PMID- 20172950
OWN - NLM
STAT- MEDLINE
DCOM- 20100624
LR  - 20211020
IS  - 1460-2180 (Electronic)
IS  - 0143-3334 (Print)
IS  - 0143-3334 (Linking)
VI  - 31
IP  - 6
DP  - 2010 Jun
TI  - Transforming growth factor beta1 enhances tumor promotion in mouse skin 
      carcinogenesis.
PG  - 1116-23
LID - 10.1093/carcin/bgq041 [doi]
AB  - Transforming growth factor beta1 (TGFbeta1) expression is elevated by tumor 
      promoters in the mouse skin, but its role in tumor promotion has not been well 
      defined. To investigate this, we have compared TGFbeta1+/+ and +/- mice in a 
      two-stage skin chemical carcinogenesis protocol. Surprisingly, TGFbeta1+/- mice 
      had fewer number and incidence of benign papillomas, reduced epidermal and tumor 
      cell proliferation and reduced epidermal TGFbeta1 and nuclear p-Smad2 
      localization in response to the tumor promoter 12-O-tetradecanoylphorbol 
      13-acetate (TPA) compared with TGFbeta1+/+ mice. Maximal TPA activation of 
      protein kinase C (PKCalpha) as measured by activity assays and activation of 
      target genes and induction of cornified envelopes correlated with TGFbeta1 gene 
      dosage in keratinocytes and addition of exogenous TGFbeta1 restored the 
      cornification defect in TGFbeta1+/- keratinocytes. Similarly, inhibition of 
      ALK5-suppressed TPA-mediated PKCalpha activation suggesting that physiological 
      levels of TGFbeta1 are required for maximal activation of PKC-dependent mitogenic 
      responses. Paradoxically, the TPA-induced inflammatory response was greater in 
      TGFbeta1+/- skin, but TGFbeta1+/+ papillomas had more tumor infiltrating 
      myeloperoxidase-positive cells and pro-inflammatory gene expression was elevated 
      in v-ras(Ha)-transduced TGFbeta1+/+ but not TGFbeta1+/- keratinocytes. Thus, ras 
      activation switches TGFbeta1 to a pro-inflammatory cytokine. Despite this 
      differential proliferative and inflammatory response to TPA and enhanced 
      papilloma formation in the TGFbeta1+/+ mice, the frequency of malignant 
      conversion was reduced compared with TGFbeta1+/- mice. Therefore, TGFbeta1 
      promotes benign tumors by modifying tumor promoter-induced cell proliferation and 
      inflammation but retains a suppressive function for malignant conversion.
FAU - Perez-Lorenzo, Rolando
AU  - Perez-Lorenzo R
AD  - Department of Veterinary and Biomedical Sciences, The Center for Molecular 
      Toxicology and Carcinogenesis, Pennsylvania State University, 201 Life Sciences 
      Building, University Park, PA 16802, USA.
FAU - Markell, Lauren Mordasky
AU  - Markell LM
FAU - Hogan, Kelly A
AU  - Hogan KA
FAU - Yuspa, Stuart H
AU  - Yuspa SH
FAU - Glick, Adam B
AU  - Glick AB
LA  - eng
GR  - CA122109/CA/NCI NIH HHS/United States
GR  - R01 CA117957/CA/NCI NIH HHS/United States
GR  - Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
DEP - 20100219
PL  - England
TA  - Carcinogenesis
JT  - Carcinogenesis
JID - 8008055
RN  - 0 (Carcinogens)
RN  - 0 (Transforming Growth Factor beta1)
RN  - NI40JAQ945 (Tetradecanoylphorbol Acetate)
SB  - IM
MH  - Animals
MH  - Carcinogens/toxicity
MH  - Cell Proliferation
MH  - Cell Transformation, Neoplastic
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Papilloma/chemically induced/pathology/*physiopathology
MH  - Skin Neoplasms/chemically induced/pathology/*physiopathology
MH  - Tetradecanoylphorbol Acetate/toxicity
MH  - Transforming Growth Factor beta1/*physiology
PMC - PMC2878359
EDAT- 2010/02/23 06:00
MHDA- 2010/06/25 06:00
PMCR- 2011/06/01
CRDT- 2010/02/23 06:00
PHST- 2010/02/23 06:00 [entrez]
PHST- 2010/02/23 06:00 [pubmed]
PHST- 2010/06/25 06:00 [medline]
PHST- 2011/06/01 00:00 [pmc-release]
AID - bgq041 [pii]
AID - 10.1093/carcin/bgq041 [doi]
PST - ppublish
SO  - Carcinogenesis. 2010 Jun;31(6):1116-23. doi: 10.1093/carcin/bgq041. Epub 2010 Feb 
      19.