PMID- 26476432
OWN - NLM
STAT- MEDLINE
DCOM- 20160202
LR  - 20240210
IS  - 1460-2105 (Electronic)
IS  - 0027-8874 (Linking)
VI  - 108
IP  - 1
DP  - 2016 Jan
TI  - Suppression of TGFbeta and Angiogenesis by Type VII Collagen in Cutaneous SCC.
LID - djv293 [pii]
LID - 10.1093/jnci/djv293 [doi]
AB  - BACKGROUND: Individuals with severe generalized recessive dystrophic 
      epidermolysis bullosa (RDEB), an inherited blistering disorder caused by 
      mutations in the COL7A1 gene, develop unexplained aggressive squamous cell 
      carcinomas (SCC). Here we report that loss of type VII collagen (Col7) in SCC 
      results in increased TGFbeta signaling and angiogenesis in vitro and in vivo. 
      METHODS: Stable knockdown (KD) of Col7 was established using shRNA, and cells 
      were used in a mouse xenograft model. Angiogenesis was assessed by 
      immunohistochemistry, endothelial tube-forming assays, and proteome arrays. Mouse 
      and zebrafish models were used to examine the effect of recombinant Col7 on 
      angiogenesis. Findings were confirmed in anonymized, archival human tissue: RDEB 
      SCC tumors, non-EB SCC tumors, RDEB skin, normal skin; and two human RDEB SCC 
      cell lines. The TGFbeta pathway was examined using immunoblotting, 
      immunohistochemistry, biochemical inhibition, and siRNA. All statistical tests 
      were two-sided. RESULTS: Increased numbers of cross-cut blood vessels were 
      observed in Col7 KD compared with control xenografts (n = 4 to 7 per group) and 
      in RDEB tumors (n = 21) compared with sporadic SCC (n = 24, P < .001). 
      Recombinant human Col7 reversed the increased SCC angiogenesis in Col7 KD 
      xenografts in vivo (n = 7 per group, P = .04). Blocking the interaction between 
      alpha2beta1 integrin and Col7 increased TGFB1 mRNA expression 1.8-fold and p-Smad2 
      levels two-fold. Increased TGFbeta signaling and VEGF expression were observed in 
      Col7 KD xenografts (n = 4) compared with control (n = 4) and RDEB tumors (TGFbeta 
      markers, n = 6; VEGF, n = 17) compared with sporadic SCC (TGFbeta markers, n = 6; 
      VEGF, n = 21). Inhibition of TGFbeta receptor signaling using siRNA resulted in 
      decreased endothelial cell tube formation (n = 9 per group, mean tubes per well 
      siC = 63.6, SD = 17.1; mean tubes per well siTbetaRII = 29.7, SD = 6.1, P = .02). 
      CONCLUSIONS: Type VII collagen suppresses TGFbeta signaling and angiogenesis in 
      cutaneous SCC. Patients with RDEB SCC may benefit from anti-angiogenic therapy.
CI  - (c) The Author 2015. Published by Oxford University Press. All rights reserved. For 
      Permissions, please e-mail: journals.permissions@oup.com.
FAU - Martins, V L
AU  - Martins VL
AD  - Centre for Cell Biology and Cutaneous Research, Blizard Institute (VLM, MPC, ZS, 
      STM, MA, RC, EOT), Barts Cancer Institute (KM, KHD, JFM), Barts and the London 
      School of Medicine and Dentistry and School of Biological and Chemical Sciences 
      (CHB), Queen Mary University of London, London, UK; Department of Dermatology, St 
      George Hospital, University of NSW, Sydney, NSW, Australia (DFM, MHK); St John's 
      Institute of Dermatology, Kings College London (Guys Campus), London, UK (JAM); 
      Department of Dermatology and MediCity Research Laboratory, University of Turku, 
      and Turku University Hospital, Turku, Finland (AK, VMK); Department of 
      Dermatology, University of Southern California, Los Angeles, CA (MC).
