MicroRNAs - The New Front-Runner in Cancer Research

What if you could take one simple blood test to detect cancer in your body?

Chief Investigators Dominik M. Duelli,PhD1 and Heidi C. Memmel, MD, FACS,2 along with Research Associate Jaime Palma3 are conducting studies that hold great promise of making that a reality in our near future. This particular collaboration focuses on identifying women at high risk of breast cancer and aims to develop a method that is non-invasive and sensitive for early detection.

For a long time, it was thought that signaling molecules called microRNAs played no significant role in molecular biology. They were tossed aside as ‘junk’, but it turns out that they actually do have a very important function and may indeed represent a valuable surrogate biomarker of disease or other processes in the body.

Our cells produce small vesicles called microvesicles which are found in all of our body fluids such as: blood, urine, saliva and tears. They carry a signaling molecule, microRNA, which reflects the health or pathology of the cell’s origin. Some researchers are just starting to appreciate that microRNAs play a role in systemic cell communication while others are merely winking at the idea as further investigation is still required.

According to Duelli, microvesicles cruise through your bloodstream or any kind of body fluid and release microRNAs from one cell to another to either: deliver a message, kill or induce cells to grow. Duelli and his team have observed that microvesicles of a healthy cell look completely different than microvesicles of a cancerous cell.

Duelli says: “A cell’s ‘plumbing’ or ‘shipping mechanism’ completely changes as it becomes cancerous releasing custom-made microvesicles that don’t exist in normal cells.

This discovery is significant because it may give clues to the presence of cancerous cells in the body. Palma explains: “Cancer cells produce a certain kind of microvesicle which has different surface proteins than a microvesicle released from healthy cells. We can use specific antibodies to proteins not found on the surface of microvesicles from healthy cells and ‘fish’ them out.”

Duelli’s lab is now trying to figure out how microvesicles of cancer cells communicate differently. Do they convey different signals, ‘talk’ to microvesicles from healthy cells or not? Understanding more about their behavior could explain why chemotherapy sometimes works and sometimes doesn’t.  He explains that microvesicles can shut down the immune system allowing cancer cells to grow. From the primary cancer site, microvesicles can migrate to the lymph nodes and perform angiogenesis, the creation of new blood vessels, and the microRNAs may provide signaling pathways for other cancer cells to feast on the supply of nutrients. Additionally, microvesicles can move into the bone marrow and educate bone marrow cells into changing their function so when cancer cells leave the primary site and arrive, they now have a prosperous place to grow.

Knowing that microRNAs are produced in the cell and then packaged into microvesicles as cargo which get launched through body fluids, Duelli suggested looking at microRNAs in the blood released by a primary breast tumor to get a better indication of what is in the tumor. If there are increased levels of microRNA in the breast tumor than there is a strong likelihood that there would be a correlation of microRNAs selectively released from the cancerous cell giving indication to the genetic make-up of the tumor. 

In cases where you can’t find the tumor, examining the specific attributes of the microvesicles released could possibly give you an indication of the tumor’s location and confirmation whether it is benign or malignant. Duelli’s team hypothesizes that microRNA levels in a primary breast tumor may give indication as to whether it will metastasize or be responsive to chemotherapies, because chemotherapy dramatically changes the microvesicle of a cancer cell that responds.

Exhibit A reveals microvesicles taken from breast cancer cells and includes microvesicles with potential diagnostic and prognostic potential.

Exhibit B reveals microvesicles that are exported from a breast cancer cell. The outline of the cell is a metastatic breast cancer cell. The nucleus, in turquoise, contains the blueprint of our genome in chromosomes.

Duelli explains: “Those green dots are the microvesicles at the surface of the cell as they are in process of lifting off into the surrounding like escape pods from a starship, dandelion seed, or the like.”

He continues: “The microvesicles are green because they are bound by antibodies (that are tethered with a fluorescent dye) that we are developing that specifically bind breast cancer microvesicles. We needed them to glow in the dark in order to detect them.”

Duelli and his team intend to use these antibodies “like bait to fish out breast-cancer specific microvesicles from the blood.” If they didn’t use antibodies, it would be challenging to find them in the sea of plasma, full of benign and possibly irrelevant microvesicles found in our body fluids.

Dr. Memmel will be gathering blood and tissue samples from a sample of forty patients diagnosed with breast cancer for Duelli’s research team and follow the patients through treatment, examining how the tumor markers change over treatment and if the change correlates with the amount of remaining tumor.

Memmel says: “If we truly develop this biomarker to be very accurate, it hopefully will be able to predict if there’s any residual disease in the rest of the body once the primary breast tumor has been removed. Then, we would like to watch this tumor marker over a person’s treatment to see if chemotherapy has been effective. If the tumor marker disappears, indicating that there are no circulating malignant cells, we could conclude that the treatment would have been effective, and potentially curative.”

Duelli adds: “It is our hope that we can learn more about the breast cancer cell from which they came. This could be especially useful to check if a woman treated for breast cancer is truly cancer-free.”

He continues: “We are also testing if we can use these antibodies to prevent the dissemination of breast cancer microvesicles, and in so doing prevent breast cancer microvesicles from suppressing the immune system, or preparing the bone and other organs to produce a friendly environment for breast cancer cells to migrate to and re-grow and establish a metastasis.”

Memmel states: “We’re moving away from treating breast cancer by tumor size, and now targeting treatment to the biology of the tumor.” 

She concludes: “We’ve made so many advancements in breast cancer treatment and diagnosis that hopefully we are on our way to prevention and cure.

On October 9th, 2012 Dr. Dominik M. Duelli, an American Cancer Society Funded Researcher 2011, will be speaking at an American Cancer Society invite-only luncheon at Lovells of Lake Forest.

Dr. Heidi C. Memmel also serves on the regional board of the American Cancer Society.

1) Dominik M. Duelli, PhD, Assistant Professor of Pathology and Chief Investigator, Duelli Lab; Department of Cellular and Molecular Pharmacology of Chicago Medical School at Rosalind Franklin University of Medicine and Science

2) Heidi C. Memmel, MD, FACS, Surgical Director; Caldwell Breast Center at Advocate Lutheran General Hospital, Assistant Clinical Professor Surgery; University of Illinois-Chicago, Lecturer; Department of Surgery, Rosalind Franklin University, Co-Chief Investigator with Duelli’s Lab,  

3) Jaime Palma, Research Associate, Duelli Lab; Cellular and Molecular Pharmacology at Rosalind Franklin University of Medicine and Science