PMID- 25993305
OWN - NLM
STAT- MEDLINE
DCOM- 20151223
LR  - 20240325
IS  - 1520-6882 (Electronic)
IS  - 0003-2700 (Print)
IS  - 0003-2700 (Linking)
VI  - 87
IP  - 12
DP  - 2015 Jun 16
TI  - MALDI-Mass Spectrometric Imaging Revealing Hypoxia-Driven Lipids and Proteins in 
      a Breast Tumor Model.
PG  - 5947-5956
LID - 10.1021/ac504503x [doi]
AB  - Hypoxic areas are a common feature of rapidly growing malignant tumors and their 
      metastases and are typically spatially heterogeneous. Hypoxia has a strong impact 
      on tumor cell biology and contributes to tumor progression in multiple ways. To 
      date, only a few molecular key players in tumor hypoxia, such as 
      hypoxia-inducible factor-1 (HIF-1), have been discovered. The distribution of 
      biomolecules is frequently heterogeneous in the tumor volume and may be driven by 
      hypoxia and HIF-1alpha. Understanding the spatially heterogeneous hypoxic response of 
      tumors is critical. Mass spectrometric imaging (MSI) provides a unique way of 
      imaging biomolecular distributions in tissue sections with high spectral and 
      spatial resolution. In this paper, breast tumor xenografts grown from 
      MDA-MB-231-HRE-tdTomato cells, with a red fluorescent tdTomato protein construct 
      under the control of a hypoxia response element (HRE)-containing promoter driven 
      by HIF-1alpha, were used to detect the spatial distribution of hypoxic regions. We 
      elucidated the 3D spatial relationship between hypoxic regions and the 
      localization of lipids and proteins by using principal component analysis-linear 
      discriminant analysis (PCA-LDA) on 3D rendered MSI volume data from 
      MDA-MB-231-HRE-tdTomato breast tumor xenografts. In this study, we identified 
      hypoxia-regulated proteins active in several distinct pathways such as glucose 
      metabolism, regulation of actin cytoskeleton, protein folding, 
      translation/ribosome, splicesome, the PI3K-Akt signaling pathway, hemoglobin 
      chaperone, protein processing in endoplasmic reticulum, detoxification of 
      reactive oxygen species, aurora B signaling/apoptotic execution phase, the RAS 
      signaling pathway, the FAS signaling pathway/caspase cascade in apoptosis, and 
      telomere stress induced senescence. In parallel, we also identified 
      colocalization of hypoxic regions and various lipid species such as 
      PC(16:0/18:0), PC(16:0/18:1), PC(16:0/18:2), PC(16:1/18:4), PC(18:0/18:1), and 
      PC(18:1/18:1), among others. Our findings shed light on the biomolecular 
      composition of hypoxic tumor regions, which may be responsible for a given 
      tumor's resistance to radiation or chemotherapy.
FAU - Jiang, Lu
AU  - Jiang L
AD  - Division of Cancer Imaging Research, Russell H. Morgan Department of Radiology 
      and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, 
      Maryland 21205, United States.
FAU - Chughtai, Kamila
AU  - Chughtai K
AD  - FOM Institute AMOLF, 1098 XG Amsterdam, The Netherlands.
FAU - Purvine, Samuel O
AU  - Purvine SO
AD  - Environmental Molecular Sciences Laboratory, Pacific Northwest National 
      Laboratory, Richland, Washington 99354, United States.
FAU - Bhujwalla, Zaver M
AU  - Bhujwalla ZM
AD  - Division of Cancer Imaging Research, Russell H. Morgan Department of Radiology 
      and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, 
      Maryland 21205, United States.
AD  - Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of 
      Medicine, Baltimore, Maryland 21231, United States.
FAU - Raman, Venu
AU  - Raman V
AD  - Division of Cancer Imaging Research, Russell H. Morgan Department of Radiology 
      and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, 
      Maryland 21205, United States.
AD  - Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of 
      Medicine, Baltimore, Maryland 21231, United States.
FAU - Pasa-Tolic, Ljiljana
AU  - Pasa-Tolic L
AD  - Environmental Molecular Sciences Laboratory, Pacific Northwest National 
      Laboratory, Richland, Washington 99354, United States.
FAU - Heeren, Ron M A
AU  - Heeren RMA
AD  - FOM Institute AMOLF, 1098 XG Amsterdam, The Netherlands.
AD  - M4I, The Maastricht MultiModal Molecular Imaging Institute, 6229 ER Maastricht, 
      The Netherlands.
FAU - Glunde, Kristine
AU  - Glunde K
AD  - Division of Cancer Imaging Research, Russell H. Morgan Department of Radiology 
      and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, 
      Maryland 21205, United States.
AD  - Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of 
      Medicine, Baltimore, Maryland 21231, United States.
LA  - eng
GR  - P30 CA006973/CA/NCI NIH HHS/United States
GR  - R01 CA134695/CA/NCI NIH HHS/United States
GR  - R01 CA154725/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20150604
PL  - United States
TA  - Anal Chem
JT  - Analytical chemistry
JID - 0370536
RN  - 0 (Lipids)
RN  - 0 (Neoplasm Proteins)
SB  - IM
MH  - Animals
MH  - *Cell Hypoxia
MH  - Cell Line, Tumor
MH  - Female
MH  - Humans
MH  - Lipids/*analysis
MH  - Mammary Neoplasms, Experimental/*chemistry
MH  - Mice
MH  - Neoplasm Proteins/*analysis
MH  - *Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
PMC - PMC4820759
MID - NIHMS760879
EDAT- 2015/05/21 06:00
MHDA- 2015/12/24 06:00
PMCR- 2016/04/05
CRDT- 2015/05/21 06:00
PHST- 2015/05/21 06:00 [entrez]
PHST- 2015/05/21 06:00 [pubmed]
PHST- 2015/12/24 06:00 [medline]
PHST- 2016/04/05 00:00 [pmc-release]
AID - 10.1021/ac504503x [doi]
PST - ppublish
SO  - Anal Chem. 2015 Jun 16;87(12):5947-5956. doi: 10.1021/ac504503x. Epub 2015 Jun 4.