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Cancers
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The Role of Cancer-Associated Fibroblasts in Cancer
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The Role of Cancer-Associated Fibroblasts in Cancer

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

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 14292

Special Issue Editors

Prof. Dr. Yasushi Shintani

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Guest Editor
Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Suita 565-0871, Japan
Interests: lung cancer; thymic epithelial tumors; cancer biology; tumor microenvironment; surgical treatment
Dr. Toru Kimura

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Guest Editor
Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, 2-2 (L5), Yamadaoka, Suita-City, Osaka 565-0871, Japan
Interests: lung cancer; interstitial lung diseases; thymic epithelial tumors; fibroblasts; fibroblast activation protein; chimeric antigen receptor T cells
Dr. Ryu Kanzaki

E-Mail Website
Guest Editor
Department of General Thoracic Surgery, Osaka International Cancer Institute, 3-1-69, Otemae, Chuo-ku, Osaka 541-8567, Japan
Interests: lung cancer; metastatic lung tumor; thymic epithelial tumors; tumor microembironment; cancer associated fibroblast

Special Issue Information

Dear Colleagues, 

Despite significant advances in cancer therapies during recent decades, the prognosis for advanced cancer remains poor. The tumor microenvironment (TME) is comprised of different types of stromal cells and functions as a key component for tumor progression. While cancer treatment generally targets cancer cells, along with elucidation of the TME, we have successfully targeted cells other than cancer cells involved in its construction, including immune checkpoint inhibitors. As compared to cancer cells, which are prone to develop drug resistance, it is considered that resistance to treatment targeting the TME is less likely to occur. Cancer-associated fibroblasts (CAFs) are one of the most dominant components in the TME, and a group of activated fibroblasts with significant heterogeneity and plasticity. CAFs secrete numerous growth factors, chemokines, cytokines, and extracellular matrix to regulate tumor initiation, development, metastasis, angiogenesis, immune system, and resistance to therapy, thus CAFs are attracting attention as a target for cancer therapy. This Special Issue will discuss recent development in our understanding of the biology and functions of CAFs as well as the possibility of novel therapies targeting CAFs.

Prof. Dr. Yasushi Shintani
Dr. Toru Kimura
Dr. Ryu Kanzaki
Guest Editors

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
  • cancer-associated fibroblast
  • cancer progression
  • anticancer resistance
  • heterogeneity
  • target therapy
  • novel markers

Published Papers (6 papers)

