Intratumoral stages of metastatic cells: a synthesis of ontogeny, Rho/Rac GTPases, epithelial-mesenchymal transitions, and more.

Metastasis is one of the clinical parameters that has a strong negative influence on the prognosis of cancer patients. In recent years, significant advances have furthered our understanding of this process at the molecular and biological levels. This paper will discuss recent discoveries relating to the earliest, intra-tumoral stages of metastasis in cancer cells, specifically focusing on: (i) the development of metastatic traits during primary tumorigenesis; (ii) intrinsic and extrinsic cancer cell programs associated with malignant traits; (iii) the intra-tumoral migration patterns of cancer cells and the dynamic roles played by the Rho/Rac GTPases and epithelial-mesenchymal transitions in this process; and (iv) the genetic strategies used by metastatic cancer cells to promote intra-tumoral cell migration and their subsequent escape to peripheral tissues. Finally, the therapeutic and diagnostic relevance of this information will be discussed, as well as potential future developments.