The Emerging Roles of Pericytes in Modulating Tumor Microenvironment

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.676342 ◽

2021 ◽

Vol 9 ◽

Author(s):

Ruipu Sun ◽

Xiangzhan Kong ◽

Xiaoyi Qiu ◽

Cheng Huang ◽

Ping-Pui Wong

Keyword(s):

Endothelial Cells ◽

Blood Flow ◽

Tumor Microenvironment ◽

Immune Cells ◽

Stromal Cells ◽

Direct Interaction ◽

Cancer Growth ◽

Mural Cells ◽

Current Review ◽

Recent Advancement

Pericytes (PCs), known as mural cells, play an important blood vessel (BV) supporting role in regulating vascular stabilization, permeability and blood flow in microcirculation as well as blood brain barrier. In carcinogenesis, defective interaction between PCs and endothelial cells (ECs) contributes to the formation of leaky, chaotic and dysfunctional vasculature in tumors. However, recent works from other laboratories and our own demonstrate that the direct interaction between PCs and other stromal cells/cancer cells can modulate tumor microenvironment (TME) to favor cancer growth and progression, independent of its BV supporting role. Furthermore, accumulating evidence suggests that PCs have an immunomodulatory role. In the current review, we focus on recent advancement in understanding PC’s regulatory role in the TME by communicating with ECs, immune cells, and tumor cells, and discuss how we can target PC’s functions to re-model TME for an improved cancer treatment strategy.

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Blood flow boosts BMP signaling to keep vessels in shape

The Journal of Cell Biology ◽

10.1083/jcb.201609038 ◽

2016 ◽

Vol 214 (7) ◽

pp. 793-795 ◽

Cited By ~ 2

Author(s):

Claudio A. Franco ◽

Holger Gerhardt

Keyword(s):

Cell Proliferation ◽

Endothelial Cells ◽

Blood Flow ◽

Vascular Remodeling ◽

Bmp Signaling ◽

Mural Cells ◽

Bone Morphogenic Proteins ◽

Cell Biol ◽

Suppress Cell Proliferation

Bone morphogenic proteins (BMPs) and blood flow regulate vascular remodeling and homeostasis. In this issue, Baeyens et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201603106) show that blood flow sensitizes endothelial cells to BMP9 signaling by triggering Alk1/ENG complexing to suppress cell proliferation and to recruit mural cells, thereby establishing endothelial quiescence.

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Toward Normalization of the Tumor Microenvironment for Cancer Therapy

Integrative Cancer Therapies ◽

10.1177/1534735419862352 ◽

2019 ◽

Vol 18 ◽

pp. 153473541986235 ◽

Cited By ~ 5

Author(s):

Jie Zheng ◽

Peng Gao

Keyword(s):

Stem Cells ◽

Extracellular Matrix ◽

Tumor Microenvironment ◽

Immune Cells ◽

Normal Tissue ◽

Cancer Growth ◽

Tissue Architecture ◽

Action Mechanisms ◽

Anticancer Effects ◽

Complex Ecosystem

The tumor microenvironment (TME) is a complex ecosystem, including blood vessels, immune cells, fibroblasts, extracellular matrix, cytokines, hormones, and so on. The TME differs from the normal tissue environment (NTE) in many aspects, such as tissue architecture, chronic inflammation, level of oxygen and pH, nutritional state of the cells, as well as tissue firmness. The NTE can inhibit the growth of cancer at the early tumorigenesis phase, whereas the TME promotes the growth of cancer in general, although it may have some anticancer effects. In particular, the TME plays a crucial role in the generation and maintenance of cancer stem cells, which lie at the root of cancer growth. Therefore, normalization of the TME to the NTE may inhibit cancer growth or improve cancer therapeutic efficiency. This review focuses on the recent emerging approaches for this normalization and the action mechanisms.

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Cancer-Associated Fibroblast Heterogeneity: A Factor That Cannot Be Ignored in Immune Microenvironment Remodeling

Frontiers in Immunology ◽

10.3389/fimmu.2021.671595 ◽

2021 ◽

Vol 12 ◽

Author(s):

Pei-Yu Chen ◽

Wen-Fei Wei ◽

Hong-Zhen Wu ◽

Liang-Sheng Fan ◽

Wei Wang

Keyword(s):

Extracellular Matrix ◽

Tumor Microenvironment ◽

Immune Cells ◽

Immune Regulation ◽

Stromal Cells ◽

Cancer Associated Fibroblasts ◽

Immune Microenvironment ◽

Cancer Associated Fibroblast ◽

Different Origins ◽

Fibroblast Heterogeneity

Cancer-associated fibroblasts (CAFs) are important, highly heterogeneous components of the tumor extracellular matrix that have different origins and express a diverse set of biomarkers. Different subtypes of CAFs participate in the immune regulation of the tumor microenvironment (TME). In addition to their role in supporting stromal cells, CAFs have multiple immunosuppressive functions, via membrane and secretory patterns, against anti-tumor immunity. The inhibition of CAFs function and anti-TME therapy targeting CAFs provides new adjuvant means for immunotherapy. In this review, we outline the emerging understanding of CAFs with a particular emphasis on their origin and heterogeneity, different mechanisms of their regulation, as well as their direct or indirect effect on immune cells that leads to immunosuppression.

