Down-modulation of TNFSF15 in ovarian cancer by VEGF and MCP-1 is a pre-requisite for tumor neovascularization

Abstract

Persistent inflammation and neovascularization are critical to cancer development. In addition to upregulation of positive control mechanisms such as overexpression of angiogenic and inflammatory factors in the cancer microenvironment, loss of otherwise normally functioning negative control mechanisms is likely to be an important attribute. Insights into the down-modulation of such negative control mechanisms remain largely unclear, however. We show here that tumor necrosis factor superfamily-15 (TNFSF15), an endogenous inhibitor of neovascularization, is a critical component of the negative control mechanism that operates in normal ovary but is missing in ovarian cancer. We show in clinical settings that TNFSF15 is present prominently in the vasculature of normal ovary but diminishes in ovarian cancer as the disease progresses. Vascular endothelial growth factor (VEGF) produced by cancer cells and monocyte chemotactic protein-1 (MCP-1) produced mainly by tumor-infiltrating macrophages and regulatory T cells effectively inhibits TNFSF15 production by endothelial cells in vitro. Using a mouse syngeneic tumor model, we demonstrate that silencing TNFSF15 by topical shRNA treatments prior to and following mouse ovarian cancer ID8 cell inoculation greatly facilitates angiogenesis and tumor growth, whereas systemic application of recombinant TNFSF15 inhibits angiogenesis and tumor growth. Our findings indicate that downregulation of TNFSF15 by cancer cells and tumor infiltrating macrophages and lymphocytes is a pre-requisite for tumor neovascularization.

IgG4 subclass antibodies impair antitumor immunity in melanoma

“…We also demonstrated that tumor cells are capable of stimulating such modified Th2 responses, featuring production of IL-10 and IL-4 and secretion of IgG4 by B cells. Also consistent with a tumor-associated inflammatory environment, VEGF, known to polarize Th2-biased cytokine production by PBMCs through induction of IL-10-secreting cells such as Tregs (53), along with well-described tumor-induced inflammatory mediators IL-6 and MCP-1 (53)(54)(55)(56), was found at significantly increased levels (P < 0.001; Supplemental Figure 3A Figure 8. n = 33.…”

TNFSF15 inhibits vasculogenesis by regulating relative levels of membrane-bound and soluble isoforms of VEGF receptor 1

“…We showed previously that TNFSF15 gene expression in EC is down-regulated by VEGF produced by ovarian cancer cells (42). This indicates that the actions of a positive modulator of angiogenesis, namely VEGF, may lead to the removal from tumor microenvironment of a negative modulator of angiogenesis, namely TNFSF15, which would otherwise functions as an obstacle in the initiation or continuation of tumor angiogenesis.…”

“…It also inhibits Lin − -Sca-1 + EPC differentiation into EC (6) and EPC incorporation into tumor vasculature in murine models (10). TNFSF15 expression is absent or marginal in tumor vasculatures in various cancers (40)(41)(42), increased in irritable bowel syndrome (43), and down-regulated in wound tissues (44). TNFSF15 down-regulation in ovarian cancer is facilitated by VEGF secreted by cancer cells as well as by other inflammatory cytokines (42).…”

“…TNFSF15 expression is absent or marginal in tumor vasculatures in various cancers (40)(41)(42), increased in irritable bowel syndrome (43), and down-regulated in wound tissues (44). TNFSF15 down-regulation in ovarian cancer is facilitated by VEGF secreted by cancer cells as well as by other inflammatory cytokines (42). Death domaincontaining receptor 3 (DR3) (TNFRSF25), a member of the TNF receptor superfamily, has been shown to be the receptor of TNFSF15 in T cells and dendritic cells (45,46).…”

Revisiting the Complexity of the Ovarian Cancer Microenvironment—Clinical Implications for Treatment Strategies

“…Nevertheless, treatment with a peptide that interferes with G-protein coupled receptors, X1/2pal-i3 pepducin, hindered PAR1 activation by MMP1 (74). Recent findings suggest that specific modulators that impede angiogenesis, such as tumor necrosis factor superfamily-15 (TNFSF15), are downregulated by VEGF and CCL2, which are not only released by cancer cells, and therefore, emphasize the importance of contributing cell populations to neoangiogenesis (75).…”