Cancer-Associated Fibroblasts Correlate with Tumor-Associated Macrophages Infiltration and Lymphatic Metastasis in Triple Negative Breast Cancer Patients

Zhou, Jing; Wang, Xiaohua; Zhao, Yixin; Chen, Cheng; Xu, Xiaoyu; Sun, Qi; Wu, Hongyan; Chen, Ming; Sang, Jianfeng; Su, Lei; X, Tang; Shi, Xuefei; Yin, Zhinan; Ye, Qiao; Yao, Yongzhong; Zhang, Weijie

doi:10.7150/jca.28583

Cited by 68 publications

(54 citation statements)

References 30 publications

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“…These results also corroborate the idea in renal cell carcinomas that different types of tumorinfiltrating immune cells modulated in different subtypes of renal carcinomas and prolonged OS or DFS (28). However, a contradictory study indicated cancer-associated fibroblasts activation correlated with tumor-associated macrophages Infiltration and lymph node metastasis could promote tumor progression by mediating inflammatory reactions in triple negative breast cancers (29). Besides, stromal cells are found to act as crucial factors during chemotherapy and endocrine therapy in breast cancer (72)(73)(74).…”

Section: Discussionsupporting

confidence: 80%

“…Interestingly, high immune score was found to be associated with ER negative and PR negative status while the latter two are considered as factors for poor prognosis in breast cancer stratification and treatment. The connection between immune infiltration and ER status could be seen as well in ductal carcinoma in situ among women patients (28,29). However, there is necessity that the level of immune or stromal infiltration should be detected further using flow cytometry and/or singlecell sequencing and their relationships with clinical features can be restated.…”

Section: Discussionmentioning

confidence: 99%

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Immune and Stroma Related Genes in Breast Cancer: A Comprehensive Analysis of Tumor Microenvironment Based on the Cancer Genome Atlas (TCGA) Database

et al. 2020

Front. Med.

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Background: Tumor microenvironment is essential for breast cancer progression and metastasis. Our study sets out to examine the genes affecting stromal and immune infiltration in breast cancer progression and prognosis. Materials and Methods: This work provides an approach for quantifying stromal and immune scores by using ESTIMATE algorithm based on gene expression matrix of breast cancer patients in TCGA database. We found differentially expressed genes (DEGs) through limma R package. Functional enrichments were accessed through Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Besides, we constructed a protein-protein network, identified several hub genes in Cytoscape, and discovered functionally similar genes in GeneMANIA. Hub genes were validated with prognostic data by Kaplan-Meier analysis both in The Cancer Genome Atlas (TCGA) database and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) database and a meta-analysis of hub genes prognosis data was utilized in multiple databases. Furthermore, their relationship with infiltrating immune cells was evaluated by Tumor IMmune Estimation Resource (TIMER) web tool. Cox regression was utilized for overall survival (OS) and recurrence-free survival (RFS) in TCGA database and OS in METABRIC database in order to evaluate the impact of stromal and immune scores on patients prognosis. Results: One thousand and eighty-five breast cancer patients were investigated and 480 differentiated expressed genes (DEGs) were found based on the analysis of mRNA expression profiles. Functional analysis of DEGs revealed their potential functions in immune response and extracellular interaction. Protein-protein interaction network gave evidence of 10 hub genes. Some of the hub genes could be used as predictive markers for patients prognosis. In this study, we found that tumor purity and specific immune cells infiltration varied in response to hub genes expression. The multivariate cox regression highlighted the fact that immune score played a detrimental role in overall survival (HR = 0.45, 95% CI: 0.27-0.74, p = 0.002) and recurrence-free survival (HR = 0.41, 95% CI: 0.22-0.77, p = 0.006) in TCGA database. These result was confirmed in Xu et al. Tumor Microenvironment in Breast Cancer METABRIC database that immune score was a protector of OS (HR = 0.88, 95% CI: 0.77-0.99, p = 0.039). Conclusions: Our findings promote a better understanding of the potential genes behind the regulation of tumor microenvironment and cells infiltration. Immune score should be considered as a prognostic factor for patients' survival.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Immune and Stroma Related Genes in Breast Cancer: A Comprehensive Analysis of Tumor Microenvironment Based on the Cancer Genome Atlas (TCGA) Database

et al. 2020

Front. Med.

