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Cells
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Cancer-Associated Fibroblasts: Challenges and Directions
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Cancer-Associated Fibroblasts: Challenges and Directions

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Microenvironment".

Deadline for manuscript submissions: 25 February 2025 | Viewed by 5557

Special Issue Editors

Dr. Paul J. Higgins

E-Mail Website
Guest Editor
Department of Regenerative & Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USA
Interests: EGFR transactivation; TGF-β signaling; gene regulation; tumor progression; fibroproliferative disease; EMT; skin cancer; cell motility; PAI-1
Special Issues, Collections and Topics in MDPI journals
Dr. Ramesh Mukkamala

E-Mail Website
Guest Editor
Department of chemistry, Purdue University, West Lafayette, IN 47907, USA
Interests: design and development of targeted ligands and drugs; molecular imaging; preclinical development of FAP-targeted radioligands

Special Issue Information

Dear Colleagues,

Cancer-associated fibroblasts (CAFs) represent a significant cellular component within the tumor microenvironment (TME) and play a crucial role in facilitating tumor growth. They directly contribute to tumor progression by releasing various growth factors, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and various chemokines that stimulate angiogenesis and promote tumor development. Additionally, CAFs indirectly support tumor growth by secreting immune-suppressive cytokines like TGF-β, IL-8, and IL-10, and by remodeling the extracellular matrix (ECM), thereby rendering tumors resistant to various therapeutic interventions.

Cancer-associated fibroblasts (CAFs) are identified through several biomarkers, including α-SMA, PDGFRα/β, and fibroblast activation protein alpha (FAPα), among others. Notably, recent interest has grown around the reprogramming of the tumor microenvironment through the use of FAP-targeting ligand conjugates. This approach has gained prominence due to the exclusive overexpression of FAP in CAFs, with minimal to undetectable expression in healthy tissues. Currently, there are ongoing developments in the clinical use of 68Ga/177Lu-labeled FAP-targeting small molecules and peptide-based PET imaging agents, as well as radiotherapeutic agents.

This Special Issue will focus on original preclinical studies or comprehensive review articles. Topics can include the methods used to target CAF directly or indirectly until depletion of CAFs or elimination of tumor promotion, as well as the immunosuppressive function of CAFs using a combination of different therapeutic strategies for cancer treatment.

Dr. Paul J. Higgins
Dr. Ramesh Mukkamala
Guest Editors

Manuscript Submission Information

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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. Cells 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 2700 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

  • cancer-associated fibroblast (CAFs)
  • tumor microenvironment (TME)
  • fibroblast activation protein alpha (FAPα)
  • immunotherapy
  • cytokines
  • angiogenesis
  • metastasis
  • FAP inhibitors
  • radioligands
  • imaging agents

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Published Papers (4 papers)

