Low Levels of Tumor Necrosis Factor α Increase Tumor Growth by Inducing an Endothelial Phenotype of Monocytes Recruited to the Tumor Site

Abstract

Microenvironmental cues instruct infiltrating tumor-associated myeloid cells to drive malignant progression. A subpopulation of tumor-associated myeloid cells coexpressing endothelial and myeloid markers, although rare in peripheral blood, are primarily associated with tumors where they enhance tumor growth and angiogenesis. These biphenotypic vascular leukocytes result from the endothelial differentiation of myeloid progenitors, a process regulated by tumor necrosis factor (TNF)A in vitro. An in vivo increase in tumor-derived TNFA expression promoted tumor growth and vascularity of mouse melanoma, lung cancer, and mammary tumors. Notably, tumor growth was accompanied by a significant increase in myeloid/endothelial biphenotypic populations. TNFA-associated tumor growth, vascularity, and generation of tumor vascular leukocytes in mouse melanoma tumors were dependent on intact host TNFA receptors. Importantly, TNFAexpressing tumors did not exhibit increased inflammation over control tumors, suggesting a unique action related to myeloid to endothelial differentiation. Our studies suggest that TNFA constitutes a tumor microenvironment signal that biases recruited monocytes toward a proangiogenic/provasculogenic myeloid/endothelial phenotype.

Blocking Tumor Necrosis Factor α Enhances CD8 T-cell–Dependent Immunity in Experimental Melanoma

“…S1C). Thus, in agreement with a previous report (10), it is unlikely that TNF directly exerts a potent pro-or antiproliferative effect toward B16 melanoma cells. B16F10 cells grew much faster in WT mice than B16K1 cells, whereas both cell lines displayed quite similar tumor growth in CD8-deficient mice (Fig.…”

“…In sharp contrast, it has been recently shown that TNF, which is produced in patients treated with BRAF V600E inhibitors (7,8), may confer treatment resistance of human melanoma by increasing Twist1 levels (9). The role of TNF in melanoma has been further investigated in mice using B16 melanoma cells, which do not express TNF endogenously (10). Whereas ectopic membrane TNF on B16 cells triggers TNF-R2-dependent myeloid cell death (11), and subsequent impaired in vivo melanoma growth, ectopic expression of soluble TNF at low levels by B16 has opposite effect on melanoma growth in mice, most likely through its ability to enhance tumor angiogenesis (10).…”

“…The role of TNF in melanoma has been further investigated in mice using B16 melanoma cells, which do not express TNF endogenously (10). Whereas ectopic membrane TNF on B16 cells triggers TNF-R2-dependent myeloid cell death (11), and subsequent impaired in vivo melanoma growth, ectopic expression of soluble TNF at low levels by B16 has opposite effect on melanoma growth in mice, most likely through its ability to enhance tumor angiogenesis (10). Both B16 cell growth and tumor angiogenesis are reduced in TNF-R2-deficient mice (12).…”

Exosomes Released by Melanoma Cells Prepare Sentinel Lymph Nodes for Tumor Metastasis

“…Paradoxically, thrombospondin 1 (Thbs1) can act on normal peripheral vasculature to increase melanoma blood flow at the expense of peripheral flow (43) and may therefore promote increased sentinel node blood flow conducive for tumor growth. Tumor microenvironment associated tumor necrosis factor a (TNF-a) promotes melanoma growth and angiogenesis (44). Furthermore, TNF-a is upregulated by myeloid derived suppressor cells (MDSC) induced by melanoma microvesicles and granulocyte-macrophage colony stimulating factor (GM-CSF; ref.…”

A novel concept in antiangiogenic and antitumoral therapy: multitarget destabilization of short-lived mRNAs by the zinc finger protein ZFP36L1

“…Indeed, IL1a has been reported to contribute to tumor angiogenesis and invasiveness in different experimental tumor models (Voronov et al, 2003). On the other hand, recent data indicate that tumor necrosis factor a not only promotes the production the angiogenic factors IL-8, VEGF and bFGF (Dirkx et al, 2006), but also induces an endothelial phenotype of monocytes recruited to the tumor site (Li et al, 2009). Finally, combined targeting of IL-6 and VEGF has been reported to inhibit glioma growth and invasiveness (Saidi et al, 2009).…”