Background

Bone is one of frequent metastasis sites for many types of cancer, including prostate, breast, and lung cancer. Based on their radiographic appearance, bone metastatic lesions are mainly classified into two types: osteolytic or osteoblastic lesions. These lesions are induced by an imbalance between bone formation and bone resorption in the tumor-bone microenvironment. In bone metastatic lesions, tumor cells interact with many types of cells, including osteoblasts, osteoclasts, or mesenchymal stem cells. According to previous reports, the increased bone-resorbing or bone-forming activity is mediated by many paracrine factors secreted by metastasized tumor cells. However, the detailed mechanisms responsible for the osteolytic or osteoblastic phenotype remain to be fully elucidated. To investigate the molecular mechanisms underlying how metastasized tumor cells can induce osteolytic or osteoblastic phenotypes, it is essential to generate animal models that mimic the behavior of tumor cells in bone metastatic lesions.

Calvarial implantation model (bone invasion model) was originally established by Mitsuru Futakuchi and his colleagues [Lynch et al., 2005]. This model accurately recapitulates the behavior of various tumor cells (e.g., rat prostate cancer cells [Lynch et al., 2005], murine breast cancer cells [Wilson et al., 2008], etc.) in bone metastatic microenvironment. In addition, surgical technique required for the implantation of tumor cells is simpler than intracardiac, intra-arterial or intraosseous injection techniques. On the other hand, this model has a couple of limitations. It does not represent the metastasis process from primary organs to bone. Besides, calvaria is not a typical metastasis site for most of cancers.

This model is especially useful in identifying key factors driving tumor-induced osteolytic or osteoblastic changes. Using this model, Futakuchi and his colleagues has demonstrated an important role of MMP-7, cathepsin G, or transforming growth factor β (TGFβ) signaling in tumor-induced osteolysis or tumor growth in bone metastatic microenvironment (Lynch et al., 2005; Sato et al., 2008; Wilson et al., 2008; Futakuchi et al., 2009). In another study, the effect of bisphosphonate or RANKL-targeting therapy was evaluated using this model (Hikosaka et al., 2006; Futakuchi et al., 2018). Hashimoto et al. also used this model to investigate the tumor-stromal interactions by cancer-secreted microRNAs (Hashimoto et al., 2018).