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Macrophages orchestrate the expansion of a proangiogenic perivascular niche during cancer progression.

ABSTRACT: Tumor-associated macrophages (TAMs) are a highly plastic stromal cell type that support cancer progression. Using single-cell RNA sequencing of TAMs from a spontaneous murine model of mammary adenocarcinoma (MMTV-PyMT), we characterize a subset of these cells expressing lymphatic vessel endothelial hyaluronic acid receptor 1 (Lyve-1) that spatially reside proximal to blood vasculature. We demonstrate that Lyve-1⁺ TAMs support tumor growth and identify a pivotal role for these cells in maintaining a population of perivascular mesenchymal cells that express α-smooth muscle actin and phenotypically resemble pericytes. Using photolabeling techniques, we show that mesenchymal cells maintain their prevalence in the growing tumor through proliferation and uncover a role for Lyve-1⁺ TAMs in orchestrating a selective platelet-derived growth factor–CC–dependent expansion of the perivascular mesenchymal population, creating a proangiogenic niche. This study highlights the inter-reliance of the immune and nonimmune stromal network that supports cancer progression and provides therapeutic opportunities for tackling the disease.

SUBMITTER: Opzoomer JW

PROVIDER: S-EPMC8565907 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Macrophages orchestrate the expansion of a proangiogenic perivascular niche during cancer progression.

Opzoomer James W JW Anstee Joanne E JE Dean Isaac I Hill Emily J EJ Bouybayoune Ihssane I Caron Jonathan J Muliaditan Tamara T Gordon Peter P Sosnowska Dominika D Nuamah Rosamond R Pinder Sarah E SE Ng Tony T Dazzi Francesco F Kordasti Shahram S Withers David R DR Lawrence Toby T Arnold James N JN

Science advances 20211103 45

Tumor-associated macrophages (TAMs) are a highly plastic stromal cell type that support cancer progression. Using single-cell RNA sequencing of TAMs from a spontaneous murine model of mammary adenocarcinoma (<i>MMTV-PyMT</i>), we characterize a subset of these cells expressing lymphatic vessel endothelial hyaluronic acid receptor 1 (Lyve-1) that spatially reside proximal to blood vasculature. We demonstrate that Lyve-1<sup>+</sup> TAMs support tumor growth and identify a pivotal role for these c ...[more]

PMID: 34730997

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Project description:BackgroundClinical trials in ischemic patients showed the safety and benefit of autologous bone marrow progenitor cell transplantation. Non-bone marrow progenitor cells with proangiogenic capacities have been described, yet they remain clinically unexploited owing to their scarcity, difficulty of access, and low ex vivo expansibility. We investigated the presence, antigenic profile, expansion capacity, and proangiogenic potential of progenitor cells from the saphenous vein of patients undergoing coronary artery bypass surgery.Methods and resultsCD34-positive cells, negative for the endothelial marker von Willebrand factor, were localized around adventitial vasa vasorum. After dissection of the vein from surrounding tissues and enzymatic digestion, CD34-positive/CD31-negative cells were isolated by selective culture, immunomagnetic beads, or fluorescence-assisted cell sorting. In the presence of serum, CD34-positive/CD31-negative cells gave rise to a highly proliferative population that expressed pericyte/mesenchymal antigens together with the stem cell marker Sox2 and showed clonogenic and multilineage differentiation capacities. We called this population "saphenous vein-derived progenitor cells" (SVPs). In culture, SVPs integrated into networks formed by endothelial cells and supported angiogenesis through paracrine mechanisms. Reciprocally, endothelial cell-released factors facilitated SVP migration. These interactive responses were inhibited by Tie-2 or platelet-derived growth factor-BB blockade. Intramuscular injection of SVPs in ischemic limbs of immunodeficient mice improved neovascularization and blood flow recovery. At 14 days after transplantation, proliferating SVPs were still detectable in the recipient muscles, where they established N-cadherin-mediated physical contact with the capillary endothelium.ConclusionsSVPs generated from human vein CD34-positive/CD31-negative progenitor cells might represent a new therapeutic tool for angiogenic therapy in ischemic patients.

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Macrophages orchestrate the expansion of a proangiogenic perivascular niche during cancer progression.

Publications

Macrophages orchestrate the expansion of a proangiogenic perivascular niche during cancer progression.

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