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Significance of a Tumor Microenvironment-Mediated P65-miR-30a-5p-BCL2L11 Amplification Loop in Multiple Myeloma

10.21203/rs.3.rs-880497/v1 ◽

2021 ◽

Author(s):

Ling Xie ◽

Xiuying Shi ◽

Hongming Huang ◽

Shaoqing Ju ◽

Xudong Wang

Keyword(s):

Multiple Myeloma ◽

Tumor Microenvironment ◽

Stromal Cells ◽

Bone Marrow Stromal Cells ◽

Molecular Mechanisms ◽

Direct Interaction ◽

Luciferase Reporter ◽

Myeloma Cells ◽

Amplification Loop

Abstract Despite significant progress in the treatment of myeloma, multiple myeloma (MM) remains an incurable hematological malignancy due to cell adhesion-mediated drug resistance (CAM-DR) phenotype. However, data on the molecular mechanisms underlying the CAM-DR remains scanty. Here, we identified a miRNA-mRNA regulatory network in myeloma cells that are directly adherent to bone marrow stromal cells (BMSCs). Our data showed that the BMSCs up-regulated miR-30a-5p and down-regulated BCL2L11 at both mRNA and protein level in the myeloma cells. Besides, luciferase reporter genes demonstrated direct interaction between miR-30a-5p and BCL2L11 gene. Moreover, the BMSCs activated NF-ΚB signaling pathway in myeloma cells and the NF-κB P65 was shown to directly bind the miR-30a-5p promoter region. Moreover, suppression of the miR-30a-5p or upregulation of the BCL2L11 promoted apoptosis of the myeloma cells independent of the BMSCs, thus suggesting clinical significance of miR-30a-5p inhibitor and PLBCL2L11 plasmid in CAM-DR. Together, our data demonstrated the role of P65-miR-30a-5p-BCL2L11 loop in CAM-DR myeloma cells. These findings give new insights into the role of tumor microenvironment in the treatment of patients with myeloma.

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Interferon-Related Secretome Plays a Vital Role in PD-L1 Expression in the Tumor Microenvironment after Direct Interaction between Immune Cells and Tumor Cells

Single Cell Biology ◽

10.4172/2168-9431.1000146 ◽

2016 ◽

Vol 5 (3) ◽

Author(s):

Yuan Qin Yang ◽

Jonathan Howard DeLong ◽

Kang Jian Zhang

Keyword(s):

Tumor Microenvironment ◽

Tumor Cells ◽

Immune Cells ◽

Direct Interaction ◽

Vital Role

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SIO: A Spatioimageomics Pipeline to Identify Prognostic Biomarkers Associated with the Ovarian Tumor Microenvironment

Cancers ◽

10.3390/cancers13081777 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1777

Author(s):

Ying Zhu ◽

Sammy Ferri-Borgogno ◽

Jianting Sheng ◽

Tsz-Lun Yeung ◽

Jared K. Burks ◽

...

Keyword(s):

Tumor Microenvironment ◽

Immune Cells ◽

Stromal Cells ◽

Ovarian Tumor ◽

Nearest Neighbor ◽

Survival Rates ◽

Cell Communication ◽

Spatial Relationship ◽

Signaling Networks ◽

Mass Cytometry

Stromal and immune cells in the tumor microenvironment (TME) have been shown to directly affect high-grade serous ovarian cancer (HGSC) malignant phenotypes, however, how these cells interact to influence HGSC patients’ survival remains largely unknown. To investigate the cell-cell communication in such a complex TME, we developed a SpatioImageOmics (SIO) pipeline that combines imaging mass cytometry (IMC), location-specific transcriptomics, and deep learning to identify the distribution of various stromal, tumor and immune cells as well as their spatial relationship in TME. The SIO pipeline automatically and accurately segments cells and extracts salient cellular features to identify biomarkers, and multiple nearest-neighbor interactions among tumor, immune, and stromal cells that coordinate to influence overall survival rates in HGSC patients. In addition, SIO integrates IMC data with microdissected tumor and stromal transcriptomes from the same patients to identify novel signaling networks, which would lead to the discovery of novel survival rate-modulating mechanisms in HGSC patients.

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Identification of prognosis-related genes in the cervical cancer immune microenvironment

10.21203/rs.3.rs-16157/v1 ◽

2020 ◽

Author(s):

Lirong Yang ◽

Yang Yang ◽

Mingyao Meng ◽

Wenju Wang ◽

Shan He ◽

...

