Exosomes: The Link between GPCR Activation and Metastatic Potential?

Abstract

The activation of G-Protein Coupled Receptors (GPCRs) by their respective ligands initiates a cascade of multiple signaling processes within the cell, regulating growth, metabolism and other essential cellular functions. Dysregulation and aberrant expression of these GPCRs and their subsequent signaling cascades are associated with many different types of pathologies, including cancer. The main life threatening complication in patients diagnosed with cancer is the dissemination of cells from the primary tumor to distant vital organs within the body, metastasis. Communication between the primary tumor, immune system, and the site of future metastasis are some of the key events in the early stages of metastasis. It has been postulated that the communication is mediated by nanovesicles that, under non-pathological conditions, are released by normal cells to relay signals to other cells in the body. These nanovesicles are called exosomes, and are utilized by the tumor cell to influence changes within the recipient cell, such as bone marrow progenitor cells, and cells within the site of future metastatic growth, in order to prepare the site for colonization. Tumor cells have been shown to release an increased number of exosomes when compared to their normal cell counterpart. Exosome production and release are regulated by proteins involved in localization, degradation and size of the multivesicular body, whose function may be altered within cancer cells, resulting in the release of an increased number of these vesicles. This review investigates the possibility of GPCR signaling cascades acting as the upstream activator of proteins involved in exosome production and release, linking a commonly targeted trans-membrane protein class with cellular communication utilized by tumor cells in early stages of metastasis.

Extracellular vesicles secreted by highly metastatic clonal variants of osteosarcoma preferentially localize to the lungs and induce metastatic behaviour in poorly metastatic clones

“…Receptor target modelling (MetaCore data-mining and pathway analysis, Thomson Reuters) of the 31 unique HiMet-C6 proteins in the list revealed that 21/31 of the proteins (67.7%) are involved in G-protein coupled receptor signaling events (GO Processes) (Figure 6) known to play critical roles in tumor growth and metastasis [37]. More recently, a link between GPCR signaling, extracellular vesicles and metastasis has been published [38]. …”

Ceramide and Exosomes: A Novel Target in Cancer Biology and Therapy

“…The function of lipid rafts was invoked in facilitating GPCR activation by these lipids. However, only a few studies have investigated if EVs or exosomes exchange GPCRs between cells (Isola & Chen, 2016; Ye et al, 2002). Recently, ectosomes, EVs budding off cilia, were reported to accumulate GPCRs, but a role of ectosome-bound GPCRs in cancer has not been described yet (Isola & Chen, 2016; Nager et al, 2017; Soetedjo & Jin, 2014).…”

“…However, only a few studies have investigated if EVs or exosomes exchange GPCRs between cells (Isola & Chen, 2016; Ye et al, 2002). Recently, ectosomes, EVs budding off cilia, were reported to accumulate GPCRs, but a role of ectosome-bound GPCRs in cancer has not been described yet (Isola & Chen, 2016; Nager et al, 2017; Soetedjo & Jin, 2014). One study found that exosomes can transfer the A2A adenosine receptor (A2AR) from A2AR expressing to non-expressing cells with functional recovery of this GPCR, which suggests that exosomal transfer of receptors endows the recipient cell with the ability to respond to the same signals as the donor cell (Clayton, Al-Taei, Webber, Mason, & Tabi, 2011; Isola & Chen, 2016) (Fig.…”

Biology, Therapy and Implications of Tumor Exosomes in the Progression of Melanoma

“…These newly released exosomes have the ability to travel long distances within the body, or interact with local cells. The uptake of exosomes by target cells can occur in different ways; engulfment of the exosomes by the recipient cells often by clathrin-dependent endocytosis or, under certain conditions, lipid-dependent membrane fusion [56]. …”