Intravital microscopy of osteolytic progression and therapy response of cancer lesions in the bone

A skin window enables noninvasive, longitudinal monitoring of cancer growth and therapy response in tissue-engineered bone in mice. Bone tumors revealed Noninvasive imaging can help monitor cancer metastasis and tumor-stroma interactions but is challenging for thick, dense tissues such as bone. Dondossola et al. studied prostate cancer metastasis to bone using tissue engineering and intravital multiphoton microscopy in mice. A skin window overlaying implanted engineered bone constructs injected with cancer cells allowed for observation of osteolysis in the bone constructs, with osteoclasts localized at the tumor-bone interface. Treatment with zoledronic acid slowed osteoclast activity (bone resorption) without affecting cancer growth. This engineered bone and imaging method gives a glimpse into tumor-bone interactions that could be useful to test therapies for bone remodeling and cancer metastasis. Intravital multiphoton microscopy (iMPM) in mice provides access to cellular and molecular mechanisms of metastatic progression of cancers and the underlying interactions with the tumor stroma. Whereas iMPM of malignant disease has been performed for soft tissues, noninvasive iMPM of solid tumor in the bone is lacking. We combined miniaturized tissue-engineered bone constructs in nude mice with a skin window to noninvasively and repetitively monitor prostate cancer lesions by three-dimensional iMPM. In vivo ossicles developed large central cavities containing mature bone marrow surrounded by a thin cortex and enabled tumor implantation and longitudinal iMPM over weeks. Tumors grew inside the bone cavity and along the cortical bone interface and induced niches of osteoclast activation (focal osteolysis). Interventional bisphosphonate therapy reduced osteoclast kinetics and osteolysis without perturbing tumor growth, indicating dissociation of the tumor-stroma axis. The ossicle window, with its high cavity-to-cortex ratio and long-term functionality, thus allows for the mechanistic dissection of reciprocal epithelial tumor-bone interactions and therapy response.