Weizmann Institute of Science scientists reveal how breast cancer cells enter dormancy, how it is maintained over years – and why they suddenly awaken and form metastases
Breast cancer treatments are improving, but in some cases the disease may recur even after several decades. The risk of recurrence of the disease stems from cells that have broken away from the original tumor and are hiding in a dormant state in the breast or other organs. Too little is known about the mechanisms that cause cancer cells to enter dormancy – and even less about those that cause them to suddenly awaken. A new article from the laboratory of Israel Prize laureate Prof. Yosef Jordan At the Weizmann Institute of Science, published today in the scientific journal Science Signaling, reveals the mechanism by which breast cancer cells are anesthetized and also reveals why they awaken from their slumber more violently than they were before.
From the embryonic stage of development, through sexual maturation to the production of breast milk during pregnancy and after birth, breast tissue changes throughout life. These changes are made possible by the metamorphosis that breast cells undergo from an early developmental state known as mesenchymal, in which they are round, rapidly dividing, and very mobile, to a mature state known as epithelial, in which they are cubic, slowly multiplying, and stationary. The cells move between the different states in a controlled and gradual manner, but sometimes they may get out of control, divide rapidly, and become malignant. This cancerous process begins with the return of the mature cells to the early developmental state, which allows them to multiply rapidly, form tumor tissue, and even migrate to other tissues. Later, cancer may actually benefit from the opposite process: cells that have been dispersed throughout the body may return to a mature state and become stationary and slow, or in other words, dormant.
Due to the great similarity between entering the dormant state and the maturation process of epithelial cells, the researchers hypothesized that it would be possible to put breast cancer cells into a dormant state in an intentional manner – by mimicking the natural process. Using a model of the 3D environment of the cancerous tumor, developed by Dr. Dalit Barkan from the University of Haifa, the researchers from Prof. Yarden's laboratory, led by Dr. Diana Drago-Garcia, engineered human breast cancer cells of the most aggressive type – triple negative (TNBC) – so that they would produce an increased amount of OVOL proteins, which are known to be involved in the natural maturation of epithelial cells. Using the engineered model, the researchers showed that overexpression of these two proteins stops the life cycle of the aggressive cancer cells and puts them into dormancy. At the same time, they showed in female mice with human tumor tissue that overexpression of OVOL inhibits the growth of the cancerous tumor.
Arguably, stopping the life cycle of cancer cells and slowing tumor growth is good news and a possible basis for cancer treatment, but it is known that breast tissue from cancer patients has high levels of one of the OVOL proteins. Therefore, the researchers hypothesized that this protein – OVOL1 – while inhibiting cancer in the short term, serves it in the long term, as it allows it to enter a dormant state and survive for a long time under the radar; when conditions in the body change and protein levels drop, the cancer will awaken more violently and aggressively than ever.
With these findings in hand, the scientists turned to examining how the tumor could affect the expression levels of OVOL proteins and thus either put the cancer cells to sleep or wake them up. Among other things, they discovered that while growth factors increase the expression of OVOL1, the hormone estrogen decreases its expression. Accordingly, the researchers showed that cancer patients whose tumors have low levels of estrogen receptors and high levels of OVOL1 tend to develop more aggressive cancer with lower chances of survival.
"These findings may pave the way for preventing the dormancy of cancer cells or preventing the awakening of cells that have already fallen asleep," explains Prof. Yarden, explaining the importance of the discovery. "For example, it is known that during menopause, fat tissue takes control of estrogen production. Therefore, it can be assumed that weight gain in old age in women who had breast cancer in their youth could lead to an increased risk of developing dormant cancer due to increased estrogen production and the resulting decrease in the expression of 1OVOL. In the future, it will be possible to test these hypotheses in animals and humans."
Urinating in your sleep
One of the questions that remains open is why when breast cancer returns from dormancy, it tends to be more aggressive. To solve this, the scientists traced the chain of messages through which OVOL1 induces dormancy. They identified that this molecular chain leads to the accumulation of unstable substances, called free radicals, which damage many substances in the cell, stopping its life cycle and putting it in a dormant state. The accumulation of these substances surprised the scientists and had not been linked to the dormancy of cancer cells until now.
The scientists later showed, in collaboration with Professor Emeritus Yosef Shiloh of Tel Aviv University, that the continuous state of stress created in dormant cells due to the accumulation of free radicals causes a change in the expression and activity of proteins in the cell nucleus, the home of DNA. As a result, the genetic material is oxidized, its integrity is compromised, and the activity of three central proteins in the repair mechanisms of DNA damage is also impaired. The researchers estimate that the extensive damage to the genetic material and the failure of their repair mechanisms explain why when cancer awakens, it contains many mutations and tends to be more aggressive and resistant to treatments.
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