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Fibroblasts as Playmakers of Cancer Progression: Current Knowledge and Future...
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Fibroblasts as Playmakers of Cancer Progression: Current Knowledge and Future Perspectives

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 18622

Special Issue Editor

Dr. Kenichiro Ishii

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Guest Editor
Department of Nursing, Nagoya University of Arts and Sciences Graduate School of Nursing, 4-1-1 Sannomaru, Naka-ku, Nagoya, Aichi 460-0001, Japan
Interests: tumor microenvironment; prostate cancer; pancreatic cancer; stromal paracrine signals; cancer-associated fibroblasts (CAFs); drug repositioning
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In homeostatic epithelial–stromal interactions of adult tissues, stromal paracrine signals (morphogens) function to maintain the functional differentiation and growth/quiescence of epithelial cells. Once cancer cells grow in the epithelial compartment, the deregulation of homeostatic interactions occurs, leading to structural alterations of the stroma—so-called stromal remodeling. In contrast, the stroma-induced malignant transformation of epithelial cells is experimentally reported in prostate cancer development, suggesting that the structure of the stroma may play a critical role in cancer development and primary cancer cell progression.

In the tumor stroma of various solid tumors, invading cancer cells interact in complex ways with each other or with the surrounding microenvironment, generating the reactive stroma. The reactive stroma is composed mainly of cancer-promoting fibroblasts—so-called cancer-associated fibroblasts (CAFs). Within a focal lesion, CAFs heterotypically communicate with cancer cells not only by direct cell–cell contact via cell adhesion molecules but also by indirect cell–cell communication via mitogenic soluble factors, including growth factors, cytokines, extracellular matrix (ECM) molecules, and miRNAs. Interestingly, recent studies have unveiled that the reactive stroma of pancreatic cancer contains multiple functionally diverse populations of fibroblasts that positively or negatively regulate cancer progression (i.e., cancer-promoting or cancer-restraining).

In the tumor microenvironment, heterotypic interactions between cancer cells and fibroblasts must be quite important for determining cancer cell behavior, but we still know very little about the biological role of fibroblasts in the reactive stroma. In this Special Issue, we focus on heterotypic interactions between cancer cells and fibroblasts to develop an initial step toward designing reactive stroma-targeted therapies for the treatment of primary solid tumors. Impairing the malignant phenotype of cancer-promoting fibroblasts (e.g., via differentiation therapy targeting the reactive stroma) may abrogate primary cancer cell progression.

Dr. Kenichiro Ishii
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. 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

  • tumor microenvironment
  • reactive stroma
  • fibroblasts
  • cancer progression
  • heterotypic interactions between cancer cells and fibroblasts
  • reactive stroma-targeted therapy

Published Papers (7 papers)

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Editorial

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3 pages, 171 KiB  
Editorial
Fibroblasts as Playmakers of Cancer Progression: Current Knowledge and Future Perspectives
by Kenichiro Ishii
Cancers 2023, 15(23), 5538; https://doi.org/10.3390/cancers15235538 - 22 Nov 2023
Viewed by 542
Abstract
This series of six articles (four original articles and two reviews) is presented by international leaders in stromal biology in the tumor microenvironment [...] Full article
(This article belongs to the Special Issue Fibroblasts as Playmakers of Cancer Progression: Current Knowledge and Future Perspectives)

