title: HIF-1-dependent stromal adaptation to ischemia mediates in vivo tumor radiation resistance.
abstract: OBJECTIVE
  Hypoxia-inducible factor 1 (HIF-1) promotes cancer cell survival and tumor progression. The specific role played by HIF-1 and tumor-stromal interactions toward determining tumor resistance to radiation treatment remains undefined. We applied a multimodality preclinical imaging platform to mechanistically characterize tumor response to radiation, with a focus on HIF-1-dependent resistance pathways.
  
  
  METHODS
  C6 glioma and HN5 human squamous carcinoma cells were stably transfected with a dual HIF-1 signaling reporter construct (dxHRE-tk/eGFP-cmvRed2XPRT). Reporter cells were serially interrogated in vitro before and after irradiation as monolayer and multicellular spheroid cultures and as subcutaneous xenografts in nu/nu mice.
  
  
  RESULTS
  In vitro, single-dose irradiation of C6 and HN5 reporter cells modestly impacted HIF-1 signaling in normoxic monolayers and inhibited HIF-1 signaling in maturing spheroids. In contrast, irradiation of C6 or HN5 reporter xenografts with 8 Gy in vivo elicited marked upregulation of HIF-1 signaling and downstream proangiogenic signaling at 48 hours which preceded recovery of tumor growth. In situ ultrasound imaging and dynamic contrast-enhanced (DCE) MRI indicated that HIF-1 signaling followed acute disruption of stromal vascular function. High-resolution positron emission tomography and dual-contrast DCE-MRI of immobilized dorsal skin window tumors confirmed postradiotherapy HIF-1 signaling to spatiotemporally coincide with impaired stromal vascular function. Targeted disruption of HIF-1 signaling established this pathway to be a determinant of tumor radioresistance.
  
  
  CONCLUSIONS
  Our results illustrate that tumor radioresistance is mediated by a capacity to compensate for stromal vascular disruption through HIF-1-dependent proangiogenic signaling and that clinically relevant vascular imaging techniques can spatially define mechanisms associated with tumor irradiation.
authors.affiliation: Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. dschwartz3@nshs.edu
authors.forename: David L
authors.initials: DL
authors.lastname: Schwartz
authors.forename: James
authors.initials: J
authors.lastname: Bankson
authors.forename: Luc
authors.initials: L
authors.lastname: Bidaut
authors.forename: Yi
authors.initials: Y
authors.lastname: He
authors.forename: Ryan
authors.initials: R
authors.lastname: Williams
authors.forename: Robert
authors.initials: R
authors.lastname: Lemos
authors.forename: Arun Kumar
authors.initials: AK
authors.lastname: Thitai
authors.forename: Junghwan
authors.initials: J
authors.lastname: Oh
authors.forename: Andrei
authors.initials: A
authors.lastname: Volgin
authors.forename: Suren
authors.initials: S
authors.lastname: Soghomonyan
authors.forename: Hsin-Hsien
authors.initials: HH
authors.lastname: Yeh
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Nishii
authors.forename: Uday
authors.initials: U
authors.lastname: Mukhopadhay
authors.forename: Mian
authors.initials: M
authors.lastname: Alauddin
authors.forename: Ioseb
authors.initials: I
authors.lastname: Mushkudiani
authors.forename: Norihito
authors.initials: N
authors.lastname: Kuno
authors.forename: Sunil
authors.initials: S
authors.lastname: Krishnan
authors.forename: William
authors.initials: W
authors.lastname: Bornman
authors.forename: Stephen Y
authors.initials: SY
authors.lastname: Lai
authors.forename: Garth
authors.initials: G
authors.lastname: Powis
authors.forename: John
authors.initials: J
authors.lastname: Hazle
authors.forename: Juri
authors.initials: J
authors.lastname: Gelovani
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D015687:Cell Hypoxia / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects*; D007511:Ischemia / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000098:blood supply* / Q000473:pathology / Q000532:radiotherapy*; D049268:Positron-Emission Tomography / Q000401:mortality; D011836:Radiation Tolerance / Q000502:physiology*; D051381:Rats; D018874:Spheroids, Cellular / Q000528:radiation effects; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000528:radiation effects; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism / Q000528:radiation effects*
chemical_list: D051793:Hypoxia-Inducible Factor 1; D042442:Vascular Endothelial Growth Factors