Endothelial focal adhesion kinase mediates cancer cell homing to discrete regions of the lungs via E-selectin up-regulation

Abstract

Primary tumors secrete factors that alter the microenvironment of distant organs, rendering those organs as fertile soil for subsequent metastatic cancer cell colonization. Although the lungs are exposed to these factors ubiquitously, lung metastases usually develop as a series of discrete lesions. The underlining molecular mechanisms of the formation of these discrete lesions are not understood. Here we show that primary tumors induce formation of discrete foci of vascular hyperpermeability in premetastatic lungs. This is mediated by endothelial cell-focal adhesion kinase (FAK), which up-regulates E-selectin, leading to preferential homing of metastatic cancer cells to these foci. Suppression of endothelial-FAK or E-selectin activity attenuates the number of cancer cells homing to these foci. Thus, localized activation of endothelial FAK and E-selectin in the lung vasculature mediates the initial homing of metastatic cancer cells to specific foci in the lungs. metastasis | permeability

Systemic inflammation promotes lung metastasis via E-selectin upregulation in mouse breast cancer model

“…39 The detected E-selectin expression was concomitant to the upregulation of VCAM-1, indicating an inflammatory activation of the metastatic microenvironment. 40,41 This notion was further supported by the observed recruitment of inflammatory cells to metastatic tumor cells. 42 A similar inflammatory activation was also observed in the sinusoidal endothelial to the upregulation of E-selectin.…”

IL17A-Mediated Endothelial Breach Promotes Metastasis Formation

“…Selectins, which belong to the family of vascular adhesion molecules, mediate tumor cell interactions with the endothelium (23). Because epithelial and endothelial cells are the main targets of IL17A, we tested the impact of IL17A on E-selectin expression by injecting B16F10 cells i.v.…”

A stroma szerepe a tumorok kialakulásában és progressziójában

“…Egy kísérletben azt találták, hogy az elsődleges tumor által termelt verzikánnal aktivált makrofágok TNF-α-t szekretálnak, amely serkenti a tumorsejtek kolonizációját [46]. Egy másik esetben a premetasztatikus niche-ben található tüdőendothelsejtekben -az elsődle-ges tumorból származó VEGF hatására -a fokális adhé-ziós kináz (focal adhesion kinase -FAK) szintje megnö-vekedett és indukálta a tumorsejtek megtelepedését segítő E-kadherin expresszióját, azaz a stabil sejt-sejt kapcsolatok kialakulását [47].…”