“In order for tumors to survive, grow bigger, and spread they have to control behavior of cancer cells and normal cells around them, we have found a means by which they do this; blocking the process may be a potential target for future cancer therapy.” explains Professor Richard Morgan, PhD.
“Protein transcription factor engrailed-2 is a nuclear protein that plays roles in early brain development which is also found at high levels in a variety of different cancer types.” “… early studies indicated EN2 has 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 has been shown to be expressed in a number of other tumor types including prostate and bladder..”
Prostate and bladder cancer patients concentration of EN2 proteins in urine has been linked with tumour size and grade, this may have clinical relevance to diagnostic and prognostic values. Molecular mechanisms underpinning EN2 activity are not fully understood, or whether the protein is present in cell membranes, or whether it is secreted or taken up by cells using active mechanisms thus the team set out to expand on this knowledge.
EN2 proteins were tagged using fluorescent markers by University of Surrey and University of Bradford scientists to track activity in human prostate cancer cells, normal prostate cells, as well as in bladder cancer, melanoma, and leukemia cells. To help monitor the fluorescent EN2 cells time lapse photography was used; results show how the cells eject vesicles containing fluorescent proteins which were taken up by dormant cancer cells causing them to reactivate, change shape, or fuse together which may influence tumor development through modification of the tumour microenvironment.
“… fusion in cancer is relatively unusual and associated with very aggressive disease, this may lead to new and unpredictable hybrid cells that are better at spreading to different sites and surviving therapy.”
The released EN2 was also taken up by normal, noncancerous prostate cells which then overexpressed MX2 proteins that acts as a cellular antiviral. While the relevance of EN2 induced MX2 expression in cells surrounding the tumour is not clear, boosting ability of cells in the tumour microenvironment to prevent viral infection may act to keep the tumour under the radar of the immune system, which could undermine effectiveness of immunotherapy treatments that try to use viruses to kill cancer by stimulating the immune system to attack it.
EN2 is also inserted in cell membranes with part of the protein remaining accessible at the cell surface, this may provide an opportunity to block the protein’s normal activity as an anticancer strategy. However, it was noted “further research is required to understand the exact mechanism of insertion and the relationship with the phospholipid bilayer. Findings suggest part of the EN2 protein is expose on the outside of the cell and hence may potentially serve as a target for antibody directed therapies.”
“When taken together findings suggest EN2 uptake and secretion represent novel mechanisms by which tumours influence behavior of surrounding cells….EN2 secretion may be a means of preventing viral mediated immune invasion of tissue immediately adjacent to the tumour..”
