Research Proposal The role of perivascular macrophages in...

Research Proposal: The role of perivascular macrophages in breast cancer metastasis. 1. Specific Aims The tumour microenvironment is comprised of both malignant and non-malignant cells. Increasing evidence suggests that the fate of malignant cells is altered by the behaviour of the surrounding nonmalignant cells. Together, the diverse composition of the microenvironment, including immune cell infiltration, stromal cells and extracellular matrix, as well as nutrient and oxygen supply, shape the fate of cancerous cells. In particular immune cells impact on tumour growth and metastasis. The co-evolution of tumour cells along with the immune system results in a continually changing and immune-suppressive or -permissive environment (1).†¦show more content†¦Conceivably, the rapidly changing tumour landscape alters tissue resident macrophages by hijacking their physiological functions resulting in a pro-tumourigenic immunosuppressive milieu. Certain tissue resident macrophages localise along blood vessels (referred to as perivascular macrophages, PVM), which are therefore strategically positioned to regulate extravasation of circulating leukocytes (7). Indeed, a recent report from our laboratory using a transgenic reporter strain specific for PVM has highlighted a unique role for these cells in recruiting neutrophils during bacterial infection that was dependent on their ability to generate chemokines (8). Similarly, previous studies have implicated the role of PVM in tumour cell invasion into blood vessels and subsequent metastasis (9), but no clear understanding of this process or any mechanistic detail exists. In this project, we aim to dissect the precise role of PVM in hematogenic and lymphatic spread of tumour cells. We will make use of cutting edge intravital multi-photon microscopy in combination with genetically engineered mice to further our understanding of PVM during tumour pathophysiology. We expect to delin eate the role of PVM in tumour cell dissemination and metastasis. Hypothesis and aims: Due to the strategic location of PVM adjacent to post-capillary venules and also lymphatics we