Abstract
BackgroundIn humans, imaging of tumors provides rapid, accurate assessment of tumor growth and location. In laboratory animals, however, the imaging of spontaneously occurring tumors continues to pose many technical and logistical problems. Recently a mouse model was generated in which a chimeric protein consisting of HIF-1α oxygen-dependent degradation domain (ODD) fused to luciferase was ubiquitously expressed in all tissues. Hypoxic stress leads to the accumulation of ODD-luciferase in the tissues of this mouse model which can be identified by non-invasive bioluminescence measurement. Since solid tumors often contain hypoxic regions, we performed proof-of-principle experiments testing whether this transgenic mouse model may be used as a universal platform for non-invasive imaging analysis of spontaneous solid tumors.Methods and Materials ODD-luciferase transgenic mice were bred with MMTV-neu/beclin1+/− mice. Upon injection of luciferin, bioluminescent background of normal tissues in the transgenic mice and bioluminescent signals from spontaneously mammary carcinomas were measured non-invasively with an IVIS Spectrum imaging station. Tumor volumes were measured manually and the histology of tumor tissues was analyzed.ConclusionOur results show that spontaneous mammary tumors in ODD-luciferase transgenic mice generate substantial bioluminescent signals, which are clearly discernable from background tissue luminescence. Moreover, we demonstrate a strong quantitative correlation between the bioluminescent tumor contour and the volume of palpable tumors. We further demonstrate that shrinkage of the volume of spontaneous tumors in response to chemotherapeutic treatment can be determined quantitatively using this system. Finally, we show that the growth and development of spontaneous tumors can be monitored longitudinally over several weeks. Thus, our results suggest that this model could potentially provide a practical, reliable, and cost-effective non-invasive quantitative method for imaging spontaneous solid tumors in mice.
Highlights
In human medicine, the detection and evaluation of tumors has been an area of ongoing research for many years
Our results show that spontaneous mammary tumors in oxygendependent degradation domain (ODD)-luciferase transgenic mice generate substantial bioluminescent signals, which are clearly discernable from background tissue luminescence
We further demonstrate that shrinkage of the volume of spontaneous tumors in response to chemotherapeutic treatment can be determined quantitatively using this system
Summary
The detection and evaluation of tumors has been an area of ongoing research for many years. Examples of technology in this rapidly expanding field include x-rays, ultrasonic imaging, computed tomography, positron emission tomography, magnetic resonance imaging, and nuclear scintigraphy Many of these imaging modalities can provide astonishingly detailed information about a tumor, including size, shape, location, vasculature and architecture; but most of the advanced techniques require extensive training and experience to master, the existence of board-certified radiologists within the medical profession. The mice used in these models are invariably immunocompromised to prevent rejection of the xenograft This condition alters the natural inhibitory factors that cancer is subjected to in an otherwise immunocompetent host [6,7], allowing the xenograft to grow and even metastasize. Since solid tumors often contain hypoxic regions, we performed proof-of-principle experiments testing whether this transgenic mouse model may be used as a universal platform for non-invasive imaging analysis of spontaneous solid tumors
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