Is There One Key Step in the Metastatic Cascade?

SIMPLE SUMMARY: To successfully metastasize, cancer cells must complete a sequence of obligatory steps called the metastatic cascade. To model the metastatic cascade, we used the framework of the Drake equation, initially created to describe the emergence of intelligent life in the Milky way, using a similar logic of a sequence of obligatory steps. Then within this framework, we used simulations on breast cancer to investigate the contribution of each step to the metastatic cascade. We show that the half-life of circulating tumor cells is one of the most important parameters in the cascade, suggesting that therapies reducing the survival of those cells in the vascular system could significantly reduce the risk of metastasis. ABSTRACT: The majority of cancer-related deaths are the result of metastases (i.e., dissemination and establishment of tumor cells at distant sites from the origin), which develop through a multi-step process classically termed the metastatic cascade. The respective contributions of each step to the metastatic process are well described but are also currently not completely understood. Is there, for example, a critical phase that disproportionately affects the probability of the development of metastases in individual patients? Here, we address this question using a modified Drake equation, initially formulated by the astrophysicist Frank Drake to estimate the probability of the emergence of intelligent civilizations in the Milky Way. Using simulations based on realistic parameter values obtained from the literature for breast cancer, we examine, under the linear progression hypothesis, the contribution of each component of the metastatic cascade. Simulations demonstrate that the most critical parameter governing the formation of clinical metastases is the survival duration of circulating tumor cells (CTCs).