Keyword(s):

Gene Expression ◽

Cervical Cancer ◽

Tumor Microenvironment ◽

Clinical Data ◽

Immune Cells ◽

Stromal Cells ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Malignant Tumours ◽

Significant Difference

Abstract Background Cervical cancer is the fourth most common cancer in women worldwide. The metastasis and invasion of this type of cancer are closely related to the tumor microenvironment. Immune cells and stromal cells dominate the tumor microenvironment in cervical cancer. Therefore, we should further understand the association between tumor progress and immune cells or stromal cells.Methods we downloaded the gene expression profiles and clinical data of 307 patients with cervical cancers based on the TCGA database. Subsequently the Estimation of Stromal and Immune cells in Malignant Tumours using Expression data (ESTIMATE) algorithm was used to calculate the scores of stromal cells and immune cells to find differential genes, and analyzed the correlation between their scores and patient survival. Moreover, we also used R language packs and network tools to analyze GO term, gene enrichment pathway, and protein-protein relationship to find genes related to inflammation and immune regulation.Results The gene expression profiles and corresponding clinical data of 307 patients were obtained from TCGA datasets. The results showed that there was a statistically significant difference between the high immunescore group and the low immunescore group. And the low immunescore group had shorter lifetimes than the high scores group (P = 0.035).Moreover, PPI network analysis CCR5 and CXCL9, -10, -11 / CXCR3 axis might be new target for cervical cancer treatment. Finally, Kaplan-Meier survival curves found out nine representative genes significantly related to survival including BTNL8 , CCR7 , CD1E , CD6 , CD27 , CD79A , GRAP2 , SP1B , LY9 .Conclusions These genes can be used as markers for the prognosis and diagnosis of cervical cancer and also might be used as treatment targets.

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Prognostic Value and Immune Infiltration of Novel Biomarkers in Glioma: Evidence From a Comprehensive Analysis of Tumor Microenvironment

10.21203/rs.3.rs-125889/v1 ◽

2020 ◽

Author(s):

Bolun Zhang ◽

Feng Guan ◽

Bin Dai ◽

Guangtong Zhu ◽

Beibei Mao ◽

...

Keyword(s):

Tumor Microenvironment ◽

Tumor Progression ◽

Immune Cells ◽

Stromal Cells ◽

Cox Regression ◽

Gene Set Enrichment Analysis ◽

Ppi Network ◽

Cox Regression Analysis ◽

Intersection Analysis ◽

Genome Atlas

Abstract BackgroundIn the glioma microenvironment, infiltrating immune cells has been shown to possess beneficial effects for tumor progression. Immune cells and stromal cells dominate the tumor microenvironment in glioma. The complex interplay between the tumor progression with immune cells or stromal cells was still unknown. MethodsIn this study, we used Estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE) calculations to calculate the proportion of tumour-infiltrating immune cells (TIC) and the number of immune and stromal components in glioma cases from the cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases. Differentially expressed genes (DEG) were analyzed by COX regression analysis and protein-protein interaction (PPI) network construction. Then, JAK3, IL2RB and CD3E were identified as predictors by the intersection analysis of univariate COX and PPI, and further analysis showed that the expression of them were positively correlated with survival and clinicopathological characteristics of glioma patients. Finally, the Cell type Identification By Estimating Relative Subsets Of known RNA Transcripts (CIBERSORT) deconvolution algorithm was applied to quantify the fraction and infiltration of 22 types of immune cells in glioma. ResultsOur results showed that ESTIMATEScores Were Correlated with the Survival of glioma Patients, DEGs Shared by ImmuneScore and StromalScore were predominantly presented as the enrichment of immune-related genes gene set enrichment analysis (GSEA). The intersection analysis of PPI network and univariate COX regression enabled us to identify three genes (JAK3, IL2RB and CD3E) that had never been reported before, whose expression was correlated with clinical characteristics such as survival and WHO grading of these patients. CITICSORT analysis of TIC ratio showed that B cell memory and CD8 + T cells were positively correlated with JAK3, IL2RB and CD3E expression, suggesting that these genes may be responsible for maintaining the immunodominant state of TME. CIBERSORT analysis for the proportion of TICs revealed that the levels of JAK3, IL2RB and CD3E affected the immune activity of TME.ConclusionOur results confirmed that the JAK3, IL2RB and CD3E can be used as diagnostic and prognostic biomarkers for glioma and may be used as therapeutic targets in the future.

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Inflammatory Cytokine Signaling during Development of Pancreatic and Prostate Cancers

Journal of Immunology Research ◽

10.1155/2017/7979637 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 4

Author(s):

Geou-Yarh Liou

Keyword(s):

Endothelial Cells ◽

Immune Cells ◽

Stromal Cells ◽

Inflammatory Cytokine ◽

Cancer Development ◽

Cytokine Signaling ◽

Environment Effects ◽

Tumor Environment ◽

Prostate Cancers ◽

Different Sources

Inflammation is essential for many diseases including cancer. Activation and recruitment of immune cells during inflammation result in a cytokine- and chemokine-enriched cell environment, which affects cancer development. Since each type of cancer has its unique tumor environment, effects of cytokines from different sources such as tumor-infiltrating immune cells, stromal cells, endothelial cells, and cancer cells on cancer development can be quite complex. In this review, how immune cells contribute to tumorigenesis of pancreatic and prostate cancers through their secreted cytokines is discussed. In addition, the cytokine signaling that tumor cells of pancreatic and prostate cancers utilize to benefit their own survival is delineated.

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