CHARACTERIZATION OF NOVEL FACTORS REGULATING ENDOTHELIAL BARRIER DURING METASTASIS
avoin
Julkaisu on tekijänoikeussäännösten alainen. Teosta voi lukea ja tulostaa henkilökohtaista käyttöä varten. Käyttö kaupallisiin tarkoituksiin on kielletty.
Lataukset263
Pysyvä osoite
Verkkojulkaisu
DOI
Tiivistelmä
Progressive, metastatic cancer is a leading cause of cancer-related deaths worldwide. One of the critical
steps of the metastatic cascade is the colonization of circulating tumor cells in the distant tissues, where
cancer cells cross the blood vessel wall to initiate metastatic growth in the distant organs. Vascular
endothelium acts as a gatekeeper between circulating tumor cells and metastatic organs. However, the
role of endothelial cells in the regulation of cancer cell fate in the metastatic niche is poorly understood.
Here, we show that endothelial Pim-3 kinase regulates the endothelial barrier integrity during early steps
of cancer cell colonization of the lungs. Single cell mRNA sequencing of the metastatic B16-F10 murine
melanoma model revealed that Pim3 was upregulated in the lung endothelial cells six hours after arrival
of the melanoma cells in the lungs. Upregulation of Pim3 was further validated in spontaneous
metastasis models. Further studies showed that administration of a pan-Pim kinase inhibitor AZD-1208
in mice increased melanoma metastasis and leakage in the murine lungs. In cultured human endothelial
cells AZD1208 decreased Cadherin 5 based cell-cell junctions and increased endothelial cell
permeability in an electrical cell impedance sensing assay. Similar Cadherin 5 reduction was seen in
PIM3 silenced endothelial cells.
Pim3 is a well-known oncogene and Pim inhibitors have been investigated as cancer therapies in recent
years. However, the inhibitors did not provide the expected outcomes, and currently clinical trials have
been attired. Therefore, whereas targeting Pim kinases is known to decrease tumor cell survival, results
from this work suggest that Pim inhibitors may simultaneously weaken the vascular barrier. Thus, the
results presented in this thesis reveal a potential mechanism behind unsuccessful Pim inhibitor cancer
trials. Notably, the results also call for a better understanding of the effects of cancer therapies on the
host cells of the tumor microenvironment.