Tumor hypoxia has been associated with tumor progression, a higher risk of metastatic spread, and resistance to therapy, and has thus become a central issue in tumor physiology and cancer treatment. To date, very little is known about the molecular pathways that are affected by tumor hypoxia, and which eventually cause the disastrous clinical effects of poor cancer prognosis and poor treatment outcome. Hypoxia-inducible factor 11 (HIF-11), whose levels increase under hypoxic conditions, plays an important role in tumor hypoxia as it affects the levels of other biomolecules. Because currently little is known about the key biomolecules in tumor hypoxia, we will seek to identify to date unknown molecules that are increased or decreased in hypoxic regions in breast tumors. We will use a unique model system to study hypoxia, which consists of human breast cancer cell lines and the corresponding tumor models grown in immune-compromised animals that were genetically engineered to contain a built-in hypoxia detector . This detector couples the natural hypoxia response of increased HIF-11 to the production of a fluorescent marker that can be detected by optical imaging. We will combine optical hypoxia detection with in vivo magnetic resonance spectroscopic imaging (MRSI), cutting- edge mass spectrometry imaging (MSI) applications, and targeted proteomics strategies. In our first specific aim, we will discover, identify, and validate biomolecules that are decreased or increased due to hypoxia in breast cancer cell cultures. We will compare three human breast cell lines representing different degrees of aggressiveness and metastatic potential that have been made hypoxic in the laboratory. In our second specific aim, we will carry out parallel studies in actual breast tumor models grown from the same breast cancer cells lines, which contain the built-in hypoxia detector . We will analyze the hypoxic regions in these breast tumors using the same MS-based proteomics approach as in the cell lines. In the third specific aim, we will evaluate the hypoxia-related biomolecules initially identified in Aims 1 and 2 using a multimodal 3D molecular imaging approach, which will combine in vivo MRSI, optical imaging, and MSI methods. MRS, optical, and MS images will be acquired of the same breast tumor models containing the built-in hypoxia detector , which will enable us to assess the spatial relationship between hypoxia, already known hypoxia marker molecules, and our newly identified hypoxia-related molecules. Our studies will lead to a better understanding of the molecular pathways that are triggered by hypoxia in breast tumors. The proposed studies may eventually translate into new breast cancer therapies for patients that have hypoxic regions in their tumors. Future studies can explore possibilities to use these newly discovered hypoxia-related molecules as targets for treating tumor hypoxia, and hopefully improve the treatment outcome of cancer patients with hypoxic breast tumors.

Public Health Relevance

Hypoxia renders breast tumors aggressive, metastatic, and resistant to treatment with radio- and chemotherapy. To date, very few molecular key players in tumor hypoxia, such as for example hypoxia inducible factor 11 (HIF-11), have been discovered. Discovering and validating relevant hypoxia-driven pathways, which potentially confer radio- and chemoresistance and tumor aggressiveness in hypoxic tumors, will be of crucial importance to overcome these detrimental effects of breast tumor hypoxia. In our application, we aim to elucidate such to date unknown molecular pathways that are produced in the heterogeneous hypoxic regions of solid breast tumors. Such hypoxia-related biomolecules may, in the future, provide novel molecular targets for innovative hypoxia-targeted breast cancer therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA134695-03
Application #
7894629
Study Section
Special Emphasis Panel (ZRG1-MEDI-A (09))
Program Officer
Knowlton, John R
Project Start
2008-08-01
Project End
2013-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
3
Fiscal Year
2010
Total Cost
$298,598
Indirect Cost
Name
Johns Hopkins University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Cheng, Menglin; Glunde, Kristine (2018) Magnetic Resonance Spectroscopy Studies of Mouse Models of Cancer. Methods Mol Biol 1718:331-345
Cheng, Menglin; Rizwan, Asif; Jiang, Lu et al. (2017) Molecular Effects of Doxorubicin on Choline Metabolism in Breast Cancer. Neoplasia 19:617-627
Cao, Maria Dung; Cheng, Menglin; Rizwan, Asif et al. (2016) Targeting choline phospholipid metabolism: GDPD5 and GDPD6 silencing decrease breast cancer cell proliferation, migration, and invasion. NMR Biomed 29:1098-107
Chan, Kannie W Y; Jiang, Lu; Cheng, Menglin et al. (2016) CEST-MRI detects metabolite levels altered by breast cancer cell aggressiveness and chemotherapy response. NMR Biomed 29:806-16
Mascini, Nadine E; Cheng, Menglin; Jiang, Lu et al. (2016) Mass Spectrometry Imaging of the Hypoxia Marker Pimonidazole in a Breast Tumor Model. Anal Chem 88:3107-14
Jiang, Lu; Chughtai, Kamila; Purvine, Samuel O et al. (2015) MALDI-Mass Spectrometric Imaging Revealing Hypoxia-Driven Lipids and Proteins in a Breast Tumor Model. Anal Chem 87:5947-5956
Glunde, Kristine; Penet, Marie-France; Jiang, Lu et al. (2015) Choline metabolism-based molecular diagnosis of cancer: an update. Expert Rev Mol Diagn 15:735-47
Wijnen, Jannie P; Jiang, Lu; Greenwood, Tiffany R et al. (2014) 1H/31P polarization transfer at 9.4 Tesla for improved specificity of detecting phosphomonoesters and phosphodiesters in breast tumor models. PLoS One 9:e102256
Penet, Marie-France; Krishnamachary, Balaji; Chen, Zhihang et al. (2014) Molecular imaging of the tumor microenvironment for precision medicine and theranostics. Adv Cancer Res 124:235-56
Wijnen, J P; Jiang, L; Greenwood, T R et al. (2014) Silencing of the glycerophosphocholine phosphodiesterase GDPD5 alters the phospholipid metabolite profile in a breast cancer model in vivo as monitored by (31) P MRS. NMR Biomed 27:692-9

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