Macroautophagy/autophagy is an evolutionarily conserved cellular stress response mechanism. Autophagy induction in the tumor microenvironment (stroma) has been shown to support
tumor metabolism. However,
cancer cell-derived secreted factors that initiate communication with surrounding cells and stimulate autophagy in the tumor microenvironment are not fully documented. We identified CTF1/CT-1 (
cardiotrophin 1) as an activator of autophagy in fibroblasts and
breast cancer-derived
carcinoma-associated fibroblasts (CAFs). We showed that CTF1 stimulated phosphorylation and nuclear translocation of STAT3, initiating transcriptional activation of key autophagy
proteins. Additionally, following CTF1 treatment, AMPK and ULK1 activation was observed. We provided evidence that autophagy was important for CTF1-dependent ACTA2/α-SMA accumulation, stress fiber formation and fibroblast activation. Moreover, promotion of
breast cancer cell migration and invasion by activated fibroblasts depended on CTF1 and autophagy. Analysis of the expression levels of CTF1 in patient-derived
breast cancer samples led us to establish a correlation between CTF1 expression and autophagy in the
tumor stroma. In line with our in vitro data on
cancer migration and invasion, higher levels of CTF1 expression in
breast tumors was significantly associated with
lymph node metastasis in patients. Therefore, CTF1 is an important mediator of
tumor-stroma interactions, fibroblast activation and
cancer metastasis, and autophagy plays a key role in all these
cancer-related events.Abbreviations: ACTA2/α-SMA: actin, alpha 2, smooth muscle CAFs:
cancer- or
carcinoma-associated fibroblasts CNT Ab.: control antibody
CNTF:
ciliary neurotrophic factor CTF1:
cardiotrophin 1 CTF1 Neut. Ab.: CTF1-specific
neutralizing antibody GFP-LC3 MEF: GFP-fused to MAP1LC3
protein transgenic MEF LIF:
leukemia inhibitory factor IL6:
interleukin 6 MEFs: mouse embryonic fibroblasts MEF-WT: wild-type MEFs OSM:
oncostatin M TGFB/TGFβ:
transforming growth factor beta.