Breaking the ‘harmony’ of TNF-α signaling for cancer treatment

Abstract

Tumor necrosis factor-alpha (TNF-α) binds to two distinct receptors, TNFR1/p55 and TNFR2/p75. TNF-α is implicated in the processes of tumor growth, survival, differentiation, invasion, metastases, secretion of cytokines and pro-angiogenic factors. We have shown that TNFR2/p75 signaling promotes ischemia-induced angiogenesis via modulation of several angiogenic growth factors. We hypothesized that TNFR2/p75 may promote tumor growth and angiogenesis. Growth of mouse Lewis lung carcinoma (LLC1) and/or mouse melanoma B16 cell was evaluated in wild type (WT), p75 knockout (KO) and double p55KO/p75KO mouse tumor xenograft models. Compared to WT and p55KO/p75KO mice, growth of tumors in p75KO mice was significantly decreased (two-fold) in both LLC and B16 tumors. Tumor growth inhibition was correlated with decreases in VEGF expression and capillary density, as well as bone marrow (BM)-derived endothelial progenitor cells (EPCs) incorporation into the functional capillary network, and an increase in apoptotic cells in LLC xenografts. Gene array analysis of tumor tissues showed a decrease in gene expression in pathways that promote tumor angiogenesis and cell survival. Blocking p75 by shRNA in cultured LLCs led to increases in TNF-mediated apoptosis, as well as decreases in the constitutive and TNF-mediated expression of angiogenic growth factors (VEGF, HGF, PLGF), and SDF-1α receptor CXCR4. In summary, p75 is essential for tumor angiogenesis and survival in highly vascularized murine lung tumor xenografts. Blocking p75 expression may lead to tumor regression. This may represent new and effective therapy against lung neoplasms and potentially tumors of other origin.

TNFα contributes to diabetes impaired angiogenesis in fracture healing

“…We previously reported that local levels of TNFα in the fracture callus are increased in diabetic mice compared to normoglycemic mice [15, 20]. Although TNFα is reported to be a pro-angiogenic cytokine that is necessary for vascular infiltration in tumorigenesis [31] and to promote physiologic fracture healing in the early phases [32], our findings indicate that in later stages of diabetic fracture healing TNFα interferes with angiogenesis. In contrast, TNFα inhibition in normal animals in the same timeframe had little effect on angiogenesis.…”

TNF-TNFR2/p75 Signaling Inhibits Early and Increases Delayed Nontargeted Effects in Bone Marrow-derived Endothelial Progenitor Cells

“…TNFR1/p55 is responsible for signaling a variety of responses predominantly cytotoxic, such as apoptosis and cell death, but also regulates inflammatory responses including cytokine secretion (30 -33). In contrast, TNFR2/p75 is generally pro-survival and pro-angiogenic and responsible for cell protective effects of TNF but regulates inflammatory signaling as well (30,31,(33)(34)(35). Both TNF receptors are ubiquitously expressed on nearly all cell types, but the p75 receptor is predominantly expressed by lymphoid cells as well as other hematopoietic and endothelial lineage cells, including endothelial progenitor cells (EPCs) (27,36,37).…”

SOCS3 is an endogenous inhibitor of pathologic angiogenesis

“…During angiogenesis, EC activation is mediated by growth factors 22 (eg, IGF-1 or VEGF) and inflammatory mediators 23 (eg, TNF␣ or IL-6; Figure 2A). IGF-1 24,25 and TNF␣ 26,27 signaling promote pathologic angiogenesis both in OIR and tumor growth, whereas inhibition of either pathway curtails pathologic angiogenesis. We therefore explored the role of SOCS3 as a central regulator of both pathways.…”