PMID- 10919643
OWN - NLM
STAT- MEDLINE
DCOM- 20000824
LR  - 20081121
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 60
IP  - 14
DP  - 2000 Jul 15
TI  - Accelerated ultraviolet radiation-induced carcinogenesis in hepatocyte growth 
      factor/scatter factor transgenic mice.
PG  - 3738-43
AB  - The dramatic rise in incidence of malignant melanoma experienced by populations 
      both within the United States and throughout the world over the last several 
      decades has been attributed to enhanced exposure to the UV spectrum of sunlight 
      radiation. This hypothesis can now be tested using genetically engineered mouse 
      models predisposed to malignant melanoma. Here we use melanoma-prone transgenic 
      mice inappropriately expressing hepatocyte growth factor/scatter factor (HGF/SF) 
      in the skin as an experimental model system to ascertain the consequences of a 
      chronic regimen of suberythemal UV radiation on melanoma genesis. HGF/SF is a 
      multifunctional regulator capable of stimulating growth, motility, invasiveness, 
      and morphogenetic transformation in cells, including melanocytes, expressing its 
      receptor tyrosine kinase Met. HGF/SF transgenic mice demonstrate ectopic 
      interfollicular localization and accumulation of melanocytes within the truncal 
      dermis, epidermis, and junction and if untreated develop primary cutaneous 
      melanoma with a mean onset age of approximately 21 months. Transgenic mice and 
      their wild-type littermates subjected to UV radiation three times weekly using 
      FS40 sunlamps (60% UVB and 40% UVA), with daily UV doses graded from 2.25 to 6.0 
      kJ/m2, developed skin tumors with a mean onset age of 26 and 37 weeks, 
      respectively (P < 0.001, Kaplan-Meier log rank test). However, the repeated doses 
      of suberythemal UV radiation used in this study failed to accelerate melanoma 
      genesis, instead inducing the development of nonmelanoma tumors that included 
      squamous cell carcinomas, squamous papillomas, and sarcomas. The conspicuous 
      absence of melanocytic tumors occurred despite the immunohistochemical detection 
      of a significant stimulation (P < 0.001) in melanocyte-specific bromodeoxyuridine 
      incorporation in response to only 2 weeks of UV irradiation (total UV dose of 
      13.5 kJ/m2), resulting in 2.6- and 4.6-fold increases in the number of 
      melanocytes in the dermis and epidermis, respectively. These data indicate that 
      chronic suberythemal UV radiation preferentially favors the development of 
      nonmelanocytic over melanocytic neoplasms in this transgenic animal, consistent 
      with the pathogenesis proposed for sun exposure-associated skin cancer based on 
      retrospective studies in the human population. Our findings suggest that the 
      HGF/SF transgenic mouse will be useful as an experimental model for determining 
      the consequences of exposure to various regimens of UV radiation and for 
      elucidating the mechanisms by which such consequences are realized.
FAU - Noonan, F P
AU  - Noonan FP
AD  - Department of Dermatology, The George Washington University Medical Center, 
      Washington, DC 20037, USA.
FAU - Otsuka, T
AU  - Otsuka T
FAU - Bang, S
AU  - Bang S
FAU - Anver, M R
AU  - Anver MR
FAU - Merlino, G
AU  - Merlino G
LA  - eng
GR  - N0I-CO-56000/CO/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (DNA, Complementary)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
SB  - IM
MH  - Age Factors
MH  - Animals
MH  - DNA, Complementary/metabolism
MH  - Disease-Free Survival
MH  - Dose-Response Relationship, Radiation
MH  - Female
MH  - Hepatocyte Growth Factor/*genetics
MH  - Male
MH  - Melanocytes/pathology/radiation effects
MH  - Melanoma, Experimental/genetics/pathology
MH  - Melanosis/genetics/pathology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Neoplasms, Radiation-Induced/*genetics/metabolism/pathology
MH  - Promoter Regions, Genetic
MH  - Skin/pathology/radiation effects
MH  - Time Factors
MH  - Ultraviolet Rays
EDAT- 2000/08/05 11:00
MHDA- 2000/08/29 11:01
CRDT- 2000/08/05 11:00
PHST- 2000/08/05 11:00 [pubmed]
PHST- 2000/08/29 11:01 [medline]
PHST- 2000/08/05 11:00 [entrez]
PST - ppublish
SO  - Cancer Res. 2000 Jul 15;60(14):3738-43.