Endocrine Abstracts

The question why thyroid carcinoma metastasises to the skeleton can be reformulated into the more general question why bone metastases occur in cancer.

In the development of bone metastases, three phases can be distinguished.

First, tumors cells have to be released into the vascular system. The process of vascular invasion and haematogenous spread involves a cascade of events that will not be summarized here, but apparent differences exist between tumors with regard to their tendency to vascular invasion.

The second phase involves the seeding and survival of metastatic cells in the skeleton. Preferential colonization of certain tissues by cancer cells and their subsequent growth are determined by interaction with the tissue-specific microenvironment. Cancer cells express attachment proteins such as integrins that interact with specific extracellular matrix proteins. Thus the match between tumor attachment proteins and the extracellular matrix ‘make-up’ are important for successful attachment and survival.

In addition, bone is continuously remodelled by bone resorption and formation. Growth factors supporting bone metastatic growth are released especially during bone resorption: transforming growth factor-ß (TGF-ß) stimulates the secretion of bone cytokines, which enhance bone resorption but also stimulate tumor growth by interfering in the BMP pathway. On its turn, thyroid tumor cells synthesize factors that enhance bone turnover, such as IGF-I but interestingly also osteoprotegerin. A relevant factor in thyroid cancer may TSH suppressive treatment: high T3 levels and low TSH levels enhance bone turnover, which from a perspective of bone metastasis is not beneficial.

The third phase involves tumor growth and extension. In this phase, tumor growth is self-maintaining by autocrine factors and as such becomes more or less independent from the bone environment. Processes involved are the synthesis of proteolytic, matrix degrading enzymes such as matrix metalloproteinases and the induction of neovascularization by angiogenetic factors.