Skip to the end: metastasis before tumorigenesis

Abstract

Mutations in the sodium channel NALCN promote epithelial cell shedding and dissemination independent of oncogenic transformation. This observation suggests that metastasis may not uniformly represent the end stage of carcinogenesis but can occur before oncogenic transformation.

Fig. 1 |. An alternative model of metastasis.

The metastatic cascade classically follows oncogenic transformation (black arrows). Normal epithelium first becomes hyperproliferative epithelium, then adenoma, followed by frank carcinoma. Metastasis, the final stage of this process, is characterized by epithelial–mesenchymal transition (EMT) and dissemination to distant anatomic sites, where these circulating tumor cells grow to form metastatic tumors. NALCN mutations enable normal epithelial cells to proceed directly to EMT and hematogenous dissemination (blue arrows), seeding distant anatomic sites where these circulating non-transformed cells incorporate into normal-appearing components of the target organ.