Breaking the 'harmony' of TNF-α signaling for cancer treatment

Oncogene. 2012 Sep 13;31(37):4117-27. doi: 10.1038/onc.2011.567. Epub 2011 Dec 12.


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 with WT and p55KO/p75KO mice, growth of tumors in p75KO mice was significantly decreased (twofold) in both LLC and B16 tumors. Tumor growth inhibition was correlated with decreases in vascular endothelial growth factor (VEGF) expression and capillary density, as well as bone marrow-derived endothelial progenitor cells 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 short-hairpin RNA 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Bone Marrow Cells
  • Carcinoma, Lewis Lung / metabolism*
  • Carcinoma, Lewis Lung / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Chemokine CXCL12 / biosynthesis
  • Hepatocyte Growth Factor / biosynthesis
  • Melanoma, Experimental / metabolism*
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neovascularization, Pathologic / genetics*
  • Placenta Growth Factor
  • Pregnancy Proteins / biosynthesis
  • RNA Interference
  • RNA, Small Interfering
  • Receptors, CXCR4 / biosynthesis
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Receptors, Tumor Necrosis Factor, Type II / genetics
  • Receptors, Tumor Necrosis Factor, Type II / metabolism*
  • Transplantation, Heterologous
  • Tumor Microenvironment
  • Tumor Necrosis Factor-alpha / metabolism*
  • Vascular Endothelial Growth Factors / biosynthesis
  • p38 Mitogen-Activated Protein Kinases / biosynthesis
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • CXCR4 protein, mouse
  • Chemokine CXCL12
  • Pgf protein, mouse
  • Pregnancy Proteins
  • RNA, Small Interfering
  • Receptors, CXCR4
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Tumor Necrosis Factor-alpha
  • Vascular Endothelial Growth Factors
  • Placenta Growth Factor
  • Hepatocyte Growth Factor
  • p38 Mitogen-Activated Protein Kinases