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Monday, April 3, 2017

EGFL6 Contributes to Ovarian Cancer Proliferation & Metastases

By Heather Lindsey​

The protein EGFL6 helps ALDH-positive ovarian cancer stem cells to proliferate and metastasize, according to new research (Cancer Res 2016;76(21):6396-6409). Blocking the growth factor with an antibody may slow cancer growth and stop it from metastasizing.

The study findings could lead to new treatments for ovarian cancer, as well as prevention strategies for women at high risk of developing the disease, said senior study author Ronald J. Buckanovich, MD, PhD, Professor of Hematology/Oncology and Gynecologic Oncology at the University of Michigan Medical School, Ann Arbor.

There is a lot of interest in the role of stem cells or cancer stem-like cells in the development and progression of cancer, commented Aprana Kamat, MD, gynecologic oncologist at Houston Methodist Hospital. The results of this paper indicate that EGFL6 is "a novel factor that promotes growth and metastasis of ovarian cancer cells and may be an important target for future therapeutic development."

Proliferation & Metastasis

"The EGFL6 protein is interesting because it is made by blood vessels in tumors and, in some cases, the cancer cells themselves," said Buckanovich. "The proteins tell cancer stem cells specifically how they should divide." Cancer stem-like cells are unique because they can replicate to make more of themselves, or they can differentiate and produce distinctive progeny, he said, adding that these new daughter cells proliferate and help the tumor grow faster.

The protein also tells ALDH-positive ovarian cancer stem-like cells to migrate. Because the protein is made by blood vessels, it can signal a cancer stem-like cell to travel to the vessel, where it can then proliferate and initiate a new metastatic site, explained Buckanovich. "One of our big findings is that EGFL6 tells cancer stem cells to metastasize, which is a huge problem in ovarian cancer."

EGFL6, which is normally made in the ovary and is probably critical for ovarian development, may also encourage cancer cells to migrate out of a blood vessel and into tissue. How and why ovarian cancer probably starts in the fallopian tube and then metastasizes to the ovary is unclear; however, ovarian production of EGFL6 may play a role, Buckanovich explained. 

Study Details

For their study, Buckanovich and his colleagues expressed EGFL6 in ovarian cancer cell lines and in mouse models and found this stimulated cancer to proliferate 2-3 times faster. When researchers eliminated EGFL6, tumors grew approximately four times more slowly. 

When the researchers used microfluidic chambers to examine how individual cells behaved, they discovered EGFL6 causes the ovarian cancer stem cells to divide asymmetrically, promoting tumor growth and cancer cell diversity. The researchers also demonstrated that EGFL6 promotes cancer stem cell migration. 

In mouse models treated with an EGFL6-blocking antibody, the investigators observed a 35 percent reduction in ovarian cancer stem cells and significant reduction of tumor growth overall. 

In addition, when EGFL6 was added to blood vessels, the cancer was more likely to metastasize. Conversely, when researchers took ovarian cancer stem cells and put them into the blood vessels of a mouse and then blocked EGFL6 with an antibody, these cells did not metastasize to the ovary. 

A Step Forward in Cancer Stem Cell Theory

"The potential of this research is huge," said Steve Vasilev MD, gynecologic oncologist and Medical Director of Integrative Gynecologic Oncology at Providence Saint John's Health Center and Professor at John Wayne Cancer Institute in Santa Monica, Calif.

One of the many approaches being studied to treat cancer is to target circulating cancer stem cells. While cancer stem cell theory applies across all cancer types, ovarian cancer hasn't been one of the types at the forefront of current research, he added.

Although highly plausible, "cancer stem cell theory isn't 100 percent proven in ovarian cancer, as with any cancer," said Vasilev. However, the theory could help explain why ovarian cancer recurs after years of quiescence. Stem cells can remain dormant because of favorable local micro-environmental and signaling factors. "If and when this environment changes, they can start dividing once again, leading to tumor regrowth and metastases," he noted.

Potential Treatment & Prevention

Overall, targeting cancer stem cells may be a way to complement treatment focused on eradicating rapidly dividing cells, said Vasilev. Perhaps of more importance is that this strategy has major preventative implications as well. 

Ovarian cancer patients often present with widely metastatic disease, noted Buckanovich, adding that, "as we treat them, their cancer continues to metastasize." However, the EGFL6-neutralizing antibody could slow the spread of cancer and potentially impact survival and quality of life.

In women with a high risk of developing ovarian cancer, such as those with BRCA mutations, and who choose to leave their ovaries because they are poor surgical candidates or for hormonal reasons, the antibody may help block the spread of early cancer, said Buckanovich.

"We could prevent the cancer from presenting at stage III or IV and may be able to treat it when it's found in the fallopian tube and surgically curable," he explained. Once the cancer spreads to the ovary, it's more likely to scatter across the abdominal cavity.

Further Research

The next step in Buckanovich's research is to humanize the EGFL6-neutralizing antibody. "We'll take the mouse antibodies and swap in human antibody chains to get rid of as much of the mouse component as possible while still keeping them active," he explained. 

While the study results are encouraging, this approach needs to be further validated in an orthotopic animal model before considering human trials, said Kamat.

EGFL6 is "one particular target out of many different approaches," noted Vasilev. While this growth factor is worthy of attention, it may take more than 10 years for it to go from bench to bedside, considering the current FDA approval process.​

Heather Lindsey is a contributing writer.