PMID- 24664144
OWN - NLM
STAT- MEDLINE
DCOM- 20150115
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 3
DP  - 2014
TI  - Therapeutic non-toxic doses of TNF induce significant regression in TNFR2-p75 
      knockdown Lewis lung carcinoma tumor implants.
PG  - e92373
LID - 10.1371/journal.pone.0092373 [doi]
LID - e92373
AB  - 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-alpha (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.
FAU - Sasi, Sharath P
AU  - Sasi SP
AD  - Cardiovascular Research Center, GeneSys Research Institute, Boston, 
      Massachusetts, United States of America.
FAU - Bae, Sanggyu
AU  - Bae S
AD  - 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.
FAU - Song, Jin
AU  - Song J
AD  - Cardiovascular Research Center, GeneSys Research Institute, Boston, 
      Massachusetts, United States of America.
FAU - Perepletchikov, Aleksandr
AU  - Perepletchikov A
AD  - 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.
FAU - Schneider, Douglas
AU  - Schneider D
AD  - 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.
FAU - Carrozza, Joseph
AU  - Carrozza J
AD  - 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.
FAU - Yan, Xinhua
AU  - Yan X
AD  - Cardiovascular Research Center, GeneSys Research Institute, Boston, 
      Massachusetts, United States of America; Tufts University School of Medicine, 
      Boston, Massachusetts, United States of America.
FAU - Kishore, Raj
AU  - Kishore R
AD  - Feinberg Cardiovascular Institute, Northwestern University, Chicago, Illinois, 
      United States of America.
FAU - Enderling, Heiko
AU  - Enderling H
AD  - Integrated Mathematical Oncology, Moffitt Cancer Center and Research Institute, 
      Tampa, Florida, United States of America.
FAU - Goukassian, David A
AU  - Goukassian DA
AD  - Cardiovascular Research Center, GeneSys Research Institute, Boston, 
      Massachusetts, United States of America; Tufts University School of Medicine, 
      Boston, Massachusetts, United States of America.
LA  - eng
GR  - R01 HL091983/HL/NHLBI NIH HHS/United States
GR  - R21 HL106098/HL/NHLBI NIH HHS/United States
GR  - HL106098/HL/NHLBI NIH HHS/United States
GR  - HL091983/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140324
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Receptors, Tumor Necrosis Factor, Type II)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
EIN - PLoS One. 2014;9(6):e101647
EIN - PLoS One. 2015;10(11):e0144213. PMID: 26619137
MH  - Animals
MH  - Carcinoma, Lewis Lung/drug therapy/genetics/*pathology
MH  - Cell Proliferation/drug effects
MH  - *Cell Transformation, Neoplastic
MH  - Dose-Response Relationship, Drug
MH  - *Gene Knockdown Techniques
MH  - Male
MH  - Mice
MH  - Models, Biological
MH  - Necrosis/chemically induced
MH  - RNA, Small Interfering/genetics
MH  - Receptors, Tumor Necrosis Factor, Type II/*deficiency/*genetics
MH  - Signal Transduction/drug effects
MH  - Tumor Necrosis Factor-alpha/*pharmacology/therapeutic use
PMC - PMC3963887
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/03/26 06:00
MHDA- 2015/01/16 06:00
PMCR- 2014/03/24
CRDT- 2014/03/26 06:00
PHST- 2014/01/14 00:00 [received]
PHST- 2014/02/19 00:00 [accepted]
PHST- 2014/03/26 06:00 [entrez]
PHST- 2014/03/26 06:00 [pubmed]
PHST- 2015/01/16 06:00 [medline]
PHST- 2014/03/24 00:00 [pmc-release]
AID - PONE-D-13-55231 [pii]
AID - 10.1371/journal.pone.0092373 [doi]
PST - epublish
SO  - PLoS One. 2014 Mar 24;9(3):e92373. doi: 10.1371/journal.pone.0092373. eCollection 
      2014.