The role of perivascular macrophages in breast cancer metastasis.
1. SPECIFIC AIMS
The solid tumor microenvironment is comprised of both malignant and non-malignant cells and an increasing body of evidence suggests that the fate of malignant cells can potentially be altered by the behavior of the surrounding non-malignant cells. It is becoming increasingly evident that the modulation of tumor microenvironment has an important role to play in tumors displaying their full neoplastic potential and thus targeting the surrounding non-malignant cells particularly the immune cells as potential therapeutic targets is not unheard of. In the last decade the general concept for tumour development has ...view middle of the document...
Previous studies have implicated PVMs in tumour cell invasion into blood vessels3, but this process is far from being understood. In this project, we aim to dissect the precise role of PVM in hematogenic and lymphatic spread of tumor cells. We expect to obtain novel insights into the function of these thus-far underappreciated cell populations in breast cancer cell biology.
OBJECTIVE: Owing to the strategic location of perivascular macrophages adjacent to post capillary venules and lymphatics which interestingly are also the routes for tumor cell extravasation and the availability of the DPE-GFP mice unique to our group we are in an ideal position to study the role of this macrophage subset during tumor progression and metastasis. The aim of this application is to study the physical and biochemical cues that aid the breast cancer cell dissemination and extravasation.
Hypothesis: PVM facilitate the intravasation of breast cancer cells cells into the blood vessels and lymphatics
Aim 1. To dissect the role of PVM in breast cancer growth and metastasis.
Aim 2. To study the process of neoangiogenesis and lymphangiogenesis during breast cancer development.
Aim 3. To generate a novel transgenic mouse model for the selective depletion of PVM and to study the effect of PVM depletion on breast cancer development and metastasis.
BREAST CANCER: Breast cancer continues to be one of the leading causes of death in women worldwide. It is the second most common cancer after lung cancer and fifth most common cause of cancer death thus suggesting that the global burden of this life threatening disease is huge. In Australia, breast cancer accounts for 28% of deaths in women (Cancer Council Australia). In 2013 alone, over 13,000 Australian people were diagnosed with breast cancer. The fatalities associated with breast cancer are usually not caused by the primary tumour itself but rather by secondary daughter (metastatic) cancers, most commonly observed in lymph nodes, lungs, bones, brain and liver. Although there are strategies for treating primary cancers, in particular surgical resection, metastatic cancers are much more difficult to treat due to development of resistance to drug therapy. Therefore, we must strive to understand the basic process of breast cancer metastasis if we are to improve the available therapies and to identify novel drug targets. In this application, we will exploit state-of-the-art imaging technology in combination with genetically engineered reporter mice unique to our group to interrogate the dynamics and mechanisms of breast cancer cell metastasis in live tissue. This will enable us to generate entirely new insight into how cancer cells spread through the organism. We anticipate not only generating a better understanding of the metastatic process, but also identifying novel therapeutic targets for this deadly disease.
ROLE OF MACROPHAGES IN BREAST CANCER: Macrophages are generally defined as the sentinel cells of the...