Research

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18 pages, 5118 KiB  
Article
Cancer-Associated Fibroblasts in a 3D Engineered Tissue Model Induce Tumor-like Matrix Stiffening and EMT Transition
by Martial Millet, Enola Bollmann, Cassandra Ringuette Goulet, Geneviève Bernard, Stéphane Chabaud, Marc-Étienne Huot, Frédéric Pouliot, Stéphane Bolduc and François Bordeleau
Cancers 2022, 14(15), 3810; https://doi.org/10.3390/cancers14153810 - 05 Aug 2022
Cited by 7 | Viewed by 2379
Abstract
A tumor microenvironment is characterized by its altered mechanical properties. However, most models remain unable to faithfully recreate the mechanical properties of a tumor. Engineered models based on the self-assembly method have the potential to better recapitulate the stroma architecture and composition. Here, [...] Read more.
A tumor microenvironment is characterized by its altered mechanical properties. However, most models remain unable to faithfully recreate the mechanical properties of a tumor. Engineered models based on the self-assembly method have the potential to better recapitulate the stroma architecture and composition. Here, we used the self-assembly method based on a bladder tissue model to engineer a tumor-like environment. The tissue-engineered tumor models were reconstituted from stroma-derived healthy primary fibroblasts (HFs) induced into cancer-associated fibroblast cells (iCAFs) along with an urothelium overlay. The iCAFs-derived extracellular matrix (ECM) composition was found to be stiffer, with increased ECM deposition and remodeling. The urothelial cells overlaid on the iCAFs-derived ECM were more contractile, as measured by quantitative polarization microscopy, and displayed increased YAP nuclear translocation. We further showed that the proliferation and expression of epithelial-to-mesenchymal transition (EMT) marker in the urothelial cells correlate with the increased stiffness of the iCAFs-derived ECM. Our data showed an increased expression of EMT markers within the urothelium on the iCAFs-derived ECM. Together, our results demonstrate that our tissue-engineered tumor model can achieve stiffness levels comparable to that of a bladder tumor, while triggering a tumor-like response from the urothelium. Full article
(This article belongs to the Special Issue Fibroblasts as Playmakers of Cancer Progression: Current Knowledge and Future Perspectives)
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15 pages, 2343 KiB  
Article
Cancer-Associated Fibroblasts Promote Tumor Aggressiveness in Head and Neck Cancer through Chemokine Ligand 11 and C-C Motif Chemokine Receptor 3 Signaling Circuit
by Wen-Yen Huang, Yaoh-Shiang Lin, Yu-Chun Lin, Shin Nieh, Yi-Ming Chang, Tsai-Yu Lee, Su-Feng Chen and Kuender D. Yang
Cancers 2022, 14(13), 3141; https://doi.org/10.3390/cancers14133141 - 27 Jun 2022
Cited by 5 | Viewed by 2307
Abstract
The tumor microenvironment (TME) plays a crucial role in tumor progression. One of its key stromal components, cancer-associated fibroblasts (CAFs), may crosstalk with cancer cells by secreting certain cytokines or chemokines. However, which important mediator(s) are released by CAFs, and the underlying molecular [...] Read more.
The tumor microenvironment (TME) plays a crucial role in tumor progression. One of its key stromal components, cancer-associated fibroblasts (CAFs), may crosstalk with cancer cells by secreting certain cytokines or chemokines. However, which important mediator(s) are released by CAFs, and the underlying molecular mechanism, remain largely unknown. In the present study, we isolated patient-derived CAFs and normal fibroblasts (NFs). Using microarray analysis, we detected chemokine ligand 11 (CCL11) overexpression in CAFs compared to NFs. CCL11 administration promoted the migration and invasion of head and neck cancer (HNC) cells with enhanced cancer stem cell-like properties and induction of epithelial-to-mesenchymal transition. Furthermore, neutralization of CCL11 activity reversed the aggressive phenotype of CAF-induced cancer cells. Confocal microscopy showed colocalization of CCL11 and CC chemokine receptor 3 (CCR3) on HNC cells. Moreover, immunohistochemical analysis of clinical samples from 104 patients with HNC showed that expression of CCL11 and CCR3 were significantly correlated with poor overall survival (p = 0.003 and 0.044, respectively). Collectively, CCL11 expressed on CAFs promotes HNC invasiveness, and neutralization of CCL11 reverses this effect. We propose that the CCL11/CCR3 signaling circuit is a potential target for optimizing therapeutic strategies against HNC. Full article
(This article belongs to the Special Issue Fibroblasts as Playmakers of Cancer Progression: Current Knowledge and Future Perspectives)
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13 pages, 1123 KiB  
Article
Associations between Normal Organs and Tumor Burden in Patients Imaged with Fibroblast Activation Protein Inhibitor-Directed Positron Emission Tomography
by Aleksander Kosmala, Sebastian E. Serfling, Niklas Dreher, Thomas Lindner, Andreas Schirbel, Constantin Lapa, Takahiro Higuchi, Andreas K. Buck, Alexander Weich and Rudolf A. Werner
