. The promise of targeting tumor neovascularization remains unrealized. Therefore new insights into how microvessel function impacts tumor biology and how tumor or endothelial signaling pathways regulate neovascularization are necessary. We developed a novel noninvasive imaging technique, photoacoustic microscopy (PAM). PAM uses laser excitation of hemoglobin (Hb) to determine neovascular architecture, Hb concentration (hematocrit), oxygen saturation (SO2), and flow in each tumor microvessel at capillary level resolution without exogenous contrast or tisue window construction. These data uniquely enable microregional determination of tumor metabolic rate of oxygen consumption (MRO2). We will combine PAM with biological, pharmacological, and genetic manipulations to test the hypothesis that tumor neovascular architecture and function regulate, and are regulated by, VEGF and PI3K signaling in tumor or in endothelial cells. We will study renal cancer because it is hypervascular due to overexpression of hypoxia- inducible factors (HIF)-2 and -1 that upregulate VEGF and other angiogenic factors. We will use human 786-O (VHL and PTEN negative) xenografts in immunodeficient mice to interrogate the same vascular network supplied by the same arteriovenous pair in all tumors. We will test our hypothesis with these Specific Aims: 1.0. Develop an integrated label-free photoacoustic microscope that longitudinally images vessel cross- section, hematocrit, SO2, blood flow, and MRO2. Currently we use two PAM instruments to image separately hematocrit (CHb)/SO2 and vessel cross section/flow vessel-by-vessel. Two systems quantifying MRO2 are prone to eror due to repositioning and asynchronicity. 2.0. Determine neovascular function, tumor metabolism, and cell biology during 786-O renal cancer xenograft growth. We will use longitudinal PAM imaging to elucidate how microvessel function, tumor MRO2, tumor and endothelial proliferative, survival, angiogenic, and PI3K signaling pathways are interlaced during tumor growth. 3.0. Inhibit VEGF signaling and determine the functional response of the neovasculature and renal cancer cells. We will use an anti- VEGF antibody, targeting human and mouse VEGF, and test for normalization of each PAM parameter, diminutions in endothelial and tumor cell proliferation and survival, and evasive angiogenic signaling upregulation. 4.1. Pharmacologically determine mTORC1 or both mTORC1 and -2 function in renal carcinoma cels and tumor-associated endothelium. We will use a rapalog (everolimus) or a dual mTORC1/2 inhibitor (PP242) and test for mechanisms of differential neovascular functional and cancer cell biological sensitivity. 4.2. Determine TORC2 function in the endothelial cells of renal carcinomas. We will conditionally delete the necesary mTORC2 component, Rictor, in adult recipient endothelium, testing for normalization of neovascular function, MRO2 and tumor cell survival and proliferative signaling. The impact of this proposed study will be to improve survival of patients with renal cancer and other solid malignancies.

Public Health Relevance

-Relevance. The blood supply to tumors is important for their growth and spread throughout the body. The vasculature is an emerging target for anti-tumor therapy. The function of tumor vessels and their interrelationship to tumor molecular signaling pathways regulating these vessels are incompletely understood. This project will use a novel technique to determine tumor neovessel function and tumor cell signaling during progressive growth and under the stress of vascular- or cancer cell targeted therapies. This project will change our understanding of how tumors grow and become therapy resistant.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA159959-04
Application #
8657908
Study Section
Special Emphasis Panel (ZRG1-SBIB-D (01))
Program Officer
Baker, Houston
Project Start
2011-07-01
Project End
2016-04-30
Budget Start
2014-05-02
Budget End
2015-04-30
Support Year
4
Fiscal Year
2014
Total Cost
$573,291
Indirect Cost
$196,126
Name
Washington University
Department
Surgery
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Lin, Li; Zhang, Pengfei; Xu, Song et al. (2017) Handheld optical-resolution photoacoustic microscopy. J Biomed Opt 22:41002
Lin, Li; Yao, Junjie; Zhang, Ruiying et al. (2017) High-speed photoacoustic microscopy of mouse cortical microhemodynamics. J Biophotonics 10:792-798
Lu, Zhi Hong; Kaliberov, Sergey; Sohn, Rebecca E et al. (2017) A new model of multi-visceral and bone metastatic prostate cancer with perivascular niche targeting by a novel endothelial specific adenoviral vector. Oncotarget 8:12272-12289
Imai, Toru; Muz, Barbara; Yeh, Cheng-Hung et al. (2017) Direct measurement of hypoxia in a xenograft multiple myeloma model by optical-resolution photoacoustic microscopy. Cancer Biol Ther 18:101-105
Zhou, Yong; Liang, Jinyang; Wang, Lihong V (2016) Cuffing-based photoacoustic flowmetry in humans in the optical diffusive regime. J Biophotonics 9:208-12
Hsu, Hsun-Chia; Wang, Lidai; Wang, Lihong V (2016) In vivo photoacoustic microscopy of human cuticle microvasculature with single-cell resolution. J Biomed Opt 21:56004
Ma, Jun; Shi, Junhui; Hai, Pengfei et al. (2016) Grueneisen relaxation photoacoustic microscopy in vivo. J Biomed Opt 21:66005
Yeh, Chenghung; Liang, Jinyang; Zhou, Yong et al. (2016) Photoacoustic microscopy of arteriovenous shunts and blood diffusion in early-stage tumors. J Biomed Opt 21:20501
Hennen, Stella N; Xing, Wenxin; Shui, Ying-Bo et al. (2015) Photoacoustic tomography imaging and estimation of oxygen saturation of hemoglobin in ocular tissue of rabbits. Exp Eye Res 138:153-8
Zhou, Yong; Poudel, Joemini; Li, Guo et al. (2015) In vivo photoacoustic flowmetry at depths of the diffusive regime based on saline injection. J Biomed Opt 20:87001

Showing the most recent 10 out of 104 publications