Modeling the Roles of Astrocytes in the Metastatic Tumor Cell Microenvironment

Astrocytes can play a seemingly contradictory dual role during tumor metastasis to the brain; they can be both protective of the brain and supportive of tumor cells during brain metastasis. The role of astrocytes is further complicated by the fact that metastatic tumor cells arriving in the brain via the circulatory system are separated from the brain perivascular space (in which the astrocytes reside) by the blood-brain barrier (BBB). It is not yet clear how tumor cells cross this highly selective barrier. The BBB can be modeled in vitro using different systems, cell types, and extracellular matrix components to study the interactions of metastatic tumor cells and astrocytes, with the specific aspects of the tumor microenvironment depending on the research questions. Some models focus on the interaction of two cell types while others are more complex and involve the neighboring neural cells and microenvironment. Regardless, these models have pointed to astrocytes as key regulators of tumor cell metastasis into the brain because they can influence tumor cells both directly and indirectly through other cells and/or the extracellular matrix (ECM). It is critical that in vitro models are carefully designed to consider how, and at which point in the metastatic cascade, astrocytes and tumor cells interact, both physically and biochemically. This chapter provides a critical evaluation of the different assays used to study metastatic tumor cell-astrocyte interactions and discusses their physiological implications.