Cancers 2022, 14(11), 2609; https://doi.org/10.3390/cancers14112609 - 25 May 2022
Cited by 9 | Viewed by 1838
Abstract
(1) Background: We aimed to quantitatively investigate [68Ga]Ga-FAPI-04 uptake in normal organs and to assess a relationship with the extent of FAPI-avid tumor burden. (2) Methods: In this single-center retrospective analysis, thirty-four patients with solid cancers underwent a total of 40 [...] Read more.
(1) Background: We aimed to quantitatively investigate [68Ga]Ga-FAPI-04 uptake in normal organs and to assess a relationship with the extent of FAPI-avid tumor burden. (2) Methods: In this single-center retrospective analysis, thirty-four patients with solid cancers underwent a total of 40 [68Ga]Ga-FAPI-04 PET/CT scans. Mean standardized uptake values (SUVmean) for normal organs were established by placing volumes of interest (VOIs) in the heart, liver, spleen, pancreas, kidneys, and bone marrow. Total tumor burden was determined by manual segmentation of tumor lesions with increased uptake. For tumor burden, quantitative assessment included maximum SUV (SUVmax), tumor volume (TV), and fractional tumor activity (FTA = TV × SUVmean). Associations between uptake in normal organs and tumor burden were investigated by applying Spearman’s rank correlation coefficient. (3) Results: Median SUVmean values were 2.15 in the pancreas (range, 1.05–9.91), 1.42 in the right (range, 0.57–3.06) and 1.41 in the left kidney (range, 0.73–2.97), 1.2 in the heart (range, 0.46–2.59), 0.86 in the spleen (range, 0.55–1.58), 0.65 in the liver (range, 0.31–2.11), and 0.57 in the bone marrow (range, 0.26–0.94). We observed a trend towards significance for uptake in the myocardium and tumor-derived SUVmax (ρ = 0.29, p = 0.07) and TV (ρ = −0.30, p = 0.06). No significant correlation was achieved for any of the other organs: SUVmax (ρ ≤ 0.1, p ≥ 0.42), TV (ρ ≤ 0.11, p ≥ 0.43), and FTA (ρ ≤ 0.14, p ≥ 0.38). In a sub-analysis exclusively investigating patients with high tumor burden, significant correlations of myocardial uptake with tumor SUVmax (ρ = 0.44; p = 0.03) and tumor-derived FTA with liver uptake (ρ = 0.47; p = 0.02) were recorded. (4) Conclusions: In this proof-of-concept study, quantification of [68Ga]Ga-FAPI-04 PET showed no significant correlation between normal organs and tumor burden, except for a trend in the myocardium. Those preliminary findings may trigger future studies to determine possible implications for treatment with radioactive FAP-targeted drugs, as higher tumor load or uptake may not lead to decreased doses in the majority of normal organs. Full article
(This article belongs to the Special Issue Fibroblasts as Playmakers of Cancer Progression: Current Knowledge and Future Perspectives)
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18 pages, 1357 KiB  
Article
High Expression of NT5DC2 Is a Negative Prognostic Marker in Pulmonary Adenocarcinoma
by Arik Bernard Schulze, Anna Kuntze, Lars Henning Schmidt, Michael Mohr, Alessandro Marra, Ludger Hillejan, Christian Schulz, Dennis Görlich, Wolfgang Hartmann, Annalen Bleckmann and Georg Evers
Cancers 2022, 14(6), 1395; https://doi.org/10.3390/cancers14061395 - 09 Mar 2022
Cited by 7 | Viewed by 1781
Abstract
Via immunohistochemistry (IHC) on tissue micro arrays (TMA) clinical and prognostic impact of p53 co-playing 5′-Nucleotidase Domain-Containing Protein 2 (NT5DC2) protein expression was evaluated in 252 NSCLC patients. Confirmatory, gene expression database. mRNA levels of NT5DC2 were studied in 1925 NSCLC patients. High [...] Read more.
Via immunohistochemistry (IHC) on tissue micro arrays (TMA) clinical and prognostic impact of p53 co-playing 5′-Nucleotidase Domain-Containing Protein 2 (NT5DC2) protein expression was evaluated in 252 NSCLC patients. Confirmatory, gene expression database. mRNA levels of NT5DC2 were studied in 1925 NSCLC patients. High protein expression of NT5DC2 resulted in reduced median overall survival (OS) of patients with stage I-III adenocarcinoma (ADC) (Log Rank p = 0.026, HR 2.04 (1.08–3.87)), but not in squamous cell carcinoma (SCC) (p = 0.514, HR 0.87 (0.57–1.33)). Findings on OS were reproduced via gene expression analysis in ADC (p < 0.001, HR 1.64 (1.30–2.08)) and SCC (p = 0.217, HR 0.86 (0.68–1.09)). Yet, NT5DC2 mRNA levels were higher in SCC compared to ADC (p < 0.001) and in pN2 tumors compared to pN0/1 tumors (p = 0.001). Likewise, NT5DC2 protein expression associated with high-grade SCC. Moreover, NT5DC2 expression was positively correlated with p53 protein (p = 0.018) and TP53 gene expression (p < 0.001) and its survival effect was p53 dependent. While p53 expression was negatively associated with the presence of CD34+ cancer associated fibroblasts (CAFs), NT5DC2 expression insignificantly tended to higher levels of SMA+ CAFs (p = 0.065). Full article
(This article belongs to the Special Issue Fibroblasts as Playmakers of Cancer Progression: Current Knowledge and Future Perspectives)
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Review

