Scientists at the University of Bradford, and the University of Surrey, in the U.K. have shown how prostate cancer cells release a protein that is taken up by surrounding normal and cancer cells, and which may promote tumor growth and help protect the cancer from the body’s immune system.

The research, headed by University of Bradford professor Richard Morgan, PhD, found that the protein—a transcription factor called engrailed-2 (EN2)—is also inserted into the plasma membranes of cancer cells, with part of the molecule sticking out at the cell surface, and so may present a potential therapeutic target. “For tumors to survive, grow bigger, and spread they need to control the behavior of cancer cells and the normal cells around them and we’ve found a means by which they do this,” Morgan commented. “Blocking this process could be a potential target for future cancer therapy.”

The team reports its findings today in Scientific Reports, in a paper titled, “Membrane insertion and secretion of the Engrailed-2 (EN2) transcription factor by prostate cancer cells may induce antiviral activity in the stroma.”

EN2 is a nuclear protein that plays a role in early brain development but is also found at high levels in a variety of different cancer types, the authors explained. “In addition to a role in neural development, early studies also indicated that EN2 had an oncogenic function in breast cancer cells as its forced expression in non-tumorigenic mammary cell lines resulted in a number of malignant characteristics …  More recently it has been shown that EN2 is expressed in a number of other tumor types, including those of the prostate and bladder.”

Of potential clinical relevance, the concentration of EN2 protein in the urine of both prostate cancer and bladder cancer patients has been linked with tumor size and grade, and so may have diagnostic and prognostic value. However, scientists have until now known very little about the molecular mechanisms that underpin EN2 activity, and are unclear about whether the protein is present in cell membranes, or whether it is secreted or taken up by cells using active mechanisms.

To try and expand on existing knowledge the researchers tagged the EN2 protein using fluorescent markers and tracked its activity in human prostate cancer cells, normal prostate cells, and in bladder cancer, melanoma and leukemia cells.

Richard Morgan, PhD, director, Institute of Cancer Therapeutics and professor of molecular oncology. [University of Bradford]
As part of their surveillance, the team used time-lapse photography to monitor prostate cancer cells containing fluorescent EN2. The resulting video showed how the cells eject vesicles containing the green fluorescent protein, which is then taken up by otherwise dormant cancer cells, causing the cancer cells to reactivate, changing shape or fusing together. “…cells that take up exogenous EN2 protein undergo distinct changes in behavior that could profoundly influence tumor development through modification of the tumor microenvironment,” the team wrote. “We think this is significant because cell fusion in cancer is relatively unusual and is associated with very aggressive disease,” commented Morgan. “It can lead to new and unpredictable hybrid cells that are frequently better at spreading to different sites and surviving chemotherapy and radiotherapy.”

EN2 released by the prostate cancer cells was also taken up by normal, noncancerous prostate cells that would be found in the tumor microenvironment. Interestingly, normal cells that took up EN2 overexpressed a protein called MX2, which acts as a cellular antiviral. “Its primary cellular function seems to be the inhibition of the viral life cycle as it can block the assembly of multiple viruses,” the team commented. The researchers suggest that while the relevance of EN2-induced MX2 expression in cells surrounding the tumor isn’t clear, boosting the ability of cells in the microenvironment to prevent viral infection might act to help to keep the tumor under the immune system radar. “We believe the cancer is trying to minimize the chances of the cells around it being infected by a virus, to avoid scrutiny by the immune system,” said Morgan. “This could undermine the effectiveness of immunotherapy treatments, which try to use viruses to kill cancer by stimulating the immune system to attack it.”

The team’s results, more surprisingly, showed that EN2 isn’t just ejected in microvesicles by the prostate cancer cells, but is also inserted in the cell membranes, with part of the protein remaining accessible at the cell surface. This may provide opportunities to block the protein’s normal activity as a potential anticancer strategy. “In addition to secretory vesicles, EN2 protein is present in the plasma membrane of cells, and although further work is needed to understand the exact mechanism of insertion and its relationship with the phospholipid bilayer, our findings indicate that part of the EN2 protein is exposed on the outside of the cell, and hence could potentially act as a target in antibody-directed therapy,” the authors noted.

“Taken together, our findings suggest that EN2 secretion and uptake represent a novel mechanism by which tumors can influence the behavior of surrounding cells … cells that take up exogenous EN2 protein undergo distinct changes in behavior that could profoundly influence tumor development through modification of the tumor microenvironment … Our findings indicate that EN2 secretion by tumors may be a means of preventing viral-mediated immune invasion of tissue immediately adjacent to the tumor.”

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