title: Linearly Patterned Programmed Cell Necrosis Induced by Chronic Hypoxia Plays a Role in Melanoma Angiogenesis.
abstract: BACKGROUND
  Highly aggressive tumors are exposed to hypoxia and increased tumor interstitial fluid pressure (IFP) conditions which is resistant to blood supply. Physiological responses of the organism may reduce IFP through induction of orderly cell death.
  
  
  OBJECTIVE
  This study demonstrates that orderly cell death provided spatial structure for early angiogenesis in the hypoxic, high-IFP tumor microenvironment and the participation of linearly patterned programmed cell necrosis (LPPCN) in nascent melanoma angiogenesis.
  
  
  METHODS
  Animal model, laser capture microdissection, wound healing and transwell assays, three-dimensional cultures, zymography assays, western-blotting analysis, immunohistochemistry and RT-PCR were performed.
  
  
  RESULTS
  This study demonstrated a special form of cell death occurring in groups of malignant tumor cells which arrayed in lines. Both features of apoptosis and necrosis can be found in this cell death pattern and were termed as LPPCN. Its role as a stimulus of tumor angiogenesis was investigated using human melanoma samples and an animal model. Computer image analysis showed that LPPCN and tumor microvessels had identical spatial distributions. It can be induced by chronic hypoxia, high IFP and subsequent calcium influx. Higher number of tumor associated macrophages (TAM) and VEGF expression were found in the tumor with LPPCN. Based on the tumor-bearing animal model, it was found that block of caspase pathway inhibited LPPCN, microvessel density and vasculogenic mimicry (VM).
  
  
  CONCLUSIONS
  LPPCN formation may play an important role in tumor angiogenesis due to stimulation of macrophage infiltration and HIF-1α regulation, and that inhibition of LPPCN may be a novel therapeutic strategy against tumor angiogenesis and metastasis.
authors.affiliation: 1. Department of Pathology, General Hospital of Tianjin Medical University ; 2. Department of Pathology, Tianjin Medical University.
authors.forename: Xiulan
authors.initials: X
authors.lastname: Zhao
authors.affiliation: 1. Department of Pathology, General Hospital of Tianjin Medical University ; 2. Department of Pathology, Tianjin Medical University ; 3. Department of Pathology, Cancer Hospital of Tianjin Medical University.
authors.forename: Baocun
authors.initials: B
authors.lastname: Sun
authors.affiliation: 1. Department of Pathology, General Hospital of Tianjin Medical University ; 2. Department of Pathology, Tianjin Medical University.
authors.forename: Yanrong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 1. Department of Pathology, General Hospital of Tianjin Medical University ; 2. Department of Pathology, Tianjin Medical University.
authors.forename: Danfang
authors.initials: D
authors.lastname: Zhang
authors.affiliation: 3. Department of Pathology, Cancer Hospital of Tianjin Medical University.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Liu
authors.affiliation: 2. Department of Pathology, Tianjin Medical University.
authors.forename: Xueming
authors.initials: X
authors.lastname: Zhao
authors.affiliation: 1. Department of Pathology, General Hospital of Tianjin Medical University ; 2. Department of Pathology, Tianjin Medical University.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gu
authors.affiliation: 2. Department of Pathology, Tianjin Medical University.
authors.forename: Chunrong
authors.initials: C
authors.lastname: Han
authors.affiliation: 1. Department of Pathology, General Hospital of Tianjin Medical University ; 2. Department of Pathology, Tianjin Medical University.
authors.forename: Xueyi
authors.initials: X
authors.lastname: Dong
authors.affiliation: 1. Department of Pathology, General Hospital of Tianjin Medical University ; 2. Department of Pathology, Tianjin Medical University.
authors.forename: Na
authors.initials: N
authors.lastname: Che
authors.affiliation: 2. Department of Pathology, Tianjin Medical University.
authors.forename: Jindan
authors.initials: J
authors.lastname: An
authors.affiliation: 2. Department of Pathology, Tianjin Medical University.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: 1. Department of Pathology, General Hospital of Tianjin Medical University ; 2. Department of Pathology, Tianjin Medical University.
authors.forename: Tieju
authors.initials: T
authors.lastname: Liu
keywords: Angiogenesis; Hypoxia; IFP; LPPCN; Melanoma; VM