Neutral Sphingomyelinase 2 (nSMase2)-dependent Exosomal Transfer of Angiogenic MicroRNAs Regulate Cancer Cell Metastasis

By N. Kosaka, Haruhisa Iguchi, Keitaro Hagiwara, Y. Yoshioka, F. Takeshita, T. Ochiya. Journal of Biological Chemistry, 2013

692 citations recorded by the source corpus.

Background: Contribution of exosomal microRNAs to cancer metastasis remains unknown. Results: Exosomal angiogenic microRNAs secreted by metastatic cancer cells promote the metastasis through the activation of endothelial cells. Conclusion: Horizontal transfer of exosomal miRNAs from cancer cells can dictate the microenviromental niche for the benefit of the cancer cell. Significance: This is the first to connect cancer metastasis to the exosomal microRNA in vivo. The release of humoral factors between cancer cells and the microenvironmental cells is critical for metastasis; however, the roles of secreted miRNAs in non-cell autonomous cancer progression against microenvironmental cells remain largely unknown. Here, we demonstrate that the neutral sphyngomyelinase 2 (nSMase2) regulates exosomal microRNA (miRNA) secretion and promotes angiogenesis within the tumor microenvironment as well as metastasis. We demonstrate a requirement for nSMase2-mediated cancer cell exosomal miRNAs in the regulation of metastasis through the induction of angiogenesis in inoculated tumors. In addition, miR-210, released by metastatic cancer cells, was shown to transport to endothelial cells and suppress the expression of specific target genes, which resulted in enhanced angiogenesis. These findings suggest that the horizontal transfer of exosomal miRNAs from cancer cells can dictate the microenviromental niche for the benefit of the cancer cell, like “on demand system” for cancer cells.

Subfields: Biomedical Engineering, Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/0c6c4d7e7303f7367916525e8c7122ee319014ad

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In Cancer Research

1. Raghu Kalluri
2. Jan Lötvall
3. D. Hanahan

In Molecular Biology

1. Raghu Kalluri
2. Jan Lötvall
3. M. Nieto
4. R. Weinberg
5. D. Hanahan
6. Zena Werb
7. Youhua Liu

Citations in the corpus

• Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood–brain barrier (2015, positive): “To identify the influence of EVs on BBB during breast cancer metastasis, we employed MDA-MB-231-luc-D3H2LN cells (D3H2LN), which are human mammary tumour cells with a high tumorigenic and metastatic capacity 13,14 to produce a new brain high-metastatic cell line.”
• The Tumor Microenvironment: A Milieu Hindering and Obstructing Antitumor Immune Responses (2020, background): “Briefly, such functions include: (1) contribution to chemotherapy resistance via miR21 and miR-155 (198); (2) provoking angiogenesis in endothelial cells with miR-210 (199); (3) NK cell inhibition by miR-23a through targeting CD107a (184); (4) T cell elimination via miR-24-3p (200); (5) inducing pol”
• Cancer Exosomes Perform Cell-Independent MicroRNA Biogenesis and Promote Tumorigenesis. (2025, neutral): “Some reports show downregulation of miRNA targets in cells incubated with exosomes without a need for culture (Kosaka et al., 2013;Narayanan et al., 2013; Pegtel et al., 2010).”
• New horizons in tumor microenvironment biology: challenges and opportunities (2015, background): “Particularly, miR-210 is released from metastatic breast cancer cells via nSMase2dependent exosomal secretion, which once transported to endothelial cells can enhance cell migration and capillary formation, thereby enhancing angiogenesis and metastasis [95].”
• Exosome and Exosomal MicroRNA: Trafficking, Sorting, and Function (2015, background): “Formation and secretion of exosomes require enzymes [21,22] and ATP [23], and the miRNA and mRNA profiles of exosomes differ from those of the parent cells [24].”
• Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells (2014, background): “(18) showed that exosomes secreted from breast cancer cells drove endothelial cells to promote angiogenesis, enabling cancer metastasis.”
• The biology and function of exosomes in cancer. (2016, background): “Efforts to suppress horizontal transfer of miRs from cancer cells to ECs via exosomes attenuates angiogenesis and metastasis (91).”