Optical Imaging of Cancer Metastasis to Bone Marrow

Abstract

The development of novel anti-cancer strategies requires more sensitive and less invasive methods to detect and monitor in vivo minimal residual disease in cancer models. Bone marrow metastases are indirectly detected by radiography as osteolytic and/or osteosclerotic lesions. Marrow micrometastases elude radiographic detection and, therefore, more sensitive methods are needed for their direct identification. Injection of cancer cells into the left cardiac ventricle of mice closely mimics micrometastatic spread. When luciferase-transfected cells are used, whole-body bioluminescent reporter imaging can detect microscopic bone marrow metastases of approximately 0.5 mm(3) volume, a size below the limit in which tumors need to induce angiogenesis for further growth. This sensitivity translates into early detection of intramedullary tumor growth, preceding the appearance of a radiologically evident osteolysis by approximately 2 weeks. Bioluminescent reporter imaging also enables continuous monitoring in the same animal of growth kinetics for each metastatic site and guides end-point analyses specifically to the bones affected by metastatic growth. This model will accelerate the understanding of the molecular events in metastasis and the evaluation of novel therapies aiming at repressing initial stages of metastatic growth.

Annexin-1 interacts with NEMO and RIP1 to constitutively activate IKK complex and NF-κB: implication in breast cancer metastasis

“…We collected void volume that is represented as fraction number 1, and immediately after void volume, the fractions 5-12, respectively. Our results are consistent with the previous findings that IKK complex exists as an B700-900 kDa protein complex (Wetterwald et al, 2002). Analysis of MCF7-EV and MCF7-V5 cells showed IKK phosphorylation in a prominent pool with a relative molecular mass (Mr) of B700 kDa (fractions 7-9) in MCF7-V5 cells, but not in MCF7-EV cells (Figure 2a).…”

Quantifying intra‐osseous growth of osteosarcoma in a murine model with radiographic analysis

“…4 Therefore, analysis of both aspects of osteosarcoma progression necessitates that at least one parameter be monitored in vivo. Current methods for monitoring the longitudinal development of tumor include direct measurement of tumor cells genetically tagged with fluorescent proteins or luciferase 4,11,12 and indirect tumor burden estimation using external calipers to measure soft tissue surrounding the primary tumor. 6 Although useful, these methods have limitations.…”

“…6 Although useful, these methods have limitations. The use of fluorescence or luminescence imaging requires prior genetic manipulation of the tumor cell 11,12 and the ultimate visual signal typically requires injection of a substrate measured with potential subjective statistical error. 16 The alternative method, quantification by calipers has the advantage that it does not require genetic manipulation of the cell; however it does not account for the loss of anatomic landmarks during tumor development.…”

“…Methods for quantifying osteosarcoma longitudinally include direct measurement of tumor cells genetically tagged with fluorescent proteins or luciferase 4,11,12 and indirect tumor burden estimation using external calipers to measure the area or volume from two-dimensional measurements. 6,13 Here, we propose a novel approach to monitor longitudinal growth of intra-osseous tumor by radiographic analysis.…”

In vivo bioluminescence imaging of locally disseminated colon carcinoma in rats

“…This photon emission can be detected by a cooled charge-coupled device (CCD) camera, minutes after the administration of the substrate. Bioluminescence imaging has been used successfully for monitoring tumour growth in mice Edinger et al, 1999;Vooijs et al, 2002;Wetterwald et al, 2002). There are also two reports of bioluminescence imaging in rats, to detect localised glioma growth in the brain (Rehemtulla et al, 2000), or to detect cardiac reporter gene expression in the heart (Wu et al, 2002).…”