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“…[33][34][35] Furthermore, we also found that CD163 was positively associated with fibroblasts ( Figure 4(a,b), lower panel), which was consistent with the previous reports that the expression of CD163 was positively associated with fibroblasts. [36][37][38] These data suggested that CD163 may participate in the regulation of stromal cells in the tumor microenvironment.…”

Section: Relationship Between Cd163 and Infiltrated Cells In The Tumomentioning

confidence: 80%

Molecular and clinical characterization of CD163 expression via large-scale analysis in glioma

Zhang

Maimela

et al. 2019

OncoImmunology

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The expression and function of CD163 in glioma are not fully understood. In this report, we collected totally 1323 glioma samples from the Chinese Glioma Genome Atlas (CGGA) dataset, including 325 RNA-seq data and 301 mRNA microarray data, and 697 glioma samples from The Cancer Genome Atlas (TCGA) dataset to characterize the molecular and clinical features of CD163 in glioma by conducting a large-scale study. We found that CD163 expression was positively associated with the grade of malignancy of glioma. CD163 expression was up-regulated in IDH wild-type glioma and mesenchymal subtype. Gene ontology analysis suggested that CD163-related genes were more involved in immune response and angiogenesis in glioma. Moreover, CD163 showed a positive relationship with stromal and immune cell populations. Kaplan-Meier curves analysis revealed that higher CD163 expression indicated significantly poor survival in glioma and glioblastoma multiforme (GBM). Pearson correlation analysis revealed that CD163 was robustly associated with the immune checkpoints and other macrophage markers. These results demonstrated that CD163 predicts poor prognosis in glioma patients. Additionally, combination of CD163 and immune checkpoints may impair angiogenesis and reverse dysfunctional phenotypes of T cells, which suggest that CD163 may be a promising biomarker and target for immunotherapeutic strategies.

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“…CAFs are the most abundant stromal cell type in the TME and play a central role in promoting breast cancer tumor vascularization, growth, invasiveness, and treatment resistance (33). Indeed, CAFs correlate with a more aggressive breast cancer phenotype and poorer patient survival (40). Similarly, MDSCs exert not only immunosuppressive functions but also directly stimulate tumor growth, tumor vascularization and metastasis (32).…”

Section: Downloaded Frommentioning

confidence: 99%

IRE1α Disruption in Triple-Negative Breast Cancer Cooperates with Antiangiogenic Therapy by Reversing ER Stress Adaptation and Remodeling the Tumor Microenvironment

Harnoss¹,

Thomas²,

Reichelt³

et al. 2020

Cancer Research

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Cancer cells exploit the unfolded protein response (UPR) to mitigate endoplasmic reticulum (ER) stress caused by cellular oncogene activation and a hostile tumor microenvironment (TME). The key UPR sensor IRE1α resides in the ER and deploys a cytoplasmic kinase-endoribonuclease module to activate the transcription factor XBP1s, which facilitates ER-mediated protein folding. Studies of triple-negative breast cancer (TNBC)-a highly aggressive malignancy with a dismal post-treatment prognosisimplicate XBP1s in promoting tumor vascularization and progression. However, it remains unknown whether IRE1α adapts the ER in TNBC cells and modulates their TME, and whether IRE1α inhibition can enhance anti-angiogenic therapy-previously found to be ineffective in TNBC patients. To gauge IRE1α function, we defined an XBP1s-dependent gene signature, which revealed significant IRE1α pathway activation in multiple solid cancers, including TNBC. IRE1α knockout in TNBC cells markedly reversed substantial ultrastructural expansion of the ER within these cells upon growth in vivo. IRE1α disruption also led to significant remodeling of the cellular TME, increasing pericyte numbers while decreasing cancer-associated fibroblasts and myeloid-derived suppressor cells. Pharmacological IRE1α kinase inhibition strongly attenuated growth of cell-line-based and patient-derived TNBC xenografts in mice and synergized with anti-VEGF-A treatment to cause tumor stasis or regression. Thus, TNBC cells critically rely on IRE1α to adapt their ER to in vivo stress and to adjust the TME to facilitate malignant growth. TNBC reliance on IRE1α is an important vulnerability that can be uniquely exploited in combination with anti-angiogenic therapy as a promising new biologic approach to combat this lethal disease. Statement of significance Pharmacologic IRE1α kinase inhibition reverses ultrastructural distension of the ER, normalizes the tumor vasculature, and remodels the cellular tumor microenvironment, attenuating TNBC growth in mice. Research.

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Cancer-Associated Fibroblasts Correlate with Tumor-Associated Macrophages Infiltration and Lymphatic Metastasis in Triple Negative Breast Cancer Patients

Cited by 68 publications

References 30 publications

Immune and Stroma Related Genes in Breast Cancer: A Comprehensive Analysis of Tumor Microenvironment Based on the Cancer Genome Atlas (TCGA) Database

Immune and Stroma Related Genes in Breast Cancer: A Comprehensive Analysis of Tumor Microenvironment Based on the Cancer Genome Atlas (TCGA) Database

Molecular and clinical characterization of CD163 expression via large-scale analysis in glioma

IRE1α Disruption in Triple-Negative Breast Cancer Cooperates with Antiangiogenic Therapy by Reversing ER Stress Adaptation and Remodeling the Tumor Microenvironment

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