Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer

Abstract

The communication between tumor-derived elements and stroma in the metastatic niche has a critical role in facilitating cancer metastasis. Yet, the mechanisms tumor cells use to control metastatic niche formation are not fully understood. Here we report that in the lung metastatic niche, high-metastatic hepatocellular carcinoma (HCC) cells exhibit a greater capacity to convert normal fibroblasts to cancer-associated fibroblasts (CAFs) than low-metastatic HCC cells. We show high-metastatic HCC cells secrete exosomal miR-1247-3p that directly targets B4GALT3, leading to activation of β1-integrin–NF-κB signaling in fibroblasts. Activated CAFs further promote cancer progression by secreting pro-inflammatory cytokines, including IL-6 and IL-8. Clinical data show high serum exosomal miR-1247-3p levels correlate with lung metastasis in HCC patients. These results demonstrate intercellular crosstalk between tumor cells and fibroblasts is mediated by tumor-derived exosomes that control lung metastasis of HCC, providing potential targets for prevention and treatment of cancer metastasis.

Exosome-based liquid biopsy in the management of hepatocellular carcinoma

“…Another study found decreased expression of serum exosomal miR-638 in HCC patients [41] . High miR-1247-3p in serum exosomal levels correlated with lung metastasis, poor overall survival and poor disease-free survival in HCC patients [19] .…”

“…However, depending on the starting material and downstream applications, other methods for the purification and enrichment of HCC-derived exosomes have also been used such as ultrafiltration, size exclusion chromatography (SEC) or the ExoQuick TC method [19,29] . Majority of HCC-derived exosomes have been identified by a combination of different methods including, round or cup shaped morphology by transmission electron microscopy, size of 50-100 nm in diameter by nanoparticle tracking analysis and exosomal surface profiling for markers such the tetraspanins (CD9, CD63, and CD81), heat shock proteins (HSP90 and HSP60), Alix and Tsg101 by immunoblot and flow cytometry [19,20,[29][30][31][32] . Studies have demonstrated high expression of glypican-3 (GPC-3) and AFP, traditional markers of HCC, within the HCC-derived exosomes, thereby confirming the hepatoma-based origin of these exosomes [31] .…”

“…Third, they are distinguishable by their size and morphology (cup-shaped appearance) through electron microscopy. Moreover, exosome surface profiling through flow cytometry and ELISAs allow classification of these subcellular vesicles to an extent [19] . Fourth, many detection and isolation techniques have been developed for exosomes in research and therapy.…”

“…MC-derived exosomes showed increased expression of miR-490 and the transfection of HepG2 and Hep3B cells with these exosomes inhibited migration and invasion in both the HCC cell lines [29] . Exosomes derived from high-metastatic cancer cells contribute to fibroblast activation to foster lung metastasis of liver cancer via transfer of miR-1247-3p [19] .…”

“…Notably, combined treatment with sorafenib and exosomes derived from highly invasive hepatoma cells resulted in the formation of larger tumours in mice than those in mice treated with sorafenib alone or sorafenib plus exosomes derived from less invasive cells [60] . After treatment with conditioned media collected from fibroblasts pre-treated by exosomes derived from high-metastatic cancer, tumour cells showed increased spheroid formation ability, motility, and resistance ability to sorafenib [19] . Thus, exosomes can modulate chemoresistance in recipient cells that incorporate these exosomes.…”