FAU - Caley, M P
AU  - Caley MP
AD  - Centre for Cell Biology and Cutaneous Research, Blizard Institute (VLM, MPC, ZS, 
      STM, MA, RC, EOT), Barts Cancer Institute (KM, KHD, JFM), Barts and the London 
      School of Medicine and Dentistry and School of Biological and Chemical Sciences 
      (CHB), Queen Mary University of London, London, UK; Department of Dermatology, St 
      George Hospital, University of NSW, Sydney, NSW, Australia (DFM, MHK); St John's 
      Institute of Dermatology, Kings College London (Guys Campus), London, UK (JAM); 
      Department of Dermatology and MediCity Research Laboratory, University of Turku, 
      and Turku University Hospital, Turku, Finland (AK, VMK); Department of 
      Dermatology, University of Southern California, Los Angeles, CA (MC).
FAU - Moore, K
AU  - Moore K
AD  - Centre for Cell Biology and Cutaneous Research, Blizard Institute (VLM, MPC, ZS, 
      STM, MA, RC, EOT), Barts Cancer Institute (KM, KHD, JFM), Barts and the London 
      School of Medicine and Dentistry and School of Biological and Chemical Sciences 
      (CHB), Queen Mary University of London, London, UK; Department of Dermatology, St 
      George Hospital, University of NSW, Sydney, NSW, Australia (DFM, MHK); St John's 
      Institute of Dermatology, Kings College London (Guys Campus), London, UK (JAM); 
      Department of Dermatology and MediCity Research Laboratory, University of Turku, 
      and Turku University Hospital, Turku, Finland (AK, VMK); Department of 
      Dermatology, University of Southern California, Los Angeles, CA (MC).
FAU - Szentpetery, Z
AU  - Szentpetery Z
AD  - Centre for Cell Biology and Cutaneous Research, Blizard Institute (VLM, MPC, ZS, 
      STM, MA, RC, EOT), Barts Cancer Institute (KM, KHD, JFM), Barts and the London 
      School of Medicine and Dentistry and School of Biological and Chemical Sciences 
      (CHB), Queen Mary University of London, London, UK; Department of Dermatology, St 
      George Hospital, University of NSW, Sydney, NSW, Australia (DFM, MHK); St John's 
      Institute of Dermatology, Kings College London (Guys Campus), London, UK (JAM); 
      Department of Dermatology and MediCity Research Laboratory, University of Turku, 
      and Turku University Hospital, Turku, Finland (AK, VMK); Department of 
      Dermatology, University of Southern California, Los Angeles, CA (MC).
FAU - Marsh, S T
AU  - Marsh ST
AD  - Centre for Cell Biology and Cutaneous Research, Blizard Institute (VLM, MPC, ZS, 
      STM, MA, RC, EOT), Barts Cancer Institute (KM, KHD, JFM), Barts and the London 
      School of Medicine and Dentistry and School of Biological and Chemical Sciences 
      (CHB), Queen Mary University of London, London, UK; Department of Dermatology, St 
      George Hospital, University of NSW, Sydney, NSW, Australia (DFM, MHK); St John's 
      Institute of Dermatology, Kings College London (Guys Campus), London, UK (JAM); 
      Department of Dermatology and MediCity Research Laboratory, University of Turku, 
      and Turku University Hospital, Turku, Finland (AK, VMK); Department of 
      Dermatology, University of Southern California, Los Angeles, CA (MC).
FAU - Murrell, D F
AU  - Murrell DF
AD  - Centre for Cell Biology and Cutaneous Research, Blizard Institute (VLM, MPC, ZS, 
      STM, MA, RC, EOT), Barts Cancer Institute (KM, KHD, JFM), Barts and the London 
      School of Medicine and Dentistry and School of Biological and Chemical Sciences 
      (CHB), Queen Mary University of London, London, UK; Department of Dermatology, St 
      George Hospital, University of NSW, Sydney, NSW, Australia (DFM, MHK); St John's 
      Institute of Dermatology, Kings College London (Guys Campus), London, UK (JAM); 
      Department of Dermatology and MediCity Research Laboratory, University of Turku, 
      and Turku University Hospital, Turku, Finland (AK, VMK); Department of 
      Dermatology, University of Southern California, Los Angeles, CA (MC).
