The tumor microenvironment as a metastasis biomarker in breast cancer

Distant metastasis is the primary cause of death in breast cancer, and metastasis often occurs despite potentially curative local therapy of the primary tumor. Prognostic factors for distant recurrence after local therapy are largely "tumor-centric". Defining the interactions between tumor cells and their microenvironment, and identifying the molecular mechanisms that define their interactions, provides a basis for development of metastasis biomarkers, and the ability to therapeutically target individual steps in the metastatic cascade. In vivo imaging modalities and other techniques have facilitated identification of the steps required for metastasis. These initial steps include streaming of tumor cells toward endothelial cells in collaboration with tumor-associated macrophages, formation of microanatomic structures consisting of tumor cells, macrophages, and endothelial cells, and transendothelial migration of tumor cells at these sites resulting in intravasation and dissemination to distant sites. Metastasis biomarkers that have been associated with distant recurrence in humans, and are based on observations of the tumor microenvironment, include a multiplex immunofluorescence assay that measures invasive isoforms of the actin regulatory protein Mena (a markerwhich we call "Menacalc") that enable tumor cell streaming. Multiplex immunohistochemical assays that identify where Mena-expressing tumor cells, endothelial cells, and macrophages form microanatomic structures can serve as platforms for transendothelial migration, intravasation, and metastasis (which we call "TMEM" for tumor microenvironment of metastasis). An understanding of the signaling molecules that drive these interactions may provide a foundation for developing therapeutic strategies to prevent metastasis. There is potential for these biomarkers to both exhibit clinical utility by more accurately characterizing prognosis and thus the potential to benefit from standard therapies. They could also to predict benefit from novel interventions that prevent metastasis.