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Tumor microenvironment as a therapeutic target in cancer.

ABSTRACT: Tumor microenvironment denotes the non-cancerous cells and components presented in the tumor, including molecules produced and released by them. The constant interactions between tumor cells and the tumor microenvironment play decisive roles in tumor initiation, progression, metastasis, and response to therapies. The tumor microenvironment as a therapeutic target in cancer has attracted great research and clinical interest. Here we summarize the current progress in targeting the tumor microenvironment in both drug development and clinical trials; highlight challenges in targeting the tumor microenvironment to achieve therapeutic efficacy; explore new technologies and approaches to better decipher the tumor microenvironment; and discuss strategies to intervene in the pro-tumor microenvironment and maximize therapeutic benefits.

SUBMITTER: Xiao Y

PROVIDER: S-EPMC8084948 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Tumor microenvironment as a therapeutic target in cancer.

Xiao Yi Y Yu Dihua D

Pharmacology & therapeutics 20201128

Tumor microenvironment denotes the non-cancerous cells and components presented in the tumor, including molecules produced and released by them. The constant interactions between tumor cells and the tumor microenvironment play decisive roles in tumor initiation, progression, metastasis, and response to therapies. The tumor microenvironment as a therapeutic target in cancer has attracted great research and clinical interest. Here we summarize the current progress in targeting the tumor microenvir ...[more]

PMID: 33259885

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Project description:BackgroundCrosstalk between neoplastic and stromal cells fosters prostate cancer (PCa) progression and dissemination. Insight in cell-to-cell communication networks provides new therapeutic avenues to mold processes that contribute to PCa tumor microenvironment (TME) alterations. Here we performed a detailed characterization of PCa tumor endothelial cells (TEC) to delineate intercellular crosstalk between TEC and the PCa TME.MethodsTEC isolated from 67 fresh radical prostatectomy (RP) specimens underwent multi-omic ex vivo characterization as well as orthogonal validation of both TEC functions and key markers by immunohistochemistry (IHC) and immunofluorescence (IF). To identify cell-cell interaction targets in TEC, we performed single-cell RNA sequencing (scRNA-seq) in four PCa patients who underwent a RP to catalogue cellular TME composition. Targets were cross-validated using IHC, publicly available datasets, cell culture expriments as well as a PCa xenograft mouse model.ResultsCompared to adjacent normal endothelial cells (NEC) bulk RNA-seq analysis revealed upregulation of genes associated with tumor vasculature, collagen modification and extracellular matrix remodeling in TEC. PTGIR, PLAC9, CXCL12 and VDR were identified as TEC markers and confirmed by IF and IHC in an independent patient cohort. By scRNA-seq we identified 27 cell (sub)types, including endothelial cells (EC) with arterial, venous and immature signatures, as well as angiogenic tip EC. A focused molecular analysis revealed that arterial TEC displayed highest CXCL12 mRNA expression levels when compared to all other TME cell (sub)populations and showed a negative prognostic role. Receptor-ligand interaction analysis predicted interactions between arterial TEC derived CXCL12 and its cognate receptor CXCR4 on angiogenic tip EC. CXCL12 was in vitro and in vivo validated as actionable TEC target by highlighting the vessel number- and density- reducing activity of the CXCR4-inhibitor AMD3100 in murine PCa as well as by inhibition of TEC proliferation and migration in vitro.ConclusionsOverall, our comprehensive analysis identified novel PCa TEC targets and highlights CXCR4/CXCL12 interaction as a potential novel target to interfere with tumor angiogenesis in PCa.

Dataset Information

Tumor microenvironment as a therapeutic target in cancer.

Publications

Tumor microenvironment as a therapeutic target in cancer.

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