Postdoctoral fellow MD Anderson Cancer Center Houston, TX, United States
Background: Clear cell renal carcinoma (ccRCC) represents 80% of renal neoplasms, with bone as a major site for distant spread (35-40% of patients). These secondary lesions cause a variety of skeletal-related complications, including pain, spinal cord compression, hypercalcemia, mobility issues and fractures, posing a significant negative impact on patient quality of life and survival. Furthermore, bone is well-known as a site of therapy resistance, which confers to patients treated with systemic therapies significantly worse time-to-treatment failure and progression-free and overall survival compared to those without bone metastases.
Methods: Because of the complexity of the bone microenvironment and the paucity of suitable models, preclinical investigation of bone metastasis and therapy response is challenging. We recently developed a window model amenable to intravital multiphoton microscopy (MPM) to longitudinally monitor ccRCC lesions in tissue engineered bone constructs (TEBCs). TEBCs were generated by functionalizing polymeric polycaprolactone scaffolds with bone morphogenetic protein 7. After in vivo implantation, bone formation was monitored by μCT, MPM and histological analysis over time.
Results: TEBC includes ossified trabeculae and interspersed bone marrow with niche-like anatomy; multi-lineage hematopoietic cells, including hematopoietic stem cells, and functional vascularization. The TEBC favors non-destructive implantation of cancer cells due to its wide/large cavity and can be implemented for imaging due to its limited cortical bone thickness. Human and murine ccRCC lesions, after implantation into the bone cavity, were longitudinally monitored for growth and niche development, using multi-parameter recording of collagen/bone matrix (SHG), bone surface (THG), blood vessels/stromal phagocytes (fluorescent dextran), and tumor cells (GFP).
Conclusions: By combining innovative tissue engineering with optical windows, state-of-the-art fluorescence reporter technology and intravital MPM, this model will provide mechanistic and applied insight into the therapy response of bone metastasis.
