title: Circadian disruption accelerates tumor growth and angio/stromagenesis through a Wnt signaling pathway.
abstract: Epidemiologic studies show a high incidence of cancer in shift workers, suggesting a possible relationship between circadian rhythms and tumorigenesis. However, the precise molecular mechanism played by circadian rhythms in tumor progression is not known. To identify the possible mechanisms underlying tumor progression related to circadian rhythms, we set up nude mouse xenograft models. HeLa cells were injected in nude mice and nude mice were moved to two different cases, one case is exposed to a 24-hour light cycle (L/L), the other is a more "normal" 12-hour light/dark cycle (L/D). We found a significant increase in tumor volume in the L/L group compared with the L/D group. In addition, tumor microvessels and stroma were strongly increased in L/L mice. Although there was a hypervascularization in L/L tumors, there was no associated increase in the production of vascular endothelial cell growth factor (VEGF). DNA microarray analysis showed enhanced expression of WNT10A, and our subsequent study revealed that WNT10A stimulates the growth of both microvascular endothelial cells and fibroblasts in tumors from light-stressed mice, along with marked increases in angio/stromagenesis. Only the tumor stroma stained positive for WNT10A and WNT10A is also highly expressed in keloid dermal fibroblasts but not in normal dermal fibroblasts indicated that WNT10A may be a novel angio/stromagenic growth factor. These findings suggest that circadian disruption induces the progression of malignant tumors via a Wnt signaling pathway.
authors.affiliation: Department of Molecular Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yasuniwa
authors.forename: Hiroto
authors.initials: H
authors.lastname: Izumi
authors.forename: Ke-Yong
authors.initials: KY
authors.lastname: Wang
authors.forename: Shohei
authors.initials: S
authors.lastname: Shimajiri
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Sasaguri
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Kawai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kasai
authors.forename: Takashi
authors.initials: T
authors.lastname: Shimada
authors.forename: Koichi
authors.initials: K
authors.lastname: Miyake
authors.forename: Eiji
authors.initials: E
authors.lastname: Kashiwagi
authors.forename: Gen
authors.initials: G
authors.lastname: Hirano
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kidani
authors.forename: Masaki
authors.initials: M
authors.lastname: Akiyama
authors.forename: Bin
authors.initials: B
authors.lastname: Han
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ieiri
authors.forename: Shun
authors.initials: S
authors.lastname: Higuchi
authors.forename: Kimitoshi
authors.initials: K
authors.lastname: Kohno
mesh_terms: D000818:Animals; D002940:Circadian Rhythm; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000473:pathology*; D009389:Neovascularization, Pathologic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D009419:Nerve Tissue Proteins; D042461:Vascular Endothelial Growth Factor A; C484142:WNT10A protein, human; D051153:Wnt Proteins; C484143:Wnt10a protein, mouse