Attempted cell escape. This scanning electron microscope image shows breast tumor cell (pink) on a thick layer of Matrigel (green), which mimics the basement membrane separating the body’s tissues. This highly invasive cell penetrates the Matrigel layer and “escapes” in a process similar to that of the invasion by tumor cells.

Two new discoveries by researchers at the Institut Curie in Paris may help shed light on why some breast cancers are more aggressive than others. The discoveries could lead to earlier identification of highly invasive tumors and the ability to block metastases formation, according to the researchers.

When tumor cells acquire the capacity to move around and invade other tissues, there is a risk of metastases and cancer treatment becomes more difficult. A team led by research director Phillippe Chavrier has discovered how breast cancer cells break the bonds that tether them to the tumor. The basement membrane around the mammary gland is a barrier to the spread of cancer cells. Three proteins in the tumor cells transport enzymes needed to perforate this barrier, and another protein puts these enzymes in the right place.

Tissues are generally formed by cells arranged side by side. Epithelial cells cover an outer surface, such as the skin or an organ such as the mammary gland, and remain tightly bound together. This cohesion is vital to the body’s functioning, and the epithelial cells remain in position in their original tissue until they die. Sometimes, though, they detach and move away, and while such migration is essential during embryonic development as cells give rise to new tissues, when tumor cells break loose this often heralds the formation of metastases.

How breast cancer cells break loose

Tumor cells can only escape from the mammary gland by accomplishing a series of modifications.

The cell first forms protrusions called invadopodia and anchors them in the basement membrane. These “feet” provide everything needed to breach the membrane. The tumor cells produce a whole range of proteases that degrade the proteins of the extracellular matrix that hems them in, part of which is the basement membrane. These proteases cut a hole in the basement membrane through which the cells can escape.

In one study, published in the June 16 issue of The Journal of Cell Biology, the researchers used a model of metastatic breast cancer cells to demonstrate how the proteins sec3, sec8 and IQGAP1 transport vesicles containing proteases to the invadopodia. Without sec3, sec8 and IQGAP1 the vesicles cannot be fastened to the ends of the invadopodia and so the cells fail to escape into the neighboring tissue. Before the proteases can degrade the membrane, they must first be released from the vesicles.

In another study published in the July 8 issue of Current Biology Chavrier and colleagues show that the protein Vamp7 fuses protease-containing vesicles with the membrane of tumor cells. Only then can the proteases at the ends of the invadopodia progressively erode the basement membrane of the mammary gland. Inactivation of Vamp7 greatly reduces the ability of the breast cancer cells to degrade the extracellular matrix.

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