FAU - Kim, M H
AU  - Kim MH
AD  - Centre for Cell Biology and Cutaneous Research, Blizard Institute (VLM, MPC, ZS, 
      STM, MA, RC, EOT), Barts Cancer Institute (KM, KHD, JFM), Barts and the London 
      School of Medicine and Dentistry and School of Biological and Chemical Sciences 
      (CHB), Queen Mary University of London, London, UK; Department of Dermatology, St 
      George Hospital, University of NSW, Sydney, NSW, Australia (DFM, MHK); St John's 
      Institute of Dermatology, Kings College London (Guys Campus), London, UK (JAM); 
      Department of Dermatology and MediCity Research Laboratory, University of Turku, 
      and Turku University Hospital, Turku, Finland (AK, VMK); Department of 
      Dermatology, University of Southern California, Los Angeles, CA (MC).
FAU - Avari, M
AU  - Avari M
AD  - Centre for Cell Biology and Cutaneous Research, Blizard Institute (VLM, MPC, ZS, 
      STM, MA, RC, EOT), Barts Cancer Institute (KM, KHD, JFM), Barts and the London 
      School of Medicine and Dentistry and School of Biological and Chemical Sciences 
      (CHB), Queen Mary University of London, London, UK; Department of Dermatology, St 
      George Hospital, University of NSW, Sydney, NSW, Australia (DFM, MHK); St John's 
      Institute of Dermatology, Kings College London (Guys Campus), London, UK (JAM); 
      Department of Dermatology and MediCity Research Laboratory, University of Turku, 
      and Turku University Hospital, Turku, Finland (AK, VMK); Department of 
      Dermatology, University of Southern California, Los Angeles, CA (MC).
FAU - McGrath, J A
AU  - McGrath JA
AD  - Centre for Cell Biology and Cutaneous Research, Blizard Institute (VLM, MPC, ZS, 
      STM, MA, RC, EOT), Barts Cancer Institute (KM, KHD, JFM), Barts and the London 
      School of Medicine and Dentistry and School of Biological and Chemical Sciences 
      (CHB), Queen Mary University of London, London, UK; Department of Dermatology, St 
      George Hospital, University of NSW, Sydney, NSW, Australia (DFM, MHK); St John's 
      Institute of Dermatology, Kings College London (Guys Campus), London, UK (JAM); 
      Department of Dermatology and MediCity Research Laboratory, University of Turku, 
      and Turku University Hospital, Turku, Finland (AK, VMK); Department of 
      Dermatology, University of Southern California, Los Angeles, CA (MC).
FAU - Cerio, R
AU  - Cerio R
AD  - Centre for Cell Biology and Cutaneous Research, Blizard Institute (VLM, MPC, ZS, 
      STM, MA, RC, EOT), Barts Cancer Institute (KM, KHD, JFM), Barts and the London 
      School of Medicine and Dentistry and School of Biological and Chemical Sciences 
      (CHB), Queen Mary University of London, London, UK; Department of Dermatology, St 
      George Hospital, University of NSW, Sydney, NSW, Australia (DFM, MHK); St John's 
      Institute of Dermatology, Kings College London (Guys Campus), London, UK (JAM); 
      Department of Dermatology and MediCity Research Laboratory, University of Turku, 
      and Turku University Hospital, Turku, Finland (AK, VMK); Department of 
      Dermatology, University of Southern California, Los Angeles, CA (MC).
FAU - Kivisaari, A
AU  - Kivisaari A
AD  - Centre for Cell Biology and Cutaneous Research, Blizard Institute (VLM, MPC, ZS, 
      STM, MA, RC, EOT), Barts Cancer Institute (KM, KHD, JFM), Barts and the London 
      School of Medicine and Dentistry and School of Biological and Chemical Sciences 
      (CHB), Queen Mary University of London, London, UK; Department of Dermatology, St 
      George Hospital, University of NSW, Sydney, NSW, Australia (DFM, MHK); St John's 
      Institute of Dermatology, Kings College London (Guys Campus), London, UK (JAM); 
      Department of Dermatology and MediCity Research Laboratory, University of Turku, 
      and Turku University Hospital, Turku, Finland (AK, VMK); Department of 
      Dermatology, University of Southern California, Los Angeles, CA (MC).
