Abstract
Cross talk, mediated by exosomes, between normal stem cells and cancer stem cells (CSCs) in the tumor microenvironment has been given less attention so far. In addition, no publications are available in the literature that address the in vivo impact of exosomes derived from CSCs and mesenchymal stem cells (MSCs) on progression of long-term hepatocellular carcinoma (HCC). Herein, we hypothesized that transfer of exosomes among the cells in the HCC microenvironment could either induce or inhibit tumor growth and metastasis depending on their source. To check this hypothesis, we investigated the effect of exosomes coming from two different stem cell populations, hepatic CSCs and bone marrow (BM) MSCs, on progression of long-term DEN-induced HCC in rats and the involved underlying mechanisms. CSCs-exosomes induced a significant increase in liver relative weight and serum levels of cancer markers (AFP and GGT) and liver enzymes (ALT, AST, and ALP), intensive immunostaining for the HCC marker GST-P, and an increased number and area of tumor nodules as compared to HCC rats injected by PBS. CSCs-exosomes also decreased apoptosis (marked by downregulation of Bax and p53 and upregulation of Bcl2, and increased immunostaining of PCNA), increased angiogenetic activity (revealed by upregulation of VEGF), enhanced metastasis and invasiveness (indicated by upregulation of P13K and ERK proteins and their downstream target MMP9 and downregulation of TIMP1), and induced epithelial mesenchymal transition (marked by increased serum and hepatic level of TGFβ1 mRNA and protein). Notably, CSCs-exosomes also elevated HCC exosomal microRNA (miR) 21, exosomal long noncoding (lnc) RNA Tuc339, lncHEIH, and the HCC lncHOTAIR and decreased liver miR122 and HCC miRs (miR148a, miR16, and miR125b). All these cellular, functional, and molecular changes were reversed following injection of BM-MSCs-exosomes. However, both CSCs- and MSCs-exosomes failed to change the elevated oxidative stress or the inhibited antioxidant activities induced by HCC. Collectively, our results revealed a tumor stimulatory effect (induction of tumor growth, progression, and metastasis) for exosomes derived from CSCs and an inhibitory effect for exosomes derived from MSCs. These results provide valuable insight on the effect of CSCs- and MSCs-exosomes on HCC growth and progression in vivo, which may be helpful to understand the mechanism of HCC development.
Highlights
Hepatocellular carcinoma (HCC) is a primary malignancy of hepatocyte and the third most frequent cause of cancerrelated death globally
The stemness of isolated cancer stem cells (CSCs) and bone marrow (BM)-mesenchymal stem cells (MSCs) was confirmed by RT-PCR detection of the two stem cell genes Nanog (120 bp) and Oct-3/4 (165 bp, Figure 1(g))
The obtained data demonstrate that CSCs- and MSCsexosomes remarkably induce and inhibit, respectively, tumor development and progression in vivo
Summary
Hepatocellular carcinoma (HCC) is a primary malignancy of hepatocyte and the third most frequent cause of cancerrelated death globally. Liver-derived exosomes play an important role in intercellular communication through assuring horizontal transfer of their nucleic acid (i.e., mRNA, micro RNA (miR), long noncoding RNA (lncRNA) molecules, and circulating DNA) and protein cargoes between different cell types in liver (reviewed by [3]). Interaction between HCC exosomal cargo and tumor microenvironment participates in tumor progression, metastasis, and chemotherapy resistance mainly through induction of immunosuppression and angiogenesis [9, 10]. The majority of these exosomal cargoes (i.e., miR18a, miR21, miR221, lncVLDLR, and lncTUC339) are enriched in HCC, with only few miRs (i.e., miR718) exhibiting a notable downregulation in HCC [11, 12]. The majority of these exosomal cargoes (i.e., miR18a, miR21, miR221, lncVLDLR, and lncTUC339) are enriched in HCC, with only few miRs (i.e., miR718) exhibiting a notable downregulation in HCC [11, 12]. lncVLDLR mediates the resistance to chemotherapeutic drugs in HCC cells [13, 14], while lncTUC339 and lncHEIH were implicated in onset and progression of HCC [12, 15]
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