Regulation of cancer cell plasmin formation by S100A10

Certain blood cells, such as neutrophils, interact with cancer cells and thereby promote the growth of these cancer cells. However, in order for neutrophils to reach the cancer cells, they must chew their way through the connective tissue that prevents their movement from the blood to the tumour site. Previous work from Dr Waisman's laboratory, using purified proteins, has shown that a protein called p11, acts like molecular scissors that chew up connective tissue. P11 is present on the surface of neutrophils. The team propose to test the possibility that neutrophils require p11 in order to move to the tumour site. If correct, these studies will establish p11 as an important target for future drug development aimed at blocking its function. Cancer cells, release a variety of signaling molecules which attract certain cells that are present in the blood, such as neutrophils. Once neutrophils reach the tumour site they release growth factors that promote the growth of the tumour and also promote the conversion of the cancer cells into highly malignant cells. In order for the neutrophils to reach the cancer cells within the tumour they must cross a number of barriers including the tissue that surrounds the tumour. The research team has previously shown that addition of a protein, called p11, to tissues results in their digestion. The researchers propose to establish if p11 which is present on the cell surface of neutrophils is used by neutrophils to digest tissue barriers and reach the tumour. If this hypothesis is correct then future studies aimed at blocking p11 will represent a novel therapeutic approach. The team will isolate neutrophils from normal mice (WT) and mice which have been engineered not to express p11 (p11 null mice). They will compare the ability of these neutrophils to generate the tissue chewing enzyme, plasmin. They will also compare their ability to move across a tissue barrier which has been constructed on a polycarbonate filter. If p11 plays an important role in tissue barrier chewing, then it is expected that the p11 null neutrophils will not function in these tests as well as the WT neutrophils. The researchers will also form tumours in WT and p11 null mice and compare the movement of neutrophils into these tumours. If the neutrophils of the p11 null mice fail to move as effectively as the neutrophils in the WT mice, it will confirm the hypothesis that p11 plays an important role in neutrophil movement into the tumour site. It is well established that the association of neutrophils with cancer cells is an important event that promotes tumour growth and the development of cancer cells into malignant cells. To get into the tumour, the neutrophils must leave the blood and then remove tissue barriers that prevent their movement into the tumour. If p11 plays a role in this potentially lethal function of neutrophils then these studies will have identified p11 as an important target for the future development of drugs aimed at blocking p11 function. Thus drugs that block p11 will prevent the movement of neutrophils into the tumour and block tumour growth and the conversion of benign tumours into malignant tumours.