New therapeutic targets for cancer bone metastasis

Abstract

Bone metastases are dejected consequences of many types of tumors including breast, prostate, lung, kidney, and thyroid cancers. This complicated process begins with the successful tumor cell epithelial-mesenchymal transition, escape from the original site, and penetration into the circulation. The homing of tumor cells to the bone depends on both tumor-intrinsic traits and various molecules supplied by the bone metastatic niche. The colonization and growth of cancer cells in the osseous environment, which awaken their dormancy to form micro- and macro-metastasis, involve an intricate interaction between the circulating tumor cells and local bone cells including osteoclasts, osteoblasts, adipocytes, and macrophages. We discuss the most recent advances in the identification of new molecules and novel mechanisms during each step of bone metastasis that may serve as promising therapeutic targets.

Keywords: bone metastatic niche; bone microenvironment; macrometastasis; osteoblast; osteoclast; tumor-intrinsic factors.

Figure 1. Multiple steps in cancer bone metastasis and the major regulatory factors in the tumor-bone microenvironment

The cellular basis of cancer progression includes tumor cell local invasion, intravasation, survival in the circulation, extravasation, colonization and thriving in the bone. In the primary site, tumor cells undergo EMT, ECM degradation and angiogenesis to invade vascular or lymphatic circulation (A). After intravasation, a few tumor cells can survive from NK cells attack with the assistance of platelets (B). Through the communication between tumor intrinsic factors and factors in the osseous environment, cancer cells extravasate to the bone and marrow. Interactions between tumor cells and bone cells mediated by adhesion molecules are critical for colonization (C). After landing, tumor cells start to interact with local cells, including osteoclasts, osteoblasts, adipocytes and macrophages, in order to thrive in bone and form micro- and macro-metastasis (D).

Figure 2. Illustration of osteolytic and osteoblastic bone metastatic lesions

Cancer causes predominantly two types of bone metastatic lesions based on the radiological appearance, with bone destructions observed in osteolytic bone metastatic lesions (A), while bone forming phenotypes are observed in osteoblastic bone metastatic lesions (B).