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Research

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18 pages, 6080 KiB  
Article
Tumor Suppression by Anti-Fibroblast Activation Protein Near-Infrared Photoimmunotherapy Targeting Cancer-Associated Fibroblasts
by Raisa A. Glabman, Colleen P. Olkowski, Hannah A. Minor, Laura L. Bassel, Noemi Kedei, Peter L. Choyke and Noriko Sato
Cancers 2024, 16(2), 449; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers16020449 - 20 Jan 2024
Viewed by 1499
Abstract
Cancer-associated fibroblasts (CAFs) constitute a prominent cellular component of the tumor stroma, with various pro-tumorigenic roles. Numerous attempts to target fibroblast activation protein (FAP), a highly expressed marker in immunosuppressive CAFs, have failed to demonstrate anti-tumor efficacy in human clinical trials. Near-infrared photoimmunotherapy [...] Read more.
Cancer-associated fibroblasts (CAFs) constitute a prominent cellular component of the tumor stroma, with various pro-tumorigenic roles. Numerous attempts to target fibroblast activation protein (FAP), a highly expressed marker in immunosuppressive CAFs, have failed to demonstrate anti-tumor efficacy in human clinical trials. Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor therapy that utilizes an antibody-photo-absorbing conjugate activated by near-infrared light. In this study, we examined the therapeutic efficacy of CAF depletion by NIR-PIT in two mouse tumor models. Using CAF-rich syngeneic lung and spontaneous mammary tumors, NIR-PIT against FAP or podoplanin was performed. Anti-FAP NIR-PIT effectively depleted FAP+ CAFs, as well as FAP+ myeloid cells, and suppressed tumor growth, whereas anti-podoplanin NIR-PIT was ineffective. Interferon-gamma production by CD8 T and natural killer cells was induced within hours after anti-FAP NIR-PIT. Additionally, lung metastases were reduced in the treated spontaneous mammary cancer model. Depletion of FAP+ stromal as well as FAP+ myeloid cells effectively suppressed tumor growth in bone marrow chimeras, suggesting that the depletion of both cell types in one treatment is an effective therapeutic approach. These findings highlight a promising therapy for selectively eliminating immunosuppressive FAP+ cells within the tumor microenvironment. Full article
(This article belongs to the Special Issue The Role of Cancer-Associated Fibroblasts in Cancer)
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14 pages, 3497 KiB  
Article
Specific Subtypes of Carcinoma-Associated Fibroblasts Are Correlated with Worse Survival in Resectable Pancreatic Ductal Adenocarcinoma
by Karl Knipper, Alexander I. Damanakis, Yue Zhao, Christiane J. Bruns, Thomas Schmidt, Felix C. Popp, Alexander Quaas and Su Ir Lyu
Cancers 2023, 15(7), 2049; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15072049 - 30 Mar 2023
Cited by 4 | Viewed by 1341
Abstract
Purpose: The pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer entities. Effective therapy options are still lacking. The tumor microenvironment possibly bears further treatment possibilities. This study aimed to describe the expression patterns of four established carcinoma-associated fibroblast (CAFs) markers [...] Read more.
Purpose: The pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer entities. Effective therapy options are still lacking. The tumor microenvironment possibly bears further treatment possibilities. This study aimed to describe the expression patterns of four established carcinoma-associated fibroblast (CAFs) markers and their correlation in PDAC tissue samples. Methods: This project included 321 patients with PDAC who underwent surgery with a curative intent in one of the PANCALYZE study centers. Immunohistochemical stainings for FAP, PDGFR, periostin, and SMA were performed. The expression patterns of each marker were divided into low- and high-expressing CAFs and correlated with patients’ survival. Results: Tumors showing SMAhigh-, PeriostinhighSMAhigh-, or PeriostinhighSMAlowPDGFRlowFAPhigh-positive CAFs demonstrated significantly worse survival. Additionally, a high expression of SMA in PDAC tissue samples was shown to be an independent risk factor for worse survival. Conclusion: This project identified three subgroups of PDAC with different expression patterns of CAF markers which showed significantly worse survival. This could be the base for the further characterization of the fibroblast subgroups in PDAC and contribute to the development of new targeted therapy options against CAFs. Full article
(This article belongs to the Special Issue The Role of Cancer-Associated Fibroblasts in Cancer)
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16 pages, 3586 KiB  
Article
In Vivo Detection of Circulating Cancer-Associated Fibroblasts in Breast Tumor Mouse Xenograft: Impact of Tumor Stroma and Chemotherapy
by Tao Lu, Lisa Oomens, Leon W. M. M. Terstappen and Jai Prakash
Cancers 2023, 15(4), 1127; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15041127 - 9 Feb 2023
Cited by 1 | Viewed by 2052
Abstract
Cancer-associated fibroblasts (CAFs) are important drivers in the tumor microenvironment and facilitate the growth and survival of tumor cells, as well as metastasis formation. They may travel together with tumor cells to support their survival and aid in the formation of a metastatic [...] Read more.
