title: Hypoxia influences vasculogenic mimicry channel formation and tumor invasion-related protein expression in melanoma.
abstract: BACKGROUND
  Hypoxia can enhance tumor cell invasion and metastasis. The cause and the molecular mechanism are still not clear.
  
  
  METHODS
  In our study, mouse melanoma B16 cells were inoculated into mouse ischemic limbs and non-ischemic controls and the engrafted melanomas were subsequently observed. Vasculogenic mimicry channels in melanoma tumors of the two groups were counted and the expression of HIF-1alpha, MMP-2, MMP-9 and VEGF was assessed by immunohistochemical staining. Formalin-fixed, paraffin-embedded tissues were used for immunohistochemical staining.
  
  
  RESULTS
  In the early stage of engrafted melanoma growth, the size of melanomas in ischemic limbs increased slower than in the controls. However, later there was no obvious difference in their size. Melanoma tumors in the ischemic group had more vasculogenic mimicry channels than those in the controls (P=0.039). Similarly, the expression of HIF-1alpha, MMP-2, MMP-9 and VEGF was higher in the ischemic group than in the non-ischemic controls (P=0.024, 0.047, 0.007 and 0.025, respectively). There was a positive association in melanoma cells of the ischemic group between expression of HIF-1alpha and VEGF, and also between MMP-9 and MMP-2. In the ischemic group, there was statistical significance for the correlation between HIF-1alpha and VEGF expression (r=0.456, P=0.038). Furthermore, MMP-2 expression was positively correlated with MMP-9 and VEGF expression (r=0.589 and 0.502, P=0.008 and 0.024, respectively).
  
  
  CONCLUSIONS
  Melanoma cells in a hypoxic microenvironment increased HIF-1alpha expression and induced the formation of vasculogenic mimicry channels to acquire an adequate blood supply. On the other hand, the expression of MMP-2 and MMP-9 in tumor tissue increased to enhance the invasiveness. HIF-1alpha, MMP-2 and MMP-9 may be associated with the failure of stop-flow perfusion in some patients with melanoma.
authors.affiliation: Department of Pathology, Tianjin Cancer Hospital, Tianjin Medical University, Tianjin 300060, PR China. zhangshiwu666@yahoo.com.cn
authors.forename: Baocun
authors.initials: B
authors.lastname: Sun
authors.forename: Danfang
authors.initials: D
authors.lastname: Zhang
authors.forename: Shiwu
authors.initials: S
authors.lastname: Zhang
authors.forename: Wenzhi
authors.initials: W
authors.lastname: Zhang
authors.forename: Hua
authors.initials: H
authors.lastname: Guo
authors.forename: Xiulan
authors.initials: X
authors.lastname: Zhao
mesh_terms: D000818:Animals; D005260:Female; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008546:Melanoma, Experimental / Q000378:metabolism* / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D019042:Muscle Neoplasms / Q000378:metabolism* / Q000556:secondary; D009361:Neoplasm Invasiveness; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse