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Endovascular progenitors infiltrate melanomas and differentiate towards a variety of vascular beds promoting tumor metastasis.

ABSTRACT: Tumor vascularization is a hallmark of cancer central to disease progression and metastasis. Current anti-angiogenic therapies have limited success prompting the need to better understand the cellular origin of tumor vessels. Using fate-mapping analysis of endothelial cell populations in melanoma, we report the very early infiltration of endovascular progenitors (EVP) in growing tumors. These cells harbored self-renewal and reactivated the expression of SOX18 transcription factor, initiating a vasculogenic process as single cells, progressing towards a transit amplifying stage and ultimately differentiating into more mature endothelial phenotypes that comprised arterial, venous and lymphatic subtypes within the core of the tumor. Molecular profiling by RNA sequencing of purified endothelial fractions characterized EVPs as quiescent progenitors remodeling the extracellular matrix with significant paracrine activity promoting growth. Functionally, EVPs did not rely on VEGF-A signaling whereas endothelial-specific loss of Rbpj depleted the population and strongly inhibited metastasis. The understanding of endothelial heterogeneity opens new avenues for more effective anti-vascular therapies in cancer.

SUBMITTER: Donovan P

PROVIDER: S-EPMC6318267 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Endovascular progenitors infiltrate melanomas and differentiate towards a variety of vascular beds promoting tumor metastasis.

Donovan Prudence P Patel Jatin J Patel Jatin J Dight James J Wong Ho Yi HY Sim Seen-Ling SL Murigneux Valentine V Francois Mathias M Khosrotehrani Kiarash K

Nature communications 20190103 1

Tumor vascularization is a hallmark of cancer central to disease progression and metastasis. Current anti-angiogenic therapies have limited success prompting the need to better understand the cellular origin of tumor vessels. Using fate-mapping analysis of endothelial cell populations in melanoma, we report the very early infiltration of endovascular progenitors (EVP) in growing tumors. These cells harbored self-renewal and reactivated the expression of SOX18 transcription factor, initiating a v ...[more]

PMID: 30604758

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Project description:Recent studies have shown that monocytes possess pluripotent plasticity. We previously reported that monocytes could differentiate into hepatic stellate cells. Although stellate cells are also present in the pancreas, their origin remains unclear. An accumulation of enhanced green fluorescent protein (EGFP)(+)CD45(-) cells was observed in the pancreases and livers of chimeric mice, which were transplanted with a single hematopoietic stem cell isolated from EGFP-transgenic mice and treated with carbon tetrachloride (CCl4). Because the vast majority of EGFP(+)CD45(-) cells in the pancreas expressed stellate cell-associated antigens such as vimentin, desmin, glial fibrillary acidic protein, procollagen-I, and α-smooth muscle actin, they were characterized as pancreatic stellate cells (PaSCs). EGFP(+) PaSCs were also observed in CCl4-treated mice adoptively transferred with monocytes but not with other cell lineages isolated from EGFP-transgenic mice. The expression of monocyte chemoattractant protein-1 (MCP-1) and angiotensin II (Ang II) increased in the pancreas of CCl4-treated mice and their respective receptors, C-C chemokine receptor 2 (CCR2) and Ang II type 1 receptor (AT1R), were expressed on Ly6C(high) monocytes isolated from EGFP-transgenic mice. We examined the effect of an AT1R antagonist, irbesartan, which is also a CCR2 antagonist, on the migration of monocytes into the pancreas. Monocytes migrated toward MCP-1 but not Ang II in vitro. Irbesartan inhibited not only their in vitro chemotaxis but also in vivo migration of adoptively transferred monocytes from peripheral blood into the pancreas. Irbesartan treatment significantly reduced the numbers of EGFP(+)F4/80(+)CCR2(+) monocytic cells and EGFP(+) PaSCs in the pancreas of CCl4-treated chimeric mice receiving EGFP(+) bone marrow cells. A specific CCR2 antagonist RS504393 inhibited the occurrence of EGFP(+) PaSCs in injured mice. We propose that CCR2(+) monocytes migrate into the pancreas possibly via the MCP-1/CCR2 pathway and give rise to PaSCs.

Dataset Information

Endovascular progenitors infiltrate melanomas and differentiate towards a variety of vascular beds promoting tumor metastasis.

Publications

Endovascular progenitors infiltrate melanomas and differentiate towards a variety of vascular beds promoting tumor metastasis.

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