FIGURE 1.

Determinants of brain metastasis‐initiating circulating tumor cells. Tumor cells from the primary tumor may spread to the brain through the blood. CTCs are present in very low concentrations in the blood of cancer patient; however, a small subset of CTCs is expected to be uniquely capable of extravasation thought the BBB. The molecular features of these brain metastasis‐initiating CTCs have been studied, and some of the key molecules involved in the brain tropism are summarized in this figure. At the cell surface, brain‐tropic CTCs are negative for EpCAM and enriched for Her2, EGFR, Notch1, and integrin B1. ¹⁶ , ¹⁷ , ¹⁸ The transmembrane receptor Semaphorin 4D and proteinase Cathepsin S are upregulated in brain‐tropic CTCs and facilitate transmigration of the BBB. ¹⁹ , ²⁰ Exosomes isolated from brain‐tropic CTC are enriched in miR‐210, phospho‐p70 S6 Kinase (Thr389), annexin VII, phospho‐PDK1‐Ser241, Chk1, and Smad3. ²¹ Copy number alterations (gain) have been detected for PDPK1, MUC1, and NOTCH1 genes in brain‐tropic CTCs. ²² The transcription factor MYC is upregulated in breast cancer brain‐tropic CTCs and promotes the antioxidant enzyme GPX1 expression. MYC/GPX1 mitigate the oxidative stress elicited by activated microglia. ²⁰ A, astrocyte; BBB, blood‐brain barrier; BM, basement membrane; CTC, circulating tumor cell; EC, endothelial cell; EpCAM, epithelial cell adhesion molecule; P, pericyte