Pirfenidone Reduces Epithelial–Mesenchymal Transition and Spheroid Formation in Breast Carcinoma through Targeting Cancer-Associated Fibroblasts (CAFs)

Es, Hamidreza Aboulkheyr; Cox, Thomas R.; Sarafraz-Yazdi, Ehsan; Thiéry, Jean Paul; Warkiani, Majid Ebrahimi

doi:10.3390/cancers13205118

Cited by 19 publications

(13 citation statements)

References 70 publications

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“…For example, Cancer-associated broblasts (CAFs) can stimulate phenotypic transformation and secrete a broad range of growth factors [42]. In addition, in recent study, pirfenidone was regarded as potential drug in suppressing invasion and potentially metastasis in breast cancer [13]. Tumor-associated macrophages (TAMs) also could be induced M2-polarization by cytokines released by tumor cells [43].…”

Section: Discussionmentioning

confidence: 99%

“…To nd out better curative effect and explore more treatments methods, many researchers have reported that the expression of immune-related genes were different among immune cells and in uenced HNSCC patient prognosis [11,12]. Just like cancer-associated broblasts cell (CAFs), a common stromal cell, it has been reported play important roles in HNSCC progression and prognosis, such as participate in tumor cell proliferation, angiogenesis, and immunosuppression [13].…”

Section: Introductionmentioning

confidence: 99%

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Development and Validation of an Individualized Immune Prognostic Signature in HNSCC

Sun

Zhao

et al. 2022

Preprint

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Head and neck cancer is the seventh most common type of cancer worldwide, and the development of immunotherapy is conducive to the preservation of function and the improvement of prognosis. Based on immune gene database ImmPort and InnateDB, we investigated prognostic value of 546 head and necks squamous cell carcinoma samples from The Cancer Genome Atlas. We intersected of the two databases, selected specific module by WGCNA, and then performed univariate and multivariate Cox regression analyses to screen their prognostic roles in HNSCC patients. Three prognostic immune genes were identified as prognostic gene, including DEFB1, PTX3and SEMA3G. According to the risk scores of patients, we divided HNSCC patients into low- and high-risk subgroups by the median value of risk scores in each dataset. In addition, we calculated immune cells and immune infiltration of the two groups and constructed K-M survival curve plot based on immune infiltration result. Enrichment analysis indicated that cytokines and cytokine receptors interaction was more common in the specific immune gene module. Moreover, we constructed a nomogram based on the results of multivariate cox analysis and clinical information and confirmed the survival of the two groups by using two GEO database. We also established a correlation analysis between immune prognostic signature genes and immune checkpoints. Finally, we believed that PTX3 was the key gene, and the expression levels of PTX3 in 30 clinical samples was detected by immunohistochemical method. In conclusion, PTX3 is a key immune gene, which may contribute to poor prognosis of HNSCC by affecting TME.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development and Validation of an Individualized Immune Prognostic Signature in HNSCC

Sun

Zhao

et al. 2022

Preprint

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“…Finally, dynamic crosstalk between CAFs and cancer cells involve transfer of genetic messages such as ncRNA-loaded exosomes, and in this field, a lncRNA was recently characterized as participating in this process . Consequently, bearing in mind all these improvements, today CAFs represent a crucial therapeutic target for getting rid of the deleterious effects of EMT in invasive cancers (Es et al, 2021).…”

Section: Tumor Microenvironmentmentioning

confidence: 99%

Curcuminoids as Modulators of EMT in Invasive Cancers: A Review of Molecular Targets With the Contribution of Malignant Mesothelioma Studies

et al. 2022

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Curcuminoids, which include natural acyclic diarylheptanoids and the synthetic analogs of curcumin, have considerable potential for fighting against all the characteristics of invasive cancers. The epithelial-to-mesenchymal transition (EMT) is a fundamental process for embryonic morphogenesis, however, the last decade has confirmed it orchestrates many features of cancer invasiveness, such as tumor cell stemness, metabolic rewiring, and drug resistance. A wealth of studies has revealed EMT in cancer is in fact driven by an increasing number of parameters, and thus understanding its complexity has now become a cornerstone for defining future therapeutic strategies dealing with cancer progression and metastasis. A specificity of curcuminoids is their ability to target multiple molecular targets, modulate several signaling pathways, modify tumor microenvironments and enhance the host’s immune response. Although the effects of curcumin on these various parameters have been the subject of many reviews, the role of curcuminoids against EMT in the context of cancer have never been reviewed so far. This review first provides an updated overview of all EMT drivers, including signaling pathways, transcription factors, non-coding RNAs (ncRNAs) and tumor microenvironment components, with a special focus on the most recent findings. Secondly, for each of these drivers the effects of curcumin/curcuminoids on specific molecular targets are analyzed. Finally, we address some common findings observed between data reported in the literature and the results of investigations we conducted on experimental malignant mesothelioma, a model of invasive cancer representing a useful tool for studies on EMT and cancer.

