Cancer‐associated fibroblasts in breast cancer: Challenges and opportunities

Hu, Dongyan; Li, Zhaoqing; Zheng, Bin; Lin, Xiaofeng; Pan, Yuehong; Gong, Peirong; Zhuo, Wenying; Hu, Yujie; Chen, Cong; Cao, Feng; Zhou, Jichun; Wang, Linbo

doi:10.1002/cac2.12291

Cited by 107 publications

(101 citation statements)

References 366 publications

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“…The study confirmed that Twist1-Prrx1-TNC can form a positive feedback loop to induce the activation of CAFs (Yeo et al, 2018). In addition, CD44, a cell surface molecule expressed by MSCs, can also induce the activation of CAFs by up regulating Twist transcription (Spaeth et al, 2013;Hu et al, 2022). Myristoylated alanine-rich protein kinase C substrate (MARCKS), the forkhead box F1 gene (FoxF1), and the zinc finger transcription factor (snail 1) by activating AKT/ Twist1 signaling to upregulate αSMA and PDGFR, the release of paracrine factors such as FGF-2 and HGF is promoted, resulting in the activation of CAFs and tumor (Saito et al, 2010;Stanisavljevic et al, 2015;Yang et al, 2016a).…”

Section: Origins and Activators Of Cafssupporting

confidence: 55%

CAFs orchestrates tumor immune microenvironment—A new target in cancer therapy?

et al. 2023

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Cancer immunotherapy has opened a new landscape in cancer treatment, however, the poor specificity and resistance of most targeted therapeutics have limited their therapeutic efficacy. In recent years, the role of CAFs in immune regulation has been increasingly noted as more evidence has been uncovered regarding the link between cancer-associated fibroblasts (CAFs) and the evolutionary process of tumor progression. CAFs interact with immune cells to shape the tumor immune microenvironment (TIME) that favors malignant tumor progression, a crosstalk process that leads to the failure of cancer immunotherapies. In this review, we outline recent advances in the immunosuppressive function of CAFs, highlight the mechanisms of CAFs-immune cell interactions, and discuss current CAF-targeted therapeutic strategies for future study.

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Section: Origins and Activators Of Cafssupporting

confidence: 55%

CAFs orchestrates tumor immune microenvironment—A new target in cancer therapy?

et al. 2023

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“…For several cancer types including hepatocellular carcinoma, pancreatic cancer, breast cancer, lung cancer, melanoma, and colon cancer it has been demonstrated that tumor cells interaction with CAFs promotes EMT and the metastatic phenotype (Kubo et al, 2016;Domen et al, 2021;Shelton et al, 2021;Ahmad Zawawi and Musa, 2022;Ando et al, 2022;Hu et al, 2022). Direct and indirect mechanisms have been shown to influence tumor metastasis by CAFs: i) ECM remodeling by secretion of collagens, fibronectin, and proteoglycans (Scott et al, 2019); ii) paracrine communication through exosomes, growth factors and cytokines that promote stemness and metastasis, such as: transforming growth factor β -TGFβ, Chemokine (CC motif) ligand 2 (CCL2), Interleukin-6 (IL-6), Hepatocyte growth factor (HGF), Osteopontin (OPN) and Stromal cell-derived factor 1 (SDF-1) (Linares et al, 2020); iii) direct contact with cancer cells and facilitated invasion and select gene transcription (Yamaguchi and Sakai, 2015;Liu et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Assessing the epithelial-to-mesenchymal plasticity in a small cell lung carcinoma (SCLC) and lung fibroblasts co-culture model

Dhungel

Youngblood

Chu

et al. 2023

Front. Mol. Biosci.

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The tumor microenvironment (TME) is the source of important cues that govern epithelial-to-mesenchymal transition (EMT) and facilitate the acquisition of aggressive traits by cancer cells. It is now recognized that EMT is not a binary program, and cancer cells rarely switch to a fully mesenchymal phenotype. Rather, cancer cells exist in multiple hybrid epithelial/mesenchymal (E/M) states responsible for cell population heterogeneity, which is advantageous for the ever-changing environment during tumor development and metastasis. How are these intermediate states generated and maintained is not fully understood. Here, we show that direct interaction between small cell lung carcinoma cells and lung fibroblasts induces a hybrid EMT phenotype in cancer cells in which several mesenchymal genes involved in receptor interaction with the extracellular matrix (ECM) and ECM remodeling are upregulated while epithelial genes such as E-cadherin remain unchanged or slightly increase. We also demonstrate that several core EMT-regulating transcription factors (EMT-TFs) are upregulated in cancer cells during direct contact with fibroblasts, as is Yes-associated protein (YAP1), a major regulator of the Hippo pathway. Further, we show that these changes are transient and reverse to the initial state once the interaction is disrupted. Altogether, our results provide evidence that tumor cells’ direct contact with the fibroblasts in the TME initiates a signaling cascade responsible for hybrid E/M states of cancer cells. These hybrid states are maintained during the interaction and possibly contribute to therapy resistance and immune evasion, while interference with direct contact will result in slow recovery and switch to the initial states.

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“…Co-culturing of breast tumor cells and fibroblasts increases cancer cell growth via metabolic reprogramming of fibroblasts producing Lactase and 3-Hydroxybutyrate, a hallmark of CAFs [ 68 ]. Studies have shown that CAFs differ from fibroblasts in adjacent normal breast tissue, as they have distinct mRNA and protein expression profiles and might impact the transcriptional profile of BC cells [ 69 , 70 ]. It is now thought that the altered phenotype of CAFs is mainly due to epigenetic modulation of the DNA [ 71 ].…”

Section: Notch Signaling Regulates Bc Progressionmentioning

confidence: 99%

Notch Signaling in Breast Tumor Microenvironment as Mediator of Drug Resistance

Chimento

D’Amico

Pezzi

et al. 2022

IJMS

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Notch signaling dysregulation encourages breast cancer progression through different mechanisms such as stem cell maintenance, cell proliferation and migration/invasion. Furthermore, Notch is a crucial driver regulating juxtracrine and paracrine communications between tumor and stroma. The complex interplay between the abnormal Notch pathway orchestrating the activation of other signals and cellular heterogeneity contribute towards remodeling of the tumor microenvironment. These changes, together with tumor evolution and treatment pressure, drive breast cancer drug resistance. Preclinical studies have shown that targeting the Notch pathway can prevent or reverse resistance, reducing or eliminating breast cancer stem cells. In the present review, we will summarize the current scientific evidence that highlights the involvement of Notch activation within the breast tumor microenvironment, angiogenesis, extracellular matrix remodeling, and tumor/stroma/immune system interplay and its involvement in mechanisms of therapy resistance.

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Cancer‐associated fibroblasts in breast cancer: Challenges and opportunities

Cited by 107 publications

References 366 publications

CAFs orchestrates tumor immune microenvironment—A new target in cancer therapy?

CAFs orchestrates tumor immune microenvironment—A new target in cancer therapy?

Assessing the epithelial-to-mesenchymal plasticity in a small cell lung carcinoma (SCLC) and lung fibroblasts co-culture model

Notch Signaling in Breast Tumor Microenvironment as Mediator of Drug Resistance

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