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The vascular landscape of human cancer.

ABSTRACT: Tumors depend on a blood supply to deliver oxygen and nutrients, making tumor vasculature an attractive anticancer target. However, only a fraction of patients with cancer benefit from angiogenesis inhibitors. Whether antiangiogenic therapy would be more effective if targeted to individuals with specific tumor characteristics is unknown. To better characterize the tumor vascular environment both within and between cancer types, we developed a standardized metric - the endothelial index (EI) - to estimate vascular density in over 10,000 human tumors, corresponding to 31 solid tumor types, from transcriptome data. We then used this index to compare hyper- and hypovascular tumors, enabling the classification of human tumors into 6 vascular microenvironment signatures (VMSs) based on the expression of a panel of 24 vascular "hub" genes. The EI and VMS correlated with known tumor vascular features and were independently associated with prognosis in certain cancer types. Retrospective testing of clinical trial data identified VMS2 classification as a powerful biomarker for response to bevacizumab. Thus, we believe our studies provide an unbiased picture of human tumor vasculature that may enable more precise deployment of antiangiogenesis therapy.

SUBMITTER: Kahn BM

PROVIDER: S-EPMC7810485 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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The vascular landscape of human cancer.

Kahn Benjamin M BM Lucas Alfredo A Alur Rohan G RG Wengyn Maximillian D MD Schwartz Gregory W GW Li Jinyang J Sun Kathryn K Maurer H Carlo HC Olive Kenneth P KP Faryabi Robert B RB Stanger Ben Z BZ

The Journal of clinical investigation 20210101 2

Tumors depend on a blood supply to deliver oxygen and nutrients, making tumor vasculature an attractive anticancer target. However, only a fraction of patients with cancer benefit from angiogenesis inhibitors. Whether antiangiogenic therapy would be more effective if targeted to individuals with specific tumor characteristics is unknown. To better characterize the tumor vascular environment both within and between cancer types, we developed a standardized metric - the endothelial index (EI) - to ...[more]

PMID: 33258803

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Project description:Background Human mesenchymal cells are culprit factors in vascular (patho)physiology and are hallmarked by phenotypic and functional heterogeneity. At present, they are subdivided by classic umbrella terms, such as "fibroblasts," "myofibroblasts," "smooth muscle cells," "fibrocytes," "mesangial cells," and "pericytes." However, a discriminative marker-based subclassification has to date not been established. Methods and Results As a first effort toward a classification scheme, a systematic literature search was performed to identify the most commonly used phenotypical and functional protein markers for characterizing and classifying vascular mesenchymal cell subpopulation(s). We next applied immunohistochemistry and immunofluorescence to inventory the expression pattern of identified markers on human aorta specimens representing early, intermediate, and end stages of human atherosclerotic disease. Included markers comprise markers for mesenchymal lineage (vimentin, FSP-1 [fibroblast-specific protein-1]/S100A4, cluster of differentiation (CD) 90/thymocyte differentiation antigen 1, and FAP [fibroblast activation protein]), contractile/non-contractile phenotype (α-smooth muscle actin, smooth muscle myosin heavy chain, and nonmuscle myosin heavy chain), and auxiliary contractile markers (h1-Calponin, h-Caldesmon, Desmin, SM22α [smooth muscle protein 22α], non-muscle myosin heavy chain, smooth muscle myosin heavy chain, Smoothelin-B, α-Tropomyosin, and Telokin) or adhesion proteins (Paxillin and Vinculin). Vimentin classified as the most inclusive lineage marker. Subset markers did not separate along classic lines of smooth muscle cell, myofibroblast, or fibroblast, but showed clear temporal and spatial diversity. Strong indications were found for presence of stem cells/Endothelial-to-Mesenchymal cell Transition and fibrocytes in specific aspects of the human atherosclerotic process. Conclusions This systematic evaluation shows a highly diverse and dynamic landscape for the human vascular mesenchymal cell population that is not captured by the classic nomenclature. Our observations stress the need for a consensus multiparameter subclass designation along the lines of the cluster of differentiation classification for leucocytes.

Project description:ObjectiveDisulfidptosis is a newly discovered disulfide stress-induced cell death form. Clinical significance and biological mechanisms of disulfidptosis in human cancers need to be further elucidated. Thus, this study was designed to characterize pan-cancer landscape of disulfidptosis across human tumors.MethodsMulti-omics features (transcriptomics, genomics, and DNA methylation) of disulfidptosis genes were investigated in TCGA pan-cancer cohorts. A disulfidptosis score system was defined across human tumors via ssGSEA. The activity of classical oncogenic pathways and hallmarks of cancer as well as the infiltration of immunocyte subpopulations were estimated, respectively. Drug sensitivity was inferred, and immune checkpoint blockade (ICB) response was evaluated in an independent cohort IMvigor210. ACHN, CAL-27, and NCI-H23 cells were transiently transfected with GYS1 siRNAs, and cell apoptosis and proliferation were measured through TUNEL and EdU assays, respectively.ResultsAberrant mRNA expression and DNA methylation of disulfidptosis genes as well as their genomic alterations were found in human tumors. The disulfidptosis score was utilized for quantifying the activity of disulfidptosis, which enabled to estimate patient prognosis. The disulfidptosis score presented positive correlations to angiogenesis and EMT, indicating the role of disulfidptosis in mediating tumor malignant features. Moreover, the score was negatively linked with infiltrating immune and stromal cells in the immune microenvironment. In the ICB cohort, shorter survival time was observed in patients with high disulfidptosis score, indicating the potential of disulfidptosis score in influencing clinical benefits from ICB. Additionally, tumors with low disulfidptosis score exhibited higher sensitivity to a few small molecular compounds, e.g., Sabutoclax, PRIMA-1MET, BIBR-1532, and Elephantin. Knockdown of disulfidptosis gene GYS1 effectively hindered tumor progression.ConclusionCollectively, our findings depict a pan-cancer map of disulfidptosis to inform functional and therapeutic research.

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The vascular landscape of human cancer.

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The vascular landscape of human cancer.

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