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“…Further, A549 lung cancer cells injected subcutaneously into mice with or without human CAFs showed that CAFs enhanced tumor growth in vivo (26). Another study analyzing data from 1084 breast cancer patients in The Cancer Genome Atlas (TCGA) observed a correlation between EMT, stemness, and samples with a high stromal index (35).…”

Section: Introductionmentioning

confidence: 99%

Intrinsic Differences in Spatiotemporal Organization and Stromal Cell Interactions Between Isogenic Lung Cancer Cells of Epithelial and Mesenchymal Phenotypes Revealed by High-Dimensional Single-Cell Analysis of Heterotypic 3D Spheroid Models

et al. 2022

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The lack of inadequate preclinical models remains a limitation for cancer drug development and is a primary contributor to anti-cancer drug failures in clinical trials. Heterotypic multicellular spheroids are three-dimensional (3D) spherical structures generated by self-assembly from aggregates of two or more cell types. Compared to traditional monolayer cell culture models, the organization of cells into a 3D tissue-like structure favors relevant physiological conditions with chemical and physical gradients as well as cell-cell and cell-extracellular matrix (ECM) interactions that recapitulate many of the hallmarks of cancer in situ. Epidermal growth factor receptor (EGFR) mutations are prevalent in non-small cell lung cancer (NSCLC), yet various mechanisms of acquired resistance, including epithelial-to-mesenchymal transition (EMT), limit the clinical benefit of EGFR tyrosine kinase inhibitors (EGFRi). Improved preclinical models that incorporate the complexity induced by epithelial-to-mesenchymal plasticity (EMP) are urgently needed to advance new therapeutics for clinical NSCLC management. This study was designed to provide a thorough characterization of multicellular spheroids of isogenic cancer cells of various phenotypes and demonstrate proof-of-principle for the applicability of the presented spheroid model to evaluate the impact of cancer cell phenotype in drug screening experiments through high-dimensional and spatially resolved imaging mass cytometry (IMC) analyses. First, we developed and characterized 3D homotypic and heterotypic spheroid models comprising EGFRi-sensitive or EGFRi-resistant NSCLC cells. We observed that the degree of EMT correlated with the spheroid generation efficiency in monocultures. In-depth characterization of the multicellular heterotypic spheroids using immunohistochemistry and high-dimensional single-cell analyses by IMC revealed intrinsic differences between epithelial and mesenchymal-like cancer cells with respect to self-sorting, spatiotemporal organization, and stromal cell interactions when co-cultured with fibroblasts. While the carcinoma cells harboring an epithelial phenotype self-organized into a barrier sheet surrounding the fibroblasts, mesenchymal-like carcinoma cells localized to the central hypoxic and collagen-rich areas of the compact heterotypic spheroids. Further, deep-learning-based single-cell segmentation of IMC images and application of dimensionality reduction algorithms allowed a detailed visualization and multiparametric analysis of marker expression across the different cell subsets. We observed a high level of heterogeneity in the expression of EMT markers in both the carcinoma cell populations and the fibroblasts. Our study supports further application of these models in pre-clinical drug testing combined with complementary high-dimensional single-cell analyses, which in turn can advance our understanding of the impact of cancer-stroma interactions and epithelial phenotypic plasticity on innate and acquired therapy resistance in NSCLC.

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Pirfenidone Reduces Epithelial–Mesenchymal Transition and Spheroid Formation in Breast Carcinoma through Targeting Cancer-Associated Fibroblasts (CAFs)

Cited by 19 publications

References 70 publications

Development and Validation of an Individualized Immune Prognostic Signature in HNSCC

Development and Validation of an Individualized Immune Prognostic Signature in HNSCC

Curcuminoids as Modulators of EMT in Invasive Cancers: A Review of Molecular Targets With the Contribution of Malignant Mesothelioma Studies

Intrinsic Differences in Spatiotemporal Organization and Stromal Cell Interactions Between Isogenic Lung Cancer Cells of Epithelial and Mesenchymal Phenotypes Revealed by High-Dimensional Single-Cell Analysis of Heterotypic 3D Spheroid Models

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