Cancer Cells Send MicroRNA In Exosomes to Macrophages, Rewiring Them for Tumorigenesis

Researchers at the National Cancer Institute in Maryland pinpoint miR-1246, a micro RNA, as a potential therapeutic target in mutant p53 colorectal cancers.

Recent studies have identified exosomal signalling as a route for cancer cells to communicate with neighboring stromal and leukocytic cells[1]. The tumors evolve to release exosomes packed with proteins and functional RNA into the extracellular matrix. The nearby cells take up the exosomes as they release their contents into their cytoplasm. Like many oncogenic phenotypes, this is an exploitation of a normal, healthy activity whereby cells communicate the need for nutrition, presence of disease, etc with the rest of the body[2]. Cancer cells, however, can package their exosomes with tumor-supporting agents to aid in the process of angiogenesis, immune-suppression, and metastasis.

The researchers in this study have discovered one of these agents in colorectal cancer- miR-1246.

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When growing macrophages and mutant colorectal cell lines in a membrane-separated culture, they observed significant upregulation of IL10 and VEGF in the macrophages.

These cytokines are hallmark of tumor-supporting in macrophages and have been targets of therapy in the past. IL-10 is an anti-inflammatory and acts as an immunosuppressant to keep the body from detecting and killing the cancer cells[3]. While VEGF is the key player in angiogenesis- the formation of blood vessels- a process that cancer cells exploit and take over to fuel their nutritious needs while rapidly expanding. VEGF inhibitors like Avastin have already been approved for clinical use by the FDA[4], but there is always a need to find more therapeutic targets.

Using mass spectrometry and Western blotting on the exosomes yielded unique signatures in the mutant p53 cell line. Subsequent RNA extraction and profiling from clinical colorectal tumor samples were able to identify a number of micro RNA’s associated with the cancer cells, the most notable of them was miR-1246.

This microRNA, 73 base pairs in length[5], is an emerging agent in cancer studies. Recently it has been associated with liver and lung cancers [6,7]. Now, in this study, it is been not only identified in colon cancer, but exosomal signalling as well. The study shows that, after being taken up by the macrophages, the miR-1246 likely acts as a transcription factor, or upstream regulator of the tumorigenic proteins IL-10 and VEGF.

In addition to miR-1246, the researchers identified another therapeutic target, hnRNPa2b1- a sorting protein involved in packaging micro RNA into exosomes. RNA:Protein pull-down assays showed a coupling between the two agents.

The study explores the quick-evolving territory of targeting micro RNA’s and manipulating exosomes in cancer therapy. Being able to identify and knock out another route that cancer uses to thrive is key in implementing personalized medicine plans. Cancers vary wildly from patient to patient as they accumulate different mutations and exploit varying pathways to thrive. Identifying another tumorigenic agent means identifying another target for therapy. With high-throughput sequencing methods, profiling tumors and identifying targets will, In my opinion, be the future of cancer treatment.

References

  1. Soung YH, Ford S, Zhang V, Chung J. Exosomes in Cancer Diagnostics. Mok SC, ed. Cancers. 2017;9(1):8. doi:10.3390/cancers9010008.
  2. Kalyanaraman B. Teaching the basics of cancer metabolism: Developing antitumor strategies by exploiting the differences between normal and cancer cell metabolism. Redox Biology. 2017;12:833-842. doi:10.1016/j.redox.2017.04.018.
  3. Hyun-Jeong Ko, Seong-Ryeol Kim, Jae-Hyoung Song and Bo-Ra Lee. Interleukin-10 Attenuate Tumor Growth by Inhibiting Interleukin-6/Signal transducer and activator of transcription 3 Axis on Myeloid-Derived Suppressor Cells.
  4. Food and Drug Administration. FDA Approval for Bevacizumab. National Cancer Institute. Updated 2014.
  5. Gene [Database]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; [1988] –. Gene ID: 100302142, Homo sapiens MIR1246. Available from: https://www.ncbi.nlm.nih.gov/nuccore/NM_001349333.1.
  6. Chai S, et al. Octamer 4/microRNA-1246 signaling axis drives Wnt/β-catenin activation in liver cancer stem cells. American Association for the Study of Liver Diseases: Hepatology. 2016. doi:10.1002/hep.28821.
  7. Dexiao Yuan, et al. Extracellular miR-1246 promotes lung cancer cell proliferation and enhances radioresistance by directly targeting DR5. Oncotarget. 2016. doi:10.18632/oncotarget.9017.

Original Study

Tomer Cooks, Ioannis S. Pateras, Lisa M. Jenkins, Keval M. Patel, Ana I. Robles, James Morris, Tim Forshew, Ettore Appella, Vassilis G. Gorgoulis & Curtis C. Harris. Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246. Nature Communicationsvolume 9, Article number: 771 (2018) . doi:10.1038/s41467-018-03224-w

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