Dr. Ronald J. Buckanovich, professor of hematology/oncology and gynecologic oncology at the University of Michigan Medical School, and his colleagues have identified a protein that help ovarian cancer cells multiply and spread to other organs. When he and his coworkers inhibited this protein with an antibody they were able to stop the spread of ovarian cancer cold.
The EGFL6 or epidermal growth factor like 6 precursor protein, which is also known as MAEG, maps to human Xp22 chromosome. The EGFL6 protein is expressed primarily in fetal tissues and during early development (see Yeung G., et al., (1999) Genomics 62, 304–307; and Buchner G., et al., (2000) Genomics 65, 16–23). The expression of MAEG has also been detected in several tissues, including the dermis of the trunk, hair follicles, and the mesenchyme of the cranio-facial region (see Buchner G., and others, (2000) Mech. Dev. 98, 179–182). EGFL6 protein has been proposed as a possible biomarker in ovarian cancer (Buckanovich R. J., and others, (2007) J. Clin. Oncol. 25, 852–861).
In this paper, which appeared in Cancer Research, Buckanovich and others amplified the expression of EGFL6 in ovarian cancer cells. Increased EGFL6 expression stimulated cancer growth some two-three times. This effect was observed in cultured ovarian cancer cells and in a mouse model of ovarian cancer. Conversely, elimination of EGFL6 greatly reduced ovarian cancer growth, decreasing the rate of growth some four-fold.
EGFL6 specifically acts in cancer stem cells. To review, in tumors, not all cancer cells are the same. Inside malignant tumors or even among circulating cancerous cells (as in the case of leukemia) there are usually a variety of different types of cancer cells. The stem cell theory of cancer proposes that among cancerous cells, a small population among them act as stem cells that reproduce themselves and sustain the cancer. Cancer stem cells, therefore, are like normal stem cells that renew and sustain our organs and tissues. Therefore, cancer cells that are not stem cells can certainly adversely affect health, but they cannot sustain the cancer long-term. Therefore, cancer stem cells fuel the growth and spread of cancers and also are often resistant to chemotherapy and radiation treatments.
Further experiments by Buckanovich and his colleagues showed that EGFL6 cause cancer stem cells to divide asymmetrically so that the one of the daughter cells remains a cancer stem cell while the other daughter cell is a cancer cell that can affect the patient but cannot sustain the cancer. This asymmetric cell division also generates a good deal of diversity among cancer cells.
Buckanovich noted: “What this means is that the stem cell population remains stable. But the daughter cells, which can have a burst of growth, multiply, and allow the cancer to grow.”.
EGFL6 does more than just promote cancer cell proliferation. EGFL6 is also a promoter of cancer stem cell migration. When blood vessels were engineered to express EGFL6, tumor metastasis (spread) was even more robust.
Treatment of tumor-afflicted mice with an antibody that specifically binds to EGFL6 and inactivates it caused a 35% reduction in cancer stem cells and significantly reduced overall tumor growth. Additionally, the antibody also prevented tumor metastasis.
Buckanovich thinks that targeting EGFL6 might be a potential therapy for women with stage 3 ovarian cancer. Such a treatment might control the growth and spread of ovarian cancers.
Dr. Buckanovich added: “The bigger implication is for women at high risk of ovarian cancer. These patients could be treated before cancer develops, potentially blocking cancer from developing or preventing it from spreading. If cancer did develop, it could be diagnosed at an early stage, which would improve patient outcomes.”.
The next step for Buckanovich and his colleagues is developing an antibody that can properly work in human cancer patients.