FAU - Kahari, V M
AU  - Kahari VM
AD  - Centre for Cell Biology and Cutaneous Research, Blizard Institute (VLM, MPC, ZS, 
      STM, MA, RC, EOT), Barts Cancer Institute (KM, KHD, JFM), Barts and the London 
      School of Medicine and Dentistry and School of Biological and Chemical Sciences 
      (CHB), Queen Mary University of London, London, UK; Department of Dermatology, St 
      George Hospital, University of NSW, Sydney, NSW, Australia (DFM, MHK); St John's 
      Institute of Dermatology, Kings College London (Guys Campus), London, UK (JAM); 
      Department of Dermatology and MediCity Research Laboratory, University of Turku, 
      and Turku University Hospital, Turku, Finland (AK, VMK); Department of 
      Dermatology, University of Southern California, Los Angeles, CA (MC).
FAU - Hodivala-Dilke, K
AU  - Hodivala-Dilke K
AD  - Centre for Cell Biology and Cutaneous Research, Blizard Institute (VLM, MPC, ZS, 
      STM, MA, RC, EOT), Barts Cancer Institute (KM, KHD, JFM), Barts and the London 
      School of Medicine and Dentistry and School of Biological and Chemical Sciences 
      (CHB), Queen Mary University of London, London, UK; Department of Dermatology, St 
      George Hospital, University of NSW, Sydney, NSW, Australia (DFM, MHK); St John's 
      Institute of Dermatology, Kings College London (Guys Campus), London, UK (JAM); 
      Department of Dermatology and MediCity Research Laboratory, University of Turku, 
      and Turku University Hospital, Turku, Finland (AK, VMK); Department of 
      Dermatology, University of Southern California, Los Angeles, CA (MC).
FAU - Brennan, C H
AU  - Brennan CH
AD  - Centre for Cell Biology and Cutaneous Research, Blizard Institute (VLM, MPC, ZS, 
      STM, MA, RC, EOT), Barts Cancer Institute (KM, KHD, JFM), Barts and the London 
      School of Medicine and Dentistry and School of Biological and Chemical Sciences 
      (CHB), Queen Mary University of London, London, UK; Department of Dermatology, St 
      George Hospital, University of NSW, Sydney, NSW, Australia (DFM, MHK); St John's 
      Institute of Dermatology, Kings College London (Guys Campus), London, UK (JAM); 
      Department of Dermatology and MediCity Research Laboratory, University of Turku, 
      and Turku University Hospital, Turku, Finland (AK, VMK); Department of 
      Dermatology, University of Southern California, Los Angeles, CA (MC).
FAU - Chen, M
AU  - Chen M
AD  - Centre for Cell Biology and Cutaneous Research, Blizard Institute (VLM, MPC, ZS, 
      STM, MA, RC, EOT), Barts Cancer Institute (KM, KHD, JFM), Barts and the London 
      School of Medicine and Dentistry and School of Biological and Chemical Sciences 
      (CHB), Queen Mary University of London, London, UK; Department of Dermatology, St 
      George Hospital, University of NSW, Sydney, NSW, Australia (DFM, MHK); St John's 
      Institute of Dermatology, Kings College London (Guys Campus), London, UK (JAM); 
      Department of Dermatology and MediCity Research Laboratory, University of Turku, 
      and Turku University Hospital, Turku, Finland (AK, VMK); Department of 
      Dermatology, University of Southern California, Los Angeles, CA (MC).
