Messengers at the junction of inflammation and cancer: exosomes

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The more we learn about exosomes, the more we realize just how powerful they are in cancer. As agents of cell-to-cell communication, exosomes play important roles in tumorigenesis, cancer progression, and metastasis. One of the most interesting areas in which exosomes are exerting their influence is at the interface of cancer and another key process known to influence its progression – inflammation and immunity.

Exosomes in cancer – in the thick of things, from start to finish

The roles of exosomes in cancer start with transformation and continue all the way through metastasis. Exosomes from a tumor cell can convert normal cells into malignant ones; for example, prostate cancer cell-derived exosomes carrying oncogenic proteins, mRNA, and various microRNAs (miR-125b, miR-130b and miR-155) can cause transformation in adipose-derived stem cells. Cancer cells can also use exosomes to resist apoptosis; for example, by taking up exosomes that carry survivin, an anti-apoptotic protein (1). In addition, cancer cell-derived exosomes can influence surrounding cells to secrete factors to enhance the cancer’s growth, such as in the case of chronic myelogenous leukemia (1). Metastasis can also be enhanced by exosomes; for example, the downregulation of the tight junction protein ZO-1 in endothelial cells after taking up miR-105 from cancer cell-derived exosomes (2).

Exosomes as links between inflammation and cancer

Inflammation and immunosuppression are well known to be involved in cancer progression. As research into extracellular vesicles progresses, it’s becoming clear that parts of these interactions are mediated by exosomes. For example, tumor-derived exosomes influence myeloid cell differentiation. Some studies have shown prevention of differentiation into dendritic cells, and others have shown that they influence myeloid differentiation toward myeloid-derived suppressor cells (MDSCs) via prostaglandin E2 (PGE2), TGF-beta, miRNAs and Hsp72 (1, 3).

In addition to affecting myeloid differentiation, the contents of exosomes derived from cancer cells are also adept at manipulating or suppressing T cells. For example, extracellular vesicles from tumor cells show high levels of molecules that lead to T-cell apoptosis, like CD95, TRAIL and galectin 9 (3). Additionally, exosomes derived from nasopharyngeal carcinoma cells recruit and expand regulatory T cells, inhibit Th1 and Th17 differentiation, and overexpress microRNAs affecting cell differentiation and proliferation (1). Moreover, exosomes derived from prostate cancer cells express NKG2D ligands and downregulate NKG2D NK cells and CD8+ T cells, reducing their cytotoxicity (1).

Intriguingly, microRNA contents in exosomes from tumor cells also assume a unique function related to immunity. MicroRNAs are typically associated with gene expression regulation, but when miR-21 and miR-29a are present in tumor-derived exosomes, they can bind to Toll-like receptors (specifically TLR7 and TLR8) (4). The immune cells bearing the TLRs secrete proinflammatory cytokines via NFkappaB activation, modulating the tumor microenvironment (4).

How can you determine what your exosomes are carrying, and how they might be affecting your disease of interest? Exosome purification has moved beyond ultracentrifugation; today’s isolation is fast and consistent, using membrane affinity spin columns for efficient isolation from serum, plasma, or cell culture supernatant. If you’re interested in the mRNA and miRNA contents specifically, you can integrate total RNA isolation with exosome purification as well. Find out how!

After exosome purification and RNA extraction, sequencing the contents using QIAseq Unique Molecular Index technology can ensure that you get the most accurate results. Check out our post on molecular barcoding to learn more, and then take a look at the QIAseq solutions for targeted RNA sequencing and microRNA-specific library construction!

 

References

  1. 1. Zhang, X., Yuan, X., Shi, H., Wu, L., Qian, H., Xu, W. (2015) Exosomes in cancer: small particle, big player. J. Hematol. Oncol. doi:10.1186/s13045-015-0181-x Link
  2. 2. Kalluri, R. (2016) The biology and function of exosomes in cancer. J. Clin. Invest. 126, 1208–1215. Link
  3. 3. Robbins, P.D. and Morelli, A.E. (2014) Regulation of immune responses by extracellular vesicles. Nat. Rev. Immunol. 14, 195–208. Link
  4. 4. Aleckovic, M. and Yang, Y. (2015) Regulation of cancer metastasis by cell-free miRNAs. Biochimica et Biophysica Acta 1855, 24–42. Link

 

Disclaimer

The QIAGEN products mentioned here are for molecular biology use only. They are not intended for the diagnosis, prevention or treatment of a disease.

Ali Bierly

Ali Bierly, PhD is a Global Market Manager in Translational Sciences at QIAGEN, and has written on a number of scientific topics in the biotech industry as the author of QIAGEN's Reviews Online. She received her PhD from Cornell University in 2009, studying the immune response to a protozoan parasite, Toxoplasma gondii. Ali has a keen interest in the emerging importance of microRNA and other circulating nucleic acids as biomarkers for disease.

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