Cancer-associated fibroblasts (CAFs) are important drivers in the tumor microenvironment and facilitate the growth and survival of tumor cells, as well as metastasis formation. They may travel together with tumor cells to support their survival and aid in the formation of a metastatic niche. In this study, we aimed to study circulating CAFs (cCAFs) and circulating tumor cells (CTCs) in a preclinical breast tumor model in mice in order to understand the effect of chemotherapy on cCAFs and CTC formation. Tumors with MDA-MB-231 human breast tumor cells with/without primary human mammary fibroblasts (representing CAFs) were coinjected in SCID mice to develop tumors. We found that the tumors with CAFs grew faster than tumors without CAFs. To study the effect of the stroma on CTCs and cCAFs, we isolated cells using microsieve filtration technology and established ITGA5 as a new cCAF biomarker, which showed good agreement with the CAF markers FAP and α-SMA. We found that ITGA5+ cCAFs shed in the blood of mice bearing stroma-rich coinjection-based tumors, while there was no difference in CTC formation. Although treatment with liposomal doxorubicin reduced tumor growth, it increased the numbers of both cCAFs and CTCs in blood. Moreover, cCAFs and CTCs were found to form clusters in the chemotherapy-treated mice. Altogether, these findings indicate that the tumor stroma supports tumor growth and the formation of cCAFs. Furthermore, chemotherapy may exacerbate the formation of cCAFs and CTCs, which may eventually support the formation of a metastasis niche in breast cancer. Full article
(This article belongs to the Special Issue The Role of Cancer-Associated Fibroblasts in Cancer)
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15 pages, 2069 KiB  
Article
Priming of Colorectal Tumor-Associated Fibroblasts with Zoledronic Acid Conjugated to the Anti-Epidermal Growth Factor Receptor Antibody Cetuximab Elicits Anti-Tumor Vδ2 T Lymphocytes
by Jordi Leonardo Castrillo Fernandez, Roberto Benelli, Delfina Costa, Alessio Campioli, Sara Tavella, Maria Raffaella Zocchi and Alessandro Poggi
Cancers 2023, 15(3), 610; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15030610 - 18 Jan 2023
Cited by 3 | Viewed by 1699
Abstract
Tumor-associated fibroblasts (TAF) exert immunosuppressive effects in colorectal carcinoma (CRC), impairing the recognition of tumor cells by effector lymphocytes, including Vδ2 T cells. Herein, we show that CRC-derived TAF can be turned by zoledronic acid (ZA), in soluble form or as antibody-drug conjugate [...] Read more.
Tumor-associated fibroblasts (TAF) exert immunosuppressive effects in colorectal carcinoma (CRC), impairing the recognition of tumor cells by effector lymphocytes, including Vδ2 T cells. Herein, we show that CRC-derived TAF can be turned by zoledronic acid (ZA), in soluble form or as antibody-drug conjugate (ADC), into efficient stimulators of Vδ2 T cells. CRC-TAF, obtained from patients, express the epidermal growth factor receptor (EGFR) and the butyrophilin family members BTN3A1/BTN2A1. These butyrophilins mediate the presentation of the phosphoantigens, accumulated in the cells due to ZA effect, to Vδ2 T cells. CRC-TAF exposed to soluble ZA acquired the ability to trigger the proliferation of Vδ2 T cells, in part represented by effector memory cells lacking CD45RA and CD27. In turn, expanded Vδ2 T cells exerted relevant cytotoxic activity towards CRC cells and CRC-TAF when primed with soluble ZA. Of note, also the ADC made of the anti-EGFR cetuximab (Cet) and ZA (Cet-ZA), that we recently described, induced the proliferation of anti-tumor Vδ2 T lymphocytes and their activation against CRC-TAF. These findings indicate that ZA can educate TAF to stimulate effector memory Vδ2 T cells; the Cet-ZA ADC formulation can lead to the precise delivery of ZA to EGFR+ cells, with a double targeting of TAF and tumor cells. Full article
(This article belongs to the Special Issue The Role of Cancer-Associated Fibroblasts in Cancer)
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25 pages, 2390 KiB  
Article
Modulation of Fibroblast Activity via Vitamin D3 Is Dependent on Tumor Type—Studies on Mouse Mammary Gland Cancer
by Natalia Łabędź, Martyna Stachowicz-Suhs, Mateusz Psurski, Artur Anisiewicz, Joanna Banach, Aleksandra Piotrowska, Piotr Dzięgiel, Adam Maciejczyk, Rafał Matkowski and Joanna Wietrzyk
Cancers 2022, 14(19), 4585; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14194585 - 21 Sep 2022
Cited by 5 | Viewed by 2076
Abstract
Vitamin D3 and its analogs are known to modulate the activity of fibroblasts under various disease conditions. However, their impact on cancer-associated fibroblasts (CAFs) is yet to be fully investigated. The aim of this study was to characterize CAFs and normal fibroblasts [...] Read more.
Vitamin D3 and its analogs are known to modulate the activity of fibroblasts under various disease conditions. However, their impact on cancer-associated fibroblasts (CAFs) is yet to be fully investigated. The aim of this study was to characterize CAFs and normal fibroblasts (NFs) from the lung of mice bearing 4T1, 67NR, and E0771 cancers and healthy mice fed vitamin-D3-normal (1000 IU), -deficient (100 IU), and -supplemented (5000 IU) diets. The groups receiving control (1000 IU) and deficient diets (100 IU) were gavaged with calcitriol (+cal). In the 4T1-bearing mice from the 100 IU+cal group, increased NFs activation (increased α-smooth muscle actin, podoplanin, and tenascin C (TNC)) with a decreased blood flow in the tumor was observed, whereas the opposite effect was observed in the 5000 IU and 100 IU groups. CAFs from the 5000 IU group of E0771-bearing mice were activated with increased expression of podoplanin, platelet-derived growth factor receptor β, and TNC. In the 100 IU+cal group of E0771-bearing mice, a decreased blood flow was recorded with decreased expression of fibroblast growth factor 23 (FGF23) and C-C motif chemokine ligand 2 (CCL2) in tumors and increased expression of TNC on CAFs. In the 67NR model, the impact of vitamin D3 on blood flow or CAFs and lung NFs was not observed despite changes in plasma and/or tumor tissue concentrations of osteopontin (OPN), CCL2, transforming growth factor-β, vascular endothelial growth factor, and FGF23. In healthy mice, divergent effects of vitamin D3 supplementation/deficiency were observed, which lead to the creation of various body microenvironments depending on the mouse strain. Tumors developing in such microenvironments themselves modified the microenvironments by producing, for example, higher concentrations of OPN and stromal-cell-derived factor 1 (4T1), which influences the response to vitamin D3 supplementation/deficiency and calcitriol administration. Full article
(This article belongs to the Special Issue The Role of Cancer-Associated Fibroblasts in Cancer)
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Review

