In vivo imaging and characterization of hypoxia-induced neovascularization and tumor invasion

Abstract

Abstract. Hypoxia is a critical event in tumor progression and angiogenesis. Hypoxia can be detected noninvasively by a novel spectroscopic photoacoustic tomography technology (SPAT) and this finding is supported by our molecular biology investigation aimed to elucidate the etiopathogenesis of SPAT detected hypoxia and angiogenesis. The present study provides an integrated approach to define oxygen status (hypoxia) of intracranial tumor xenografts using spectroscopic photoacoustic tomography. Brain tumors can be identified based on their distorted vascular architecture and oxygen saturation (SO2) images. Noninvasive in vivo tumor oxygenation imaging using SPAT is based on the spectroscopic absorption differences between oxyhemoglobin (O 2 Hb) and deoxyhemoblobin (HHb). Sprague-Dawley rats inoculated intracranially with ENU1564, a carcinogen-induced rat mammary adenocarcinoma cell line, were imaged with SPAT three weeks post inoculation. Proteins important for tumor angiogenesis and invasion were detected in hypoxic brain foci identified by SPAT and were elevated compared with control brain. Immunohistochemistry, Western blotting, and semi-quantitative RT-PCR showed that HIF-1·, VEGF-A, and VEGFR2 (Flk-1) protein and mRNA expression levels were significantly higher (P<0.05) in brain tumor tissues compared to normal brain. Gelatin zymography and RT-PCR demonstrated the upregulation of MMP-9 in tumor foci compared with brain control. Together these results suggest the critical role of hypoxia in driving tumor angiogenesis and invasion through upregulation of target genes important for these functions. Moreover this report validates our hypothesis that a novel noninvasive technology (SPAT) developed in our laboratory is suitable for detection of tumors, hypoxia, and angiogenesis.

Whole-body three-dimensional optoacoustic tomography system for small animals

“…16 Since aggressively growing tumors are densely vascularized, optoacoustic systems have been used in the past to image various tumors on the macroscopic and microscopic scales. [17][18][19][20][21][22][23] In cancer research using orthotopic models, in which primary tumors are induced in the internal organs and their metastases spontaneously appear in various parts of the animal body, whole-body imaging is desirable. Whole-body mouse imaging may enable the detection of tumors in internal organs, not only subcutaneous tumors.…”

Simultaneous Molecular and Hypoxia Imaging of Brain Tumors In Vivo Using Spectroscopic Photoacoustic Tomography

“…In a separate rat model demonstrating the etiopathogenesis of hypoxia in intracranial tumor xenografts, we evaluated the expressions of the hypoxia-inducible factor-1 (HIF-1), the vascular endothelial growth factor (VEGF), the vascular endothelial growth factor receptor 2 (VEGFR2), and the matrix metalloproteinases-9 (MMP-9) proteins and the associated mRNA levels [26] in hypoxic brain tumor foci [44]; the levels of these proteins and the associated mRNA in the brain tumor foci were found to be higher than those in normal brain tissues. This model supports the SPAT data that show both hypoxia and up-regulation of proteins in the brain tumor foci.…”

Biomedical photoacoustics: fundamentals, instrumentation and perspectives on nanomedicine

“…The endogenous contrast agents for PAI such as melanin and hemoglobin have been utilized to evaluate the oxygen saturation and hemoglobin concentration in tumors. 41 On the other hand, the development of exogenous contrast agents has attracted increasing attention, and numerous advanced nanomaterials including gold nanoparticles (AuNPs), single-walled carbon nanotubes (SWNTs), semi-conductive nanoparticles, organic dyes, etc. have been designed as contrast agents for PA molecular imaging (Figure 3).…”