Breast cancer is the most occuring type of cancer and the leading course of cancer-related deaths in women in Europe. In 2012, 464.000 new cases of breast cancer were diagnosed, while 131.000 deaths were the results of this devastating disease. As a result of the aging population, breast cancer occurence and related mortality are expected to increase. Current therapies are aimed at the treatment of primary tumor, by using cytotoxic agents, hormone treatment, radiation and small moleculat inhibitors. Tumor growth and metastasis depend strongly on the support of the tumor microenvironment (TME), where stromal components such as macrophages, fibroblasts or myeloid derived supressor cells promote neo-angiongenesis and matrix remodelling, as well as cause suppression of the adaptive immune system.
Modulation of Macrophages
Macrophages play a major role in the process of breast cancer. These cells are phagocytic cells of the immune system and display a wide range of different functionalities. In general macrophages can display two different phenotypes. They may be described as 'classically activated' M1 macrophages or 'alternatively activated' M2 macrophages. M1 macrophages are involved in acute inflammation, where they are responsible for the detection and killing of pathogens. Furthermore, M1 macrophages are also effective in recognizing and killing tumor cells. In contrast, M2 macrophages are mostly involved in wound healing, allergies and the removal of paracytes. These cells release immunosuppressive cytokines and components necessary for collagen synthesis and cellular proliferation. Macrophages that are recruited during tumor development are mostly differentiated into M2-like tumor-associated macrophages (TAMs). Due to their immunosuppressive and wound healing properties, they faciliate tumor growth and metastasis.
- Reprogramming of TAMs towards an M1 tumor suppressive behaviour using (targeted) nanomedicine.
- Inhibition of the new recruitment and differentiation of TAMs
Moulation of Fibroblasts
Fibroblasts, as the most abundant component in breast cancer, are pro-tumorigenic, and can transform into cancer associated-fibroblasts (CAFs). CAFs secrete an enormous amount of ECM which develops fibrotic tissue within the tumor stroma. Furthermore, CAFs provide resistance to tumor cells by secreting growth factors, which ultimately leads to treatment failure.
- Inhibition of fibroblast differentiation into their CAF-like phenotype