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19 pages, 1025 KiB  
Review
Therapeutic Targeting of Cancer-Associated Fibroblasts in the Non-Small Cell Lung Cancer Tumor Microenvironment
by Yasushi Shintani, Toru Kimura, Soichiro Funaki, Naoko Ose, Takashi Kanou and Eriko Fukui
Cancers 2023, 15(2), 335; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15020335 - 4 Jan 2023
Cited by 11 | Viewed by 4313
Abstract
Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer death worldwide. The most common lung cancer is non-small cell lung cancer (NSCLC), with an overall 5-year survival rate of around 20% because NSCLC is a metastatic disease. A [...] Read more.
Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer death worldwide. The most common lung cancer is non-small cell lung cancer (NSCLC), with an overall 5-year survival rate of around 20% because NSCLC is a metastatic disease. A better understanding of the mechanism underlying lung cancer metastasis is therefore urgently needed. The tumor microenvironment involves different types of stromal cells and functions as key components in the progression of NSCLC. Through epithelial–mesenchymal transition (EMT), in which epithelial cells lose their polarity and acquire mesenchymal potential, cancer cells acquire metastatic abilities, as well as cancer stem-cell-like potential. We previously reported that cancer-associated fibroblasts (CAFs) interact with lung cancer cells to allow for the acquisition of malignancy and treatment resistance by paracrine loops via EMT signals in the tumor microenvironment. Furthermore, CAFs regulate the cytotoxic activity of immune cells via various cytokines and chemokines, creating a microenvironment of immune tolerance. Regulation of CAFs can therefore affect immune responses. Recent research has shown several roles of CAFs in NSCLC tumorigenesis, owing to their heterogeneity, so molecular markers of CAFs should be elucidated to better classify tumor-promoting subtypes and facilitate the establishment of CAF-specific targeted therapies. CAF-targeted cancer treatments may suppress EMT and regulate the niche of cancer stem cells and the immunosuppressive network and thus may prove useful for NSCLC treatment through multiple mechanisms. Full article
(This article belongs to the Special Issue The Role of Cancer-Associated Fibroblasts in Cancer)
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