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79 pages, 1062 KiB  
Review
Fibroblasts as Turned Agents in Cancer Progression
by Robert Wieder
Cancers 2023, 15(7), 2014; https://doi.org/10.3390/cancers15072014 - 28 Mar 2023
Cited by 13 | Viewed by 2538
Abstract
Differentiated epithelial cells reside in the homeostatic microenvironment of the native organ stroma. The stroma supports their normal function, their G0 differentiated state, and their expansion/contraction through the various stages of the life cycle and physiologic functions of the host. When malignant [...] Read more.
Differentiated epithelial cells reside in the homeostatic microenvironment of the native organ stroma. The stroma supports their normal function, their G0 differentiated state, and their expansion/contraction through the various stages of the life cycle and physiologic functions of the host. When malignant transformation begins, the microenvironment tries to suppress and eliminate the transformed cells, while cancer cells, in turn, try to resist these suppressive efforts. The tumor microenvironment encompasses a large variety of cell types recruited by the tumor to perform different functions, among which fibroblasts are the most abundant. The dynamics of the mutual relationship change as the sides undertake an epic battle for control of the other. In the process, the cancer “wounds” the microenvironment through a variety of mechanisms and attracts distant mesenchymal stem cells to change their function from one attempting to suppress the cancer, to one that supports its growth, survival, and metastasis. Analogous reciprocal interactions occur as well between disseminated cancer cells and the metastatic microenvironment, where the microenvironment attempts to eliminate cancer cells or suppress their proliferation. However, the altered microenvironmental cells acquire novel characteristics that support malignant progression. Investigations have attempted to use these traits as targets of novel therapeutic approaches. Full article
(This article belongs to the Special Issue Fibroblasts as Playmakers of Cancer Progression: Current Knowledge and Future Perspectives)
21 pages, 751 KiB  
Review
Cancer-Associated Fibroblasts: Tumorigenicity and Targeting for Cancer Therapy
by Raisa A. Glabman, Peter L. Choyke and Noriko Sato
Cancers 2022, 14(16), 3906; https://doi.org/10.3390/cancers14163906 - 12 Aug 2022
Cited by 53 | Viewed by 6229
Abstract
Cancer-associated fibroblasts (CAFs) are a heterogenous group of activated fibroblasts and a major component of the tumor stroma. CAFs may be derived from fibroblasts, epithelial cells, endothelial cells, cancer stem cells, adipocytes, pericytes, or stellate cells. These complex origins may underlie their functional [...] Read more.
Cancer-associated fibroblasts (CAFs) are a heterogenous group of activated fibroblasts and a major component of the tumor stroma. CAFs may be derived from fibroblasts, epithelial cells, endothelial cells, cancer stem cells, adipocytes, pericytes, or stellate cells. These complex origins may underlie their functional diversity, which includes pro-tumorigenic roles in extracellular matrix remodeling, the suppression of anti-tumor immunity, and resistance to cancer therapy. Several methods for targeting CAFs to inhibit tumor progression and enhance anti-tumor immunity have recently been reported. While preclinical studies have shown promise, to date they have been unsuccessful in human clinical trials against melanoma, breast cancer, pancreas cancer, and colorectal cancers. This review summarizes recent and major advances in CAF-targeting therapies, including DNA-based vaccines, anti-CAF CAR-T cells, and modifying and reprogramming CAF functions. The challenges in developing effective anti-CAF treatment are highlighted, which include CAF heterogeneity and plasticity, the lack of specific target markers for CAFs, the limitations in animal models recapitulating the human cancer microenvironment, and the undesirable off-target and systemic side effects. Overcoming these challenges and expanding our understanding of the basic biology of CAFs is necessary for making progress towards safe and effective therapeutic strategies against cancers in human patients. Full article
(This article belongs to the Special Issue Fibroblasts as Playmakers of Cancer Progression: Current Knowledge and Future Perspectives)
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