Cancer-Associated Fibroblasts in the Breast Tumor Microenvironment

Breast cancer (BrCa) is the leading cause of death among women worldwide, with about one million new cases diagnosed each year. In spite of the improvements in diagnosis, early detection and treatment, there is still a high incidence of mortality and failure to respond to current therapies. With the use of several well-established biomarkers, such as hormone receptors and human epidermal growth factor receptor-2 (HER2), as well as genetic analysis, BrCa patients can be categorized into multiple subgroups: Luminal A, Luminal B, HER2-enriched, and Basal-like, with specific treatment strategies. Although chemotherapy and targeted therapies have greatly improved the survival of patients with BrCa, there is still a large number of patients who relapse or who fail to respond. The role of the tumor microenvironment in BrCa progression is becoming increasingly understood. Cancer-associated fibroblasts (CAFs) are the principal population of stromal cells in breast tumors. In this review, we discuss the current understanding of CAFs’ role in altering the tumor response to therapeutic agents as well as in fostering metastasis in BrCa. In addition, we also review the available CAFs-directed molecular therapies and their potential implications for BrCa management.

Section: Contribution Of Cafs From Primary Tumor Stroma To Metastasis Progressionmentioning

confidence: 99%

Cancer-Associated Fibroblasts in Breast Cancer Treatment Response and Metastasis

Fernández‐Nogueira

Fuster

Gutiérrez-Uzquiza

et al. 2021

“…Cancers are not fully autonomous but depend on growth-promoting signals provided by supporting cells, including FBs, and their biochemical and physical properties that are altered by the microenvironment [ 3 ]. Cancer-associated fibroblasts (CAFs) have emerged as potential targets for reprogramming tumor microenvironment and optimizing therapeutic strategies [ 4 , 5 ]. However, targeting CAFs has been challenging because of the lack of specific biochemical markers and their functional and phenotypic heterogeneity [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Protein Ligands in the Secretome of CD36+ Fibroblasts Induce Growth Suppression in a Subset of Breast Cancer Cell Lines

Jabbari

Winkelmaier

Andersen

et al. 2021

Reprogramming the tumor stroma is an emerging approach to circumventing the challenges of conventional cancer therapies. This strategy, however, is hampered by the lack of a specific molecular target. We previously reported that stromal fibroblasts (FBs) with high expression of CD36 could be utilized for this purpose. These studies are now expanded to identify the secreted factors responsible for tumor suppression. Methodologies included 3D colonies, fluorescent microscopy coupled with quantitative techniques, proteomics profiling, and bioinformatics analysis. The results indicated that the conditioned medium (CM) of the CD36+ FBs caused growth suppression via apoptosis in the triple-negative cell lines of MDA-MB-231, BT549, and Hs578T, but not in the ERBB2+ SKBR3. Following the bioinformatic analysis of the CM of CD36+ versus CD36− FBs, we determined KLF10 as one of the transcription factors responsible for growth suppression. We also identified FBLN1, SLIT3, and PENK as active ligands, where their minimum effective concentrations were determined. Finally, in MDA-MB-231, we showed that a mixture of FBLN1, SLIT3, and PENK could induce an amount of growth suppression similar to the CM of CD36+ FBs. In conclusion, our findings suggest that these ligands, secreted by CD36+ FBs, can be targeted for breast cancer treatment.

“…CAF are a heterogeneous group of tumor stromal cells that are morphologically fibroblast-like. They are not necessarily derived from transformation of normal fibroblasts in the TME, but could origin from different tissues or precursor cells, including stellate cells, bone-marrow-derived fibrocytes, mesenchymal stem cells, or even endothelial cells, adipocytes, pericytes and smooth muscle cells [46]. Immunohistochemically, CAF express α-SMA, FAP, S100A4 and platelet derived growth factor receptor-β (PDGFR-β).…”

Section: The Regional Microenvironmentmentioning

confidence: 99%

Tumor Microenvironment in Breast Cancer—Updates on Therapeutic Implications and Pathologic Assessment

Tsang

Tse

2021

108

The tumor microenvironment (TME) in breast cancer comprises local factors, cancer cells, immune cells and stromal cells of the local and distant tissues. The interaction between cancer cells and their microenvironment plays important roles in tumor proliferation, propagation and response to therapies. There is increasing research in exploring and manipulating the non-cancerous components of the TME for breast cancer treatment. As the TME is now increasingly recognized as a treatment target, its pathologic assessment has become a critical component of breast cancer management. The latest WHO classification of tumors of the breast listed stromal response pattern/fibrotic focus as a prognostic factor and includes recommendations on the assessment of tumor infiltrating lymphocytes and PD-1/PD-L1 expression, with therapeutic implications. This review dissects the TME of breast cancer, describes pathologic assessment relevant for prognostication and treatment decision, and details therapeutic options that interacts with and/or exploits the TME in breast cancer.