**2. Endocytosis pathways**

Endocytosis is a basic cellular function that is performed by all cell types in the process of maintaining homeostasis. Many of the molecules essential for cellular function are small enough to cross the cell membrane either passively or actively, however, other structures, such as exosomes, are too large and require a more complicated process. This general process of internalization is called endocytosis and is separated into various types based on the shape [24] and the size of particles internalized [25]. There are many well-written reviews covering the specifics of the endocytic pathways [25, 26], but here we will address them only superficially. Classification under the umbrella of endocytosis varies, but the major methods include phagocytosis, macropinocytosis, clathrin-mediated endocytosis, caveolinmediated endocytosis, and clathrin/caveolin-independent or lipid raft-mediated endocytosis [25, 26]. Receptor-mediated endocytosis (RME) is an additional type that is often considered to be a subcategory under several of those previously mentioned (**Figure 1**).

#### **2.1 Phagocytosis**

Phagocytosis is the mechanism by which specialized cells (such as macrophages and monocytes) engulf large particles (>0.5 μm) by way of receptor/ligand interactions [25, 27] (**Figure 1A**). Promiscuous receptors allow for a broad range of ligand recognition and binding, facilitating a key role phagocytes play in clearing apoptotic cells [27]. Exosomes, derived from a diverse population of cells, present a vast array of available ligands that make phagocytes ideal recipient cells. This process of phagocytosis is designed to not only internalize extracellular material by enveloping it, but also to regulate the immune response by presenting degraded proteins as antigens on the phagocyte surface [25]. Tumor-derived exosomes influence immune involvement in the tumor [28, 29] which may be facilitated by this mechanism of endocytosis. Other non-phagocytic cells, such as epithelial cells, Sertoli, liver endothelial, astrocytes, and cancer cells have also been shown to perform

**43**

**Figure 1.**

*Cellular-Defined Microenvironmental Internalization of Exosomes*

some function and if that influence is cell type dependent.

phagocytosis [27], potentially expanding the impact of exosomal communication. It is therefore important to define how the process of phagocytosis influences exo-

While phagocytosis or "cell eating" involves ingestion of large molecules, macropinocytosis ("cell drinking") internalizes slightly smaller particles (>1 μm) [25] (**Figure 1B**). This method is a way for cells to sample the external environment without specific receptors or ligands. It is a constitutive process in specialized antigen presenting cells, but is stimulated by growth factors in most others [30]. Macropinocytosis has a unique membrane ruffling process caused by projections from the cell surface encircling extracellular fluid and fusing to the membrane [25], resulting in an increased membrane surface area and volume of engulfed material. Nakase et al., showed that stimulation of the epidermal growth factor (EGF)

*Endocytosis pathways involved in exosome uptake: (A) Phagocytosis, (B) Macropinocytosis, (C) Clathrinmediated endocytosis, (D) Caveolin-mediated endocytosis, (E) Lipid Raft-dependent or clathrin−/caveolin-*

*independent endocytosis, (F) Receptor-mediated endocytosis.*

*DOI: http://dx.doi.org/10.5772/intechopen.86020*

**2.2 Macropinocytosis**

*Cellular-Defined Microenvironmental Internalization of Exosomes DOI: http://dx.doi.org/10.5772/intechopen.86020*

phagocytosis [27], potentially expanding the impact of exosomal communication. It is therefore important to define how the process of phagocytosis influences exosome function and if that influence is cell type dependent.
