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    Research Grants Awarded

    The Role Of Tumor-Associated Macrophages In The Metastatic Progression Of Breast Cancer

    Grant Mechanism:
    Postdoctoral Fellowships

    Scientific Abstract:
    Breast cancer is among the most prevalent cancer in women worldwide. Despite recent advances in our understanding of molecular mechanisms underlying the initiation and progression of breast cancer, prognosis has remained poor mainly due to a high mortality from metastatic dissemination and colonization in other organs including lung, brain and bone. On top of intrinsic oncogenic alterations that contribute to metastasis, it is now acknowledged that a permissive pre-metastatic microenvironment is a critical determinant for metastasis. Pre-metastatic niche is a permissive microenvironment in metastatic organs, which confers survival and growth advantages of metastatic tumor cells, and is thought to be created by primary tumor cell factors and bone marrow derived hematopoietic progenitor cells. However, mechanisms by which a primary tumor cell initiates and maintains a permissive microenvironment in specific distant tissues remain to be determined. Inflammatory cell infiltration of tumors is a key determinant of the tumor microenvironment. In particular, macrophages form a major component of tumor microenvironment, and these tumor-associated macrophages have shown to promote tumor growth, invasion, angiogenesis and metastasis. High levels of macrophage infiltration have been associated with a poor prognosis in various cancers including breast cancer. In a preliminary study using mouse transgenic model of human breast cancer (MMTV-PyMT), we observed a significant macrophage infiltration during malignant progression, particularly at the onset of malignant conversion to carcinoma. Furthermore, recent studies demonstrated that systemic deletion of macrophages in MMTV-PyMT mouse inhibited malignant progression of primary tumors as well as the development of metastasis. Given the contribution of tumor-associated macrophages to the malignant progression and metastasis formation, we hypothesize that tumor-associated macrophages contribute to the metastatic progression of breast cancer through the promotion of tumor cell dissemination and the initiation of a permissive pre-metastatic niche in preferential distant organs. To test this hypothesis, we propose following specific aims using a well-characterized mouse model of human breast cancer, MMTV-PyMT that allows us to recapitulate each step of tumorigenic and metastatic progressions. Aim 1 is proposed to determine the relationship of tumor-associated macrophage infiltration to the stages of metastatic progression of breast cancer. Specifically, using triple transgenic mice, MMTV-PyMT;beta-actin-CFP;c-fms-GFP mice that allow us to visualize both tumor cells (CFP) and macrophage / myeloid lineage cells (GFP) in vivo, we will determine if macrophages are recruited to the pre-metastatic niche and metastatic lesions of distant tissues as well as primary tumor lesions at the onset of dissemination. We will also characterize the microenvironmental changes that define the pre-metastatic niche in relation to macrophage infiltration. This series of experiments proposed for aim 1 will provide compelling evidence to better pinpoint the spatial and temporal relationship of tumor-associated macrophage infiltration to the metastatic progression. Next, aim 2 is proposed to determine the causal role of tumor-associated macrophages in metastatic progression of breast cancer. We will perform gain- and loss-of function experiments to study the roles of tumor-associated macrophages in metastatic progression. In the gain-function experiments, we will analyze the consequence of introduction of tumor-associated macrophages or media conditioned by these macrophages in MMTV-PyMT mice on tumor cell dissemination, formation of pre-metastatic niche and development of metastatic lesions. In the loss-of function experiments, we will perform a genetic or chemical ablation of macrophages at various stages of metastatic progression and determine if this results in a delay or inhibition of metastatic progression. We anticipate that while metastatic progression is accelerated and enhanced by introduction of tumor-associated macrophages or conditioned media, ablation of macrophages leads to a delay of metastatic progression or loss of capacity to fully develop metastatic lesions. Despite recent advances in our understanding of molecular mechanisms underlying the initiation and progression of breast cancer, prognosis has remained poor. This may result from insufficiency of targeting tumor cells alone and a high mortality from tumor dissemination and metastasis. It becomes obvious that on top of cell-autonomous, intrinsic malignant progression in tumor cells, microenvironmental factors such as macrophage infiltration and a pre-metastatic niche at the distant tissues are essentially required for the tumor growth and development of metastatic lesions. In this regard, specific aims proposed here may reveal the potential molecular implication of tumor-associated macrophages in the microenvironment of metastatic progression that facilitates the better understanding of cross-talk between tumor cells and the host microenvironment. This mutual communication can be exploited for more effective therapeutic tactics to treat breast cancers.

