Therapeutic non-toxic doses of TNF induce significant regression in TNFR2-p75 knockdown Lewis lung carcinoma tumor implants

PLoS One. 2014 Mar 24;9(3):e92373. doi: 10.1371/journal.pone.0092373. eCollection 2014.

Abstract

Tumor necrosis factor-alpha (TNF) binds to two receptors: TNFR1/p55-cytotoxic and TNFR2/p75-pro-survival. We have shown that tumor growth in p75 knockout (KO) mice was decreased more than 2-fold in Lewis lung carcinoma (LLCs). We hypothesized that selective blocking of TNFR2/p75 LLCs may sensitize them to TNF-induced apoptosis and affect the tumor growth. We implanted intact and p75 knockdown (KD)-LLCs (>90%, using shRNA) into wild type (WT) mice flanks. On day 8 post-inoculation, recombinant murine (rm) TNF-α (12.5 ng/gr of body weight) or saline was injected twice daily for 6 days. Tumor volumes (tV) were measured daily and tumor weights (tW) on day 15, when study was terminated due to large tumors in LLC+TNF group. Tubular bones, spleens and peripheral blood (PB) were examined to determine possible TNF toxicity. There was no significant difference in tV or tW between LLC minus (-) TNF and p75KD/LLC-TNF tumors. Compared to 3 control groups, p75KD/LLC+TNF showed >2-5-fold decreases in tV (p<0.001) and tW (p<0.0001). There was no difference in tV or tW end of study vs. before injections in p75KD/LLC+TNF group. In 3 other groups tV and tW were increased 2.7-4.5-fold (p<0.01, p<0.0002 and p<0.0001). Pathological examination revealed that 1/3 of p75KD/LLC+rmTNF tumors were 100% necrotic, the remaining revealed 40-60% necrosis. No toxicity was detected in bone marrow, spleen and peripheral blood. We concluded that blocking TNFR2/p75 in LLCs combined with intra-tumoral rmTNF injections inhibit LLC tumor growth. This could represent a novel and effective therapy against lung neoplasms and a new paradigm in cancer therapeutics.

Publication types

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

MeSH terms

  • Animals
  • Carcinoma, Lewis Lung / drug therapy
  • Carcinoma, Lewis Lung / genetics
  • Carcinoma, Lewis Lung / pathology*
  • Cell Proliferation / drug effects
  • Cell Transformation, Neoplastic*
  • Dose-Response Relationship, Drug
  • Gene Knockdown Techniques*
  • Male
  • Mice
  • Models, Biological
  • Necrosis / chemically induced
  • RNA, Small Interfering / genetics
  • Receptors, Tumor Necrosis Factor, Type II / deficiency*
  • Receptors, Tumor Necrosis Factor, Type II / genetics*
  • Signal Transduction / drug effects
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Tumor Necrosis Factor-alpha / therapeutic use

Substances

  • RNA, Small Interfering
  • Receptors, Tumor Necrosis Factor, Type II
  • Tumor Necrosis Factor-alpha