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Research

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20 pages, 10232 KiB  
Article
AREG Upregulation in Cancer Cells via Direct Interaction with Cancer-Associated Fibroblasts Promotes Esophageal Squamous Cell Carcinoma Progression Through EGFR-Erk/p38 MAPK Signaling
by Takashi Nakanishi, Yu-ichiro Koma, Shoji Miyako, Rikuya Torigoe, Hiroki Yokoo, Masaki Omori, Keitaro Yamanaka, Nobuaki Ishihara, Shuichi Tsukamoto, Takayuki Kodama, Mari Nishio, Manabu Shigeoka, Hiroshi Yokozaki and Yoshihiro Kakeji
Cells 2024, 13(20), 1733; https://doi.org/10.3390/cells13201733 - 19 Oct 2024
Viewed by 1017
Abstract
Cancer-associated fibroblasts (CAFs) are a key component of the tumor microenvironment and significantly contribute to the progression of various cancers, including esophageal squamous cell carcinoma (ESCC). Our previous study established a direct co-culture system of human bone marrow-derived mesenchymal stem cells (progenitors of [...] Read more.
Cancer-associated fibroblasts (CAFs) are a key component of the tumor microenvironment and significantly contribute to the progression of various cancers, including esophageal squamous cell carcinoma (ESCC). Our previous study established a direct co-culture system of human bone marrow-derived mesenchymal stem cells (progenitors of CAFs) and ESCC cell lines, which facilitates the generation of CAF-like cells and enhances malignancy in ESCC cells. In this study, we further elucidated the mechanism by which CAFs promote ESCC progression using cDNA microarray analysis of monocultured ESCC cells and those co-cultured with CAFs. We observed an increase in the expression and secretion of amphiregulin (AREG) and the expression and phosphorylation of its receptor EGFR in co-cultured ESCC cells. Moreover, AREG treatment of ESCC cells enhanced their survival and migration via the EGFR-Erk/p38 MAPK signaling pathway. Immunohistochemical analysis of human ESCC tissues showed a positive correlation between the intensity of AREG expression at the tumor-invasive front and the expression level of the CAF marker FAP. Bioinformatics analysis confirmed significant upregulation of AREG in ESCC compared with normal tissues. These findings suggest that AREG plays a crucial role in CAF-mediated ESCC progression and could be a novel therapeutic target for ESCC. Full article
(This article belongs to the Special Issue Cancer-Associated Fibroblasts: Challenges and Directions)
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18 pages, 7214 KiB  
Article
Podoplanin Expression in Early-Stage Colorectal Cancer-Associated Fibroblasts and Its Utility as a Diagnostic Marker for Colorectal Lesions
by Shuichi Tsukamoto, Takayuki Kodama, Mari Nishio, Manabu Shigeoka, Tomoo Itoh, Hiroshi Yokozaki and Yu-ichiro Koma
Cells 2024, 13(20), 1682; https://doi.org/10.3390/cells13201682 - 11 Oct 2024
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Abstract
(Background) Cancer-associated fibroblasts (CAFs) are major cancer stromal components. CAFs have diverse functions and cell origins. Podoplanin (PDPN), a lymphatic vessel marker, is also a CAF marker in certain cancers. On daily diagnosis of early colorectal carcinoma (CRC), PDPN upregulation in the stroma [...] Read more.
(Background) Cancer-associated fibroblasts (CAFs) are major cancer stromal components. CAFs have diverse functions and cell origins. Podoplanin (PDPN), a lymphatic vessel marker, is also a CAF marker in certain cancers. On daily diagnosis of early colorectal carcinoma (CRC), PDPN upregulation in the stroma is often encountered, suggesting PDPN-positive CAFs have emerged. However, PDPN-positive CAFs in early CRC have not been studied well. (Methods) On immunohistochemistry, PDPN expression in the lamina propria or stroma of adenomas, early CRCs, and neuroendocrine tumors, their normal neighbors, and non-neoplastic colorectal lesions were compared. Single-cell RNA sequencing (scRNA-seq) of CRC was used to explore PDPNhigh CAFs’ cell origins. (Results) Reticular cells or pericryptal fibroblasts in the lamina propria of adenomas and early CRCs showed higher PDPN expression than did normal mucosae and non-neoplastic lesions (p < 0.01). Pericryptal PDPN expression was a diagnostic feature of adenomas and early CRCs. scRNA-seq of CRCs highlighted that PDPNhigh CAFs had distinctly higher COL4A1, COL4A2, and WNT5A expression, unlike well-known CAFs characterized by high FAP, POSTN, or ACTA2 expression. (Conclusions) We demonstrated that pericryptal fibroblasts and reticular cells in the lamina propria are origins of early-stage CRC CAFs and thus have potential as a diagnostic marker for distinguishing colorectal non-neoplastic from neoplastic lesions. Full article
(This article belongs to the Special Issue Cancer-Associated Fibroblasts: Challenges and Directions)
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26 pages, 7315 KiB  
Article
Breast Cancer Stem Cells Upregulate IRF6 in Stromal Fibroblasts to Induce Stromagenesis
by Harshini Muralidharan, Thomas Hansen, Anja Steinle, David Schumacher, Elmar Stickeler and Jochen Maurer
Cells 2024, 13(17), 1466; https://doi.org/10.3390/cells13171466 - 31 Aug 2024
Viewed by 1019
Abstract
The microenvironment of a cancer stem cell (CSC) niche is often found in coexistence with cancer-associated fibroblasts (CAFs). Here, we show the first in-depth analysis of the interaction between primary triple-negative breast cancer stem cells (BCSCs) with fibroblasts. Using 2D co-culture models with [...] Read more.
The microenvironment of a cancer stem cell (CSC) niche is often found in coexistence with cancer-associated fibroblasts (CAFs). Here, we show the first in-depth analysis of the interaction between primary triple-negative breast cancer stem cells (BCSCs) with fibroblasts. Using 2D co-culture models with specific seeding ratios, we identified stromal fibroblast aggregation at the BCSC cluster periphery, and, on closer observation, the aggregated fibroblasts was found to encircle BCSC clusters in nematic organization. In addition, collagen type I and fibronectin accumulation were also found at the BCSC–stromal periphery. MACE-Seq analysis of BCSC-encapsulating fibroblasts displayed the transformation of stromal fibroblasts to CAFs and the upregulation of fibrosis regulating genes of which the Interferon Regulatory Factor 6 (IRF6) gene was identified. Loss of function experiments with the IRF6 gene decreased fibroblast encapsulation around BCSC clusters in 2D co-cultures. In BCSC xenografts, fibroblast IRF6 expression led to an increase in the stromal area and fibroblast density in tumors, in addition to a reduction in necrotic growth. Based on our findings, we propose that fibroblast IRF6 function is an important factor in the development of the stromal microenvironment and in sustaining the BCSC tumor niche. Full article
(This article belongs to the Special Issue Cancer-Associated Fibroblasts: Challenges and Directions)
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Review

