article · Stem Cells International
This in vivo study investigated the effects of exosomes derived from hepatic cancer stem cells and bone marrow mesenchymal stem cells on long-term hepatocellular carcinoma progression in rats. Exosomes from cancer stem cells actively promoted tumour growth, invasion, metastasis, and angiogenesis while suppressing programmed cell death. They also elevated cancer markers, liver enzymes, and specific non-coding RNAs, alongside inducing epithelial-mesenchymal transition. In contrast, exosomes derived from bone marrow mesenchymal stem cells counteracted and reversed these cellular and molecular alterations, demonstrating a tumour-inhibitory role. However, neither exosome type altered the elevated oxidative stress or suppressed antioxidant levels caused by the carcinoma. These findings clarify the distinct regulatory functions of stem cell-derived exosomes within the liver cancer microenvironment.
Hepatocellular carcinoma is a major form of liver cancer with complex progression mechanisms. Understanding how different types of stem cells communicate within tumours through exosomes highlights potential biological targets. Demonstrating that bone marrow stem cell exosomes can reverse tumour growth while cancer stem cell exosomes accelerate it offers critical insights into the molecular processes driving liver tumour progression and suppression.
This early-stage animal research indicates potential therapeutic targets and cellular tools for biotechnology and pharmaceutical developers focusing on liver cancer therapies. Bone marrow mesenchymal stem cell exosomes could inform future biologic drug or therapeutic candidate development, while cancer stem cell exosomes offer markers for monitoring progression. However, as this work is limited to preclinical rat models, it remains far from clinical or commercial use.
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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 <i>in vivo</i> 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 <i>Bax</i> and <i>p53</i> and upregulation of <i>Bcl2</i>, and increased immunostaining of PCNA), increased angiogenetic activity (revealed by upregulation of <i>VEGF</i>), enhanced metastasis and invasiveness (indicated by upregulation of P13K and ERK proteins and their downstream target <i>MMP9</i> and downregulation of <i>TIMP1</i>), and induced epithelial mesenchymal transition (marked by increased serum and hepatic level of TGF<i>β</i>1 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 <i>in vivo</i>, which may be helpful to understand the mechanism of HCC development.
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DOI: 10.1155/2018/8058979
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