Dr. Raghu Kalluri speaks with Cancer Network about the role of exosomes in cancer progression ahead of his presentation at ESMO 2018.
As part of our coverage of the 2018 annual European Society for Medical Oncology (ESMO), being held October 19–23 in Munich, we are speaking with Dr. Raghu Kalluri, MD, PhD, and chairman of the department of cancer biology at the University of Texas MD Anderson Cancer Center in Houston about exosomes in cancer progression and metastasis. On October 19, Kalluri will be giving a talk entitled "Extracellular Vesicles and Exosomes in Cancer."
-Interviewed by Anna Azvolinsky
Cancer Network: First, Dr. Kalluri, what are exosomes?
Dr. Kalluri: Thank you very much for the opportunity. Exosomes are small vesicles that are released by cells. Pretty much every cell in the human body releases exosomes and they are an average of 100 nanometer in size and have a lipid bilayer and have proteins on their surface and also on their inside. They also contain DNA, RNA and microRNAs. They are small vesicles that come out of every cell in large numbers.
Cancer Network: On a high-level, what do we know about the biology of exosomes in cancer development and progression?
Dr. Kalluri: It turns out that virtually every cell in the human body produces exosomes and no one really understands what makes cells produce exosomes. There are some ideas that certain pathways are involved in the generation of exosomes, potentially to take away certain proteins or other cell constituents that are in excess. But, they may strategically be putting out certain cell constituents that the cell doesn’t need or would like to transport outside of the cell. It turns out that in cancer cells, this production of exosomes is even higher than in non-cancerous cells. This is likely because of the higher metabolic status of cancer cells. They generate exosomes at higher levels and carry information that people are now evaluating carefully and finding that these vesicles may carry oncogenic information or information for inducing other tissues to accept metastatic cells to produce secondary tumors in those tissues.
Right now the field is very young. I would say that the field is as young as the field of immunology was in the 1960s. There are many things that we need to learn about the biology of exosomes, why they are made by cells, how they are made, and why they contain certain molecules.
In recent years, there have been exciting developments to show that exosomes from cancer patients, especially exosomes in the [blood] circulation of these patients could be used as diagnostics and in fact, that exosomes can be engineered to carry certain drugs that might help control tumor growth.
These early studies are providing examples of ways to exploit the biology of exosomes to help diagnose cancer, but also using exosomes on the applied side, to engineer them to carry drugs that might target tumors.
Cancer Network: Your lab studies the potential role of exosomes in cancer. Could you highlight recent results from your lab that to your mind are particularly important and/or surprising as far as cancer development and/or progression?
Dr. Kalluri: We’ve been trying to understand what exosomes contain when they come out of cancer cells compared to the exosomes that come out of normal cells. In that process, we discovered that exosomes contain double-stranded DNA along with RNA and microRNA and in fact, we found that the exosomes coming from cancer cells have a unique set of microRNAs that are oncogenic in nature compared to the exosomes coming from normal cells. That, I think is a pretty exciting finding and we think that these exosomes can actually regulate cancer progression rates and how metastasis evolves.
More importantly, we have developed methods to isolate exosomes and show that exosomes can contain certain proteins on their surface and inside of these vesicles that enable us to tell that these exosomes are coming from cancer cells vs normal cells. This allows us to pull these exosomes from the blood of an individual, including from cancer patients, and ask the question, ‘what do these exosomes contain that can tell us about the nature of the cancer, the level of aggression or stage of the cancer, or if the cancer is metastasizing?’
With respect to exosomes, there is another feature that is very exciting from our laboratory studies and that is that exosomes are able to enter other cells pretty efficiently. If you add exosomes to cells, the cells will take them up well. We exploited that feature and engineered exosomes to carry drugs against oncogenes including Ras, which has been very difficult to target otherwise.
We showed that by using small interfering RNAs and other means to target Ras, we can deliver these Ras-targeting RNAs to tumor-containing pancreas of mice and show significant control of cancer in these mouse models. These results will hopefully lead to additional studies and ultimately to clinical studies in patients, that could start in the next several months.
Cancer Network: You mentioned that it is still early days for exosome, but what role do you see exosomes playing in cancer therapy? Are there clinical trials that are already ongoing with exosome-based therapies that you could highlight?
Dr. Kalluri: There are no clinical trials at the moment, but I would definitely predict that within the next year to year and a half there will be new clinical trials in the area of exosomes and cancer. There is a trial that MD Anderson has put together that I am not involved in that has taken some of our findings into clinical trials and the protocol for the trial is now listed on clinicaltrials.gov.
The trial aims to use exosomes to treat patients with oncogenic K-Ras mutations. These laboratory studies are leading to potential clinical trials and I predict that in the next year or so, there will be several trials initiated, looking at the potential of exosomes to treat cancer patients.
Cancer Network: Thank you so much for joining us today Dr. Kalluri.
Dr. Kalluri: Thank you so much for the opportunity to speak to you.
Disclosure: Dr. Raghu Kalluri is the scientific co-founder and is on the board of directors of Codiak Biosciences and holds equity stock in Codiak Biosciences and receives research support from codiak biosceinces.