| Abstract |
Cholangiocarcinoma (CCA), the cancer arising from the epithelial cells of bile ducts, is a prototype of inflammatory-
driven cancer. Cytokines released by cancer associated fibroblasts (CAFs) play a pivotal role in CCA
progression, driving the epigenetic Epithelial-to-Mesenchymal transition and the growth and metastasization of
CCA cells. Consistently, the conditioned medium from CCA-derived CAFs further stimulated the secretion of IL-6,
and to a lesser extent of IL-8, by CCA cells. CCA has a poor prognosis, because of late diagnosis and of high
resistance to radio- and chemo-therapy of CCA cells. Targeting the CAFs and their secretion could be an alternative
option. We found that while IL-6 indeed promoted the cell migration of invasive CCA cells, the nutraceutical
Resveratrol strongly counteracted this effect both in CCA cells and in immortalized cholangiocytes.
More importantly, here we show that Resveratrol has the potential to abrogate the secretion of IL-6 by CAFs.
While the conditioned medium from CAFs strongly induced IL-6 mediated motility of CCA cells, the conditioned
medium from CAFs pre-treated with Resveratrol completely halted cancer cell motility and reverted the N-to Ecadherin
switch in migrating cells. This effect was associated with stimulation of autophagy in the cancer cells.
This is the first demonstration that CAFs secretory products directly affect the regulation of autophagy and
consequently the behavior of CCA cells, and that a nutraceutical may revert the malignant phenotype of cancer
cells by acting on CAFs metabolism and secretion. |
Publication
Journal Publication
ไทย