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16 pages, 2197 KiB  
Review
SERPINE1: Role in Cholangiocarcinoma Progression and a Therapeutic Target in the Desmoplastic Microenvironment
by Ralf-Peter Czekay, Craig E. Higgins, Hasan Basri Aydin, Rohan Samarakoon, Nusret Bekir Subasi, Stephen P. Higgins, Hwajeong Lee and Paul J. Higgins
Cells 2024, 13(10), 796; https://doi.org/10.3390/cells13100796 - 7 May 2024
Cited by 1 | Viewed by 1836
Abstract
A heterogenous population of inflammatory elements, other immune and nonimmune cells and cancer-associated fibroblasts (CAFs) are evident in solid malignancies where they coexist with the growing tumor mass. In highly desmoplastic malignancies, CAFs are the prominent mesenchymal cell type in the tumor microenvironment [...] Read more.
A heterogenous population of inflammatory elements, other immune and nonimmune cells and cancer-associated fibroblasts (CAFs) are evident in solid malignancies where they coexist with the growing tumor mass. In highly desmoplastic malignancies, CAFs are the prominent mesenchymal cell type in the tumor microenvironment (TME), where their presence and abundance signal a poor prognosis. CAFs play a major role in the progression of various cancers by remodeling the supporting stroma into a dense, fibrotic matrix while secreting factors that promote the maintenance of cancer stem-like characteristics, tumor cell survival, aggressive growth and metastasis and reduced sensitivity to chemotherapeutics. Tumors with high stromal fibrotic signatures are more likely to be associated with drug resistance and eventual relapse. Identifying the molecular underpinnings for such multidirectional crosstalk among the various normal and neoplastic cell types in the TME may provide new targets and novel opportunities for therapeutic intervention. This review highlights recent concepts regarding the complexity of CAF biology in cholangiocarcinoma, a highly desmoplastic cancer. The discussion focuses on CAF heterogeneity, functionality in drug resistance, contributions to a progressively fibrotic tumor stroma, the involved signaling pathways and the participating genes. Full article
(This article belongs to the Special Issue Cancer-Associated Fibroblasts: Challenges and Directions)
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