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

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

Author information

1
Cardiovascular Research Center, GeneSys Research Institute, Boston, Massachusetts, United States of America.
2
Cardiovascular Research Center, GeneSys Research Institute, Boston, Massachusetts, United States of America; Departments of Medicine and Pathology, Steward St. Elizabeth' Medical Center, Boston, Massachusetts, United States of America.
3
Departments of Medicine and Pathology, Steward St. Elizabeth' Medical Center, Boston, Massachusetts, United States of America; Tufts University School of Medicine, Boston, Massachusetts, United States of America.
4
Cardiovascular Research Center, GeneSys Research Institute, Boston, Massachusetts, United States of America; Tufts University School of Medicine, Boston, Massachusetts, United States of America.
5
Feinberg Cardiovascular Institute, Northwestern University, Chicago, Illinois, United States of America.
6
Integrated Mathematical Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America.

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.

PMID:
24664144
PMCID:
PMC3963887
DOI:
10.1371/journal.pone.0092373
[Indexed for MEDLINE]
Free PMC Article
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