    Lay Abstract:
    Breast cancer is among the most prevalent cancer in women worldwide. Every year more than one million women are diagnosed with breast cancer and almost half million women die from breast cancer worldwide. This is almost 1% of all deaths. Most breast cancer arises from epithelial cells of mammary gland, a cell population that lines the mammary glands. Despite recent advances in our understanding of how normal mammary epithelial cells are transformed into cancer cells, the success rate of treatment including surgery, chemotherapy and radiation therapy has remained poor. In particular, most breast cancer deaths result from cancer cell dissemination to distant organs such as lung, bone and brain, and formation of secondary malignant lesions in these organs (termed metastasis). Currently, little is known about the mechanisms underlying tumor cell dissemination and the development of metastatic lesions that cause most breast cancer deaths. There are no cures for metastatic lesions. The cancer cell is dependent on its microenvironment or tumor microenvironment. This tumor microenvironment is the host microenvironment in which cancer cells originate, multiply and spread. Recent studies have shown that the tumor microenvironment has a pivotal role on cancer cell?s growth, malignant progression and metastasis. Over the past several decades, cancer biologists have made significant achievements to understand cancer cells? genetic alterations that lead to the initiation and progression of cancer. However, little is known about the composition and characteristics of tumor microenvironment, and how a cancer cell interacts with its microenvironment. It becomes acknowledged that the tumor microenvironment can be an attractive therapeutic target for cancer prevention and treatment. The tumor microenvironment is composed of host fibroblasts (supporting cells), inflammatory cells and various extracellular materials such as collagens and fibronectins. In particular, macrophages (immune cells that remove cell debris and pathogens by engulfing and digesting them) are the key components of the tumor microenvironment. However, paradoxically, tumor-associated macrophages have been shown to accelerate cancer growth and metastatic spread. Hence, there has been an enormous effort to target these macrophages (tumor-associated macrophages) for cancer treatment. However, the molecular mechanisms underlying the role of tumor-associated macrophages in the promotion of tumor growth and metastasis are poorly understood. Given the profound role of tumor-associated macrophages in tumor microenvironment and their necessity for the metastatic spread of breast cancer, we propose to test the hypothesis that tumor-associated macrophages contribute to the metastatic progression of breast cancer through the promotion of tumor cell dissemination and the initiation of a permissive microenvironment that permits and supports the development of metastatic lesions (also called a pre-metastatic niche) in preferential distant organs. Taking advantage of genetically engineered mouse models of human breast cancer (MMTV-PyMT;beta-actin-CFP;c-fms-GFP mice) that develop breast cancer in the mammary glands, and that allow us to visualize both tumor cells and macrophages in live mice, we will characterize the spatial and temporal distribution of tumor-associated macrophage at various stages of metastatic progression. We will add or remove tumor-associated macrophages in live mice to determine if tumor-associated macrophages are directly involved in the process of metastatic spread and the formation of the permissive metastatic microenvironment in breast cancer. Our research plan proposed here may reveal the potential molecular implications of tumor-associated macrophages in the microenvironment of tumors during metastasis and may provide a better understanding of cross-talk between tumor cells and the host microenvironment. Furthermore, our research plan will provide insight into potentials for targeting tumor-associated macrophages in blocking malignant progression and the metastatic spread of breast cancer. Targeting cancer cells alone may not be sufficient to achieve the best therapeutic outcome for breast cancer patients, especially those in highly advanced stages. In this regard, cross communication between cancer cells and their microenvironment may be exploited for more effective therapeutic tactics in treating breast cancers.