Tumor-derived exosomes: A message delivery system for tumor progression

Abstract

Intercellular communication is a key process in the development and progression of cancer. The dynamic and reciprocal interplays between the tumor and its microenvironment orchestrate events critical to the establishment of primary and metastatic niches and maintenance of a permissive environment at the tumor-stroma interface. Atay and colleagues found that gastrointestinal stromal tumor cells secrete vesicles known as exosomes. These exosomes contain oncogenic KIT and their transfer and uptake by surrounding smooth muscle cells lead to enhanced AKT and MAPK signaling and phenotypic modulation of several cellular processes, including morphological changes, expression of tumor-associated markers, secretion of matrix metalloproteinases, and enhanced tumor cell invasion. This provocative study emphasizes that exosome-mediated signaling within the tumor microenvironment acts as a positive feedback loop that contributes to invasiveness and that interfering with this message delivery system may represent promising therapeutic approaches, not only for GIST, but for other types of cancer.

Keywords: Exosomes; GIST; feedback loop; invasion; tumor micro-environment.

Figure 1. Proposed model of tumor-stromal positive feed-back loop mediated by oncogenic KIT-bearing tumor exosomes in the regulation of tumor invasion. GIST cells secrete a gradient of exosomes carrying mutant KIT, which after internalization by surrounding smooth muscle cells activate downstream signaling pathways of KIT (e.g., AKT and MAPK pathways) and induce an enhanced expression of endoglin, vimentin (VIM), smooth muscle actin (SMA), and plasminogen activator inhibitor-1 (PAI-1) in the recipient cells, resembling an ICC-like phenotype. This tumor−stromal interaction creates a positive feed-back loop in which tumor-derived exosome-mediated signaling in stromal cells increases MMP1 secretion. In turn, tumor cells utilized MMP1 to invade the submucosa. This model describes a previously unreported mechanism by which tumor-derived exosomes can modulate their host microenvironment and promote local invasion and potentially distant metastasis.