3-Dependent Gastric Cancer Progression
by Janson Tse, Thomas Pierce, Annalisa L. E. Carli, Mariah G. Alorro, Stefan Thiem, Eric G. Marcusson, Matthias Ernst and Michael Buchert
Cancers 2022, 14(2), 264; https://doi.org/10.3390/cancers14020264 - 6 Jan 2022
Cited by 18 | Viewed by 2668
Abstract
MicroRNA-21 (miR-21) is a small, non-coding RNA overexpressed in gastric cancer and many other solid malignancies, where it exhibits both pro-and anti-tumourigenic properties. However, the pathways regulating miR-21 and the consequences of its inhibition in gastric cancer remain incompletely understood. By exploiting the [...] Read more.
MicroRNA-21 (miR-21) is a small, non-coding RNA overexpressed in gastric cancer and many other solid malignancies, where it exhibits both pro-and anti-tumourigenic properties. However, the pathways regulating miR-21 and the consequences of its inhibition in gastric cancer remain incompletely understood. By exploiting the spontaneous Stat3-dependent formation of inflammation-associated gastric tumors in Gp130F/F mice, we functionally established miR-21 as a Stat3-controlled driver of tumor growth and progression. We reconciled our discoveries by identifying several conserved Stat3 binding motifs upstream of the miR-21 gene promoter, and showed that the systemic administration of a miR-21-specific antisense oligonucleotide antagomir reduced the established gastric tumor burden in Gp130F/F mice. We molecularly delineated the therapeutic benefits of miR-21 inhibition with the functional restoration of PTEN in vitro and in vivo, alongside an attenuated epithelial-to-mesenchymal transition and the extracellular matrix remodeling phenotype of tumors. We corroborated our preclinical findings by correlating high STAT3 and miR-21 expression with the reduced survival probability of gastric cancer patients. Collectively, our results provide a molecular framework by which miR-21 mediates inflammation-associated gastric cancer progression, and establish miR-21 as a robust therapeutic target for solid malignancies characterized by excessive Stat3 activity. Full article
(This article belongs to the Special Issue Multicellular Effects of STAT3 in the Tumour Microenvironment)
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Review

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16 pages, 2360 KiB  
Review
Cell Type-Specific Roles of STAT3 Signaling in the Pathogenesis and Progression of K-ras Mutant Lung Adenocarcinoma
by Michael J. Clowers and Seyed Javad Moghaddam
Cancers 2022, 14(7), 1785; https://doi.org/10.3390/cancers14071785 - 31 Mar 2022
Cited by 6 | Viewed by 2787
Abstract
Worldwide, lung cancer, particularly K-ras mutant lung adenocarcinoma (KM-LUAD), is the leading cause of cancer mortality because of its high incidence and low cure rate. To treat and prevent KM-LUAD, there is an urgent unmet need for alternative strategies targeting downstream effectors of [...] Read more.
Worldwide, lung cancer, particularly K-ras mutant lung adenocarcinoma (KM-LUAD), is the leading cause of cancer mortality because of its high incidence and low cure rate. To treat and prevent KM-LUAD, there is an urgent unmet need for alternative strategies targeting downstream effectors of K-ras and/or its cooperating pathways. Tumor-promoting inflammation, an enabling hallmark of cancer, strongly participates in the development and progression of KM-LUAD. However, our knowledge of the dynamic inflammatory mechanisms, immunomodulatory pathways, and cell-specific molecular signals mediating K-ras-induced lung tumorigenesis is substantially deficient. Nevertheless, within this signaling complexity, an inflammatory pathway is emerging as a druggable target: signal transducer and activator of transcription 3 (STAT3). Here, we review the cell type-specific functions of STAT3 in the pathogenesis and progression of KM-LUAD that could serve as a new target for personalized preventive and therapeutic intervention for this intractable form of lung cancer. Full article
(This article belongs to the Special Issue Multicellular Effects of STAT3 in the Tumour Microenvironment)
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20 pages, 993 KiB  
Review
STAT3 Signaling in Breast Cancer: Multicellular Actions and Therapeutic Potential
by Sarah Q. To, Rhynelle S. Dmello, Anna K. Richards, Matthias Ernst and Ashwini L. Chand
Cancers 2022, 14(2), 429; https://doi.org/10.3390/cancers14020429 - 15 Jan 2022
Cited by 36 | Viewed by 14698
Abstract
Interleukin (IL)-6 family cytokines, such as IL-6 and IL-11, are defined by the shared use of the gp130 receptor for the downstream activation of STAT3 signaling and the activation of genes which contribute to the “hallmarks of cancer”, including proliferation, survival, invasion and [...] Read more.
Interleukin (IL)-6 family cytokines, such as IL-6 and IL-11, are defined by the shared use of the gp130 receptor for the downstream activation of STAT3 signaling and the activation of genes which contribute to the “hallmarks of cancer”, including proliferation, survival, invasion and metastasis. Increased expression of these cytokines, or the ligand-specific receptors IL-6R and IL-11RA, in breast tumors positively correlate to disease progression and poorer patient outcome. In this review, we examine evidence from pre-clinical studies that correlate enhanced IL-6 and IL-11 mediated gp130/STAT3 signaling to the progression of breast cancer. Key processes by which the IL-6 family cytokines contribute to the heterogeneous nature of breast cancer, immune evasion and metastatic potential, are discussed. We examine the latest research into the therapeutic targeting of IL-6 family cytokines that inhibit STAT3 transcriptional activity as a potential breast cancer treatment, including current clinical trials. The importance of the IL-6 family of cytokines in cellular processes that promote the development and progression of breast cancer warrants further understanding of the molecular basis for its actions to help guide the development of future therapeutic targets. Full article
(This article belongs to the Special Issue Multicellular Effects of STAT3 in the Tumour Microenvironment)
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31 pages, 2728 KiB  
Review
Multicellular Effects of STAT3 in Non-small Cell Lung Cancer: Mechanistic Insights and Therapeutic Opportunities
by Sagun Parakh, Matthias Ernst and Ashleigh R. Poh
Cancers 2021, 13(24), 6228; https://doi.org/10.3390/cancers13246228 - 11 Dec 2021
Cited by 33 | Viewed by 4450
Abstract
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and accounts for 85% of lung cancer cases. Aberrant activation of the Signal Transducer and Activator of Transcription 3 (STAT3) is frequently observed in NSCLC and is associated with a [...] Read more.
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and accounts for 85% of lung cancer cases. Aberrant activation of the Signal Transducer and Activator of Transcription 3 (STAT3) is frequently observed in NSCLC and is associated with a poor prognosis. Pre-clinical studies have revealed an unequivocal role for tumor cell-intrinsic and extrinsic STAT3 signaling in NSCLC by promoting angiogenesis, cell survival, cancer cell stemness, drug resistance, and evasion of anti-tumor immunity. Several STAT3-targeting strategies have also been investigated in pre-clinical models, and include preventing upstream receptor/ligand interactions, promoting the degradation of STAT3 mRNA, and interfering with STAT3 DNA binding. In this review, we discuss the molecular and immunological mechanisms by which persistent STAT3 activation promotes NSCLC development, and the utility of STAT3 as a prognostic and predictive biomarker in NSCLC. We also provide a comprehensive update of STAT3-targeting therapies that are currently undergoing clinical evaluation, and discuss the challenges associated with these treatment modalities in human patients. Full article
(This article belongs to the Special Issue Multicellular Effects of STAT3 in the Tumour Microenvironment)
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