Macrophages orchestrate the expansion of a pro-angiogenic perivascular niche during cancer progression

Abstract

Tumor associated macrophages (TAMs) are a highly plastic stromal cell type which are exquisitely polarized by the tumor microenvironment to support cancer progression. Single-cell RNA-sequencing (scRNA-seq) of TAMs from a spontaneous murine model of mammary adenocarcinoma (MMTV-PyMT) identified three distinct polarization trajectories for these cells within the tumor microenvironment. We reveal sub-divisions within the protumoral TAM population with one subset expressing Lyve-1 and residing in a spatial niche proximal to blood vasculature within the tumor. We demonstrate that selective depletion of the Lyve-1+ TAM population significantly slows tumor growth because of a non-redundant role of these cells in orchestrating the platelet derived growth factor-CC (PDGF-CC)-dependent expansion of tumor-resident pericytes which underpins vasculature growth and development. This study uncovers that local pericyte expansion in cancer is not an autonomous event but tightly regulated by the perivascular Lyve-1+ TAM population, which ultimately govern the success of angiogenesis in cancer.

The effects of radiation therapy on the macrophage response in cancer

“…Once these factors bind to their respective receptor, monocytes undergo polarization and maturation into more specialised TAM phenotypes through downstream signal transduction pathways altering transcription within these cells ( 68 ). Recently, it has been identified that TAM polarization can be refined to a three-way polarization program in a spontaneous murine model of breast cancer ( 11 ). This three-way program is broadly split into an alternatively-activated-like, angiogenic/immunosuppressive, and inflammatory phenotypic specialization of these cells ( 11 ).…”

“…Recently, it has been identified that TAM polarization can be refined to a three-way polarization program in a spontaneous murine model of breast cancer ( 11 ). This three-way program is broadly split into an alternatively-activated-like, angiogenic/immunosuppressive, and inflammatory phenotypic specialization of these cells ( 11 ).…”

“…TAMs can also facilitate angiogenesis to meet the metabolic demands of the cancer while assisting the passage of tumor cells into circulation and setting up the site for secondary tumor growth ( 7 – 9 ). Interestingly, the TAM population is phenotypically diverse to the extent that both pro- and anti-tumoral phenotypes of these cells can reside in the same tumor ( 10 , 11 ). The prevalence of the TAM population correlates with poor patient prognosis in all cancers (except colorectal) ( 12 – 14 ) highlighting this population as a potential therapeutic target in cancer.…”

The prognostic influence of lymphatic endothelium–specific hyaluronan receptor 1 in cancer: A systematic review

“…More importantly, LYVE‐1 knockdown in tumor cells not only inhibited their lymphogenic activity but also impaired tumor cell metastasis in vivo 10 . A recent preprint study reported that selective targeting of LYVE‐1 +ve tumor‐associated macrophages significantly impairs the growth of cancer‐related vasculature and hence slows tumor development 11 . Furthermore, targeting LYVE‐1 revealed therapeutic and prognostic potential in common aggressive neoplasms including breast cancer, wherein lymph node metastasis (LNM) can influence the treatment modality and survival expectancy 12,13 …”

“…10 A recent preprint study reported that selective targeting of LYVE-1 +ve tumor-associated macrophages significantly impairs the growth of cancer-related vasculature and hence slows tumor development. 11 Furthermore, targeting LYVE-1 revealed therapeutic and prognostic potential in common aggressive neoplasms including breast cancer, wherein lymph node metastasis (LNM) can influence the treatment modality and survival expectancy. 12,13 Numerous studies have investigated the association between LYVE-1 status and the clinical outcome of cancer; however, results are variable.…”