FAU - Marshall, J F
AU  - Marshall JF
AD  - Centre for Cell Biology and Cutaneous Research, Blizard Institute (VLM, MPC, ZS, 
      STM, MA, RC, EOT), Barts Cancer Institute (KM, KHD, JFM), Barts and the London 
      School of Medicine and Dentistry and School of Biological and Chemical Sciences 
      (CHB), Queen Mary University of London, London, UK; Department of Dermatology, St 
      George Hospital, University of NSW, Sydney, NSW, Australia (DFM, MHK); St John's 
      Institute of Dermatology, Kings College London (Guys Campus), London, UK (JAM); 
      Department of Dermatology and MediCity Research Laboratory, University of Turku, 
      and Turku University Hospital, Turku, Finland (AK, VMK); Department of 
      Dermatology, University of Southern California, Los Angeles, CA (MC).
FAU - O'Toole, E A
AU  - O'Toole EA
AD  - Centre for Cell Biology and Cutaneous Research, Blizard Institute (VLM, MPC, ZS, 
      STM, MA, RC, EOT), Barts Cancer Institute (KM, KHD, JFM), Barts and the London 
      School of Medicine and Dentistry and School of Biological and Chemical Sciences 
      (CHB), Queen Mary University of London, London, UK; Department of Dermatology, St 
      George Hospital, University of NSW, Sydney, NSW, Australia (DFM, MHK); St John's 
      Institute of Dermatology, Kings College London (Guys Campus), London, UK (JAM); 
      Department of Dermatology and MediCity Research Laboratory, University of Turku, 
      and Turku University Hospital, Turku, Finland (AK, VMK); Department of 
      Dermatology, University of Southern California, Los Angeles, CA (MC). 
      e.a.otoole@qmul.ac.uk.
LA  - eng
GR  - 12007/CRUK_/Cancer Research UK/United Kingdom
GR  - G1000053/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction 
      of Animals in Research/United Kingdom
GR  - G0901609/MRC_/Medical Research Council/United Kingdom
GR  - 18673/CRUK_/Cancer Research UK/United Kingdom
GR  - 12-1068/AICR_/Worldwide Cancer Research/United Kingdom
GR  - G0800825/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151016
PL  - United States
TA  - J Natl Cancer Inst
JT  - Journal of the National Cancer Institute
JID - 7503089
RN  - 0 (Angiogenesis Inhibitors)
RN  - 0 (COL7A1 protein, human)
RN  - 0 (Collagen Type VII)
RN  - 0 (Integrin alpha2beta1)
RN  - 0 (RNA, Messenger)
RN  - 0 (SMAD2 protein, human)
RN  - 0 (Smad2 Protein)
RN  - 0 (TGFB1 protein, human)
RN  - 0 (Transforming Growth Factor beta1)
SB  - IM
MH  - Angiogenesis Inhibitors/*pharmacology
MH  - Animals
MH  - Carcinoma, Squamous Cell/*drug therapy/genetics
MH  - Collagen Type VII/*genetics/metabolism
MH  - Epidermolysis Bullosa Dystrophica/*complications/genetics
MH  - Humans
MH  - Immunoblotting
MH  - Immunohistochemistry
MH  - Integrin alpha2beta1/metabolism
MH  - Mice
MH  - Mutation
MH  - Neovascularization, Pathologic/drug therapy
MH  - RNA, Messenger/metabolism
MH  - Signal Transduction/drug effects
MH  - Skin Neoplasms/*drug therapy/genetics
MH  - Smad2 Protein/metabolism
MH  - Transforming Growth Factor beta1/*antagonists & inhibitors/genetics
MH  - Xenograft Model Antitumor Assays
EDAT- 2015/10/18 06:00
MHDA- 2016/02/03 06:00
CRDT- 2015/10/18 06:00
PHST- 2015/04/13 00:00 [received]
PHST- 2015/09/22 00:00 [accepted]
PHST- 2015/10/18 06:00 [entrez]
PHST- 2015/10/18 06:00 [pubmed]
PHST- 2016/02/03 06:00 [medline]
AID - djv293 [pii]
AID - 10.1093/jnci/djv293 [doi]
PST - epublish
SO  - J Natl Cancer Inst. 2015 Oct 16;108(1):djv293. doi: 10.1093/jnci/djv293. Print 
      2016 Jan.