The potential roles of exosomes in pancreatic cancer initiation and metastasis

Abstract

Pancreatic cancer (PaCa) is an insidious and highly metastatic malignancy, with a 5-year survival rate of less than 5%. So far, the pathogenesis and progression mechanisms of PaCa have been poorly characterized. Exosomes correspond to a class of extracellular nanovesicles, produced by a broad range of human somatic and cancerous cells. These particular nanovesicles are mainly composed by proteins, genetic substances and lipids, which mediate signal transduction and material transport. A large number of studies have indicated that exosomes may play decisive roles in the occurrence and metastatic progression of PaCa. This article summarizes the specific functions of exosomes and their underlying molecular mechanisms in mediating the initiation and metastatic capability of PaCa.

Keywords: Exosome; Metastasis; Pancreatic cancer; Tumor biomarker; Tumorigenesis.

Fig. 1

The main features of exosome

Fig. 2

Exosome secretion and uptake. (i) Specific areas of the plasma membrane can invaginate along with cargo (es) to form an early endosome structure. Early endosomes then further continue to collect various cargoes from the cytosol, during which with the assistance of ESCRTs and other related proteins, the endosomal lipid membrane can wrap a range of wanted cargoes to form a variety of independently closed ILVs inside the late endosomes (MVBs). MVBs can move to and combine with lysosomes to digest their content and recycle them or, alternatively, fuse with the plasma membrane to secrete ILVs out of cells, thus forming exosomes. (ii) Exosomes can be transported by the body fluids, including blood, to reach their target or recipient cells. Exosomes function by directly transmitting signals upon binding to surface receptors of recipient cells, or being absorbed into the recipient cells through different endocytosis mechanisms to form endosomes again. Inside the target cells, exosomes can release their content into cytosol to fulfill various signaling transduction, be merged with lysosomes digest and recycle content, or re-fuse with the plasma membrane to accomplish the transcellular transportation

Fig. 3

Crosstalk between PaCa cells and PaCa-related cells. PaCa cells can interact with a variety of PaCa-related cells to fulfill their metastatic progress. On one hand, PaCa-related cells (CAFs, TAMs, PSCs, and PaCaCICs) generate exosomes that can promote PaCa cell survival, proliferation, apoptotic resistance, drug resistance, EMT, migration and metastatic invasion. Notably, MSCs can produce exosomes that induce apoptosis, cell cycle arrest and growth inhibition in PaCa cells. On the other hand, PaCa cells can also produce exosomes to stimulate various related cells to secrete various cytokines or exosomes, which may create a facilitating tumor microenvironment for their own survival and metastasis. Specifically, PaCa-derived exosomes can stimulate TAMs to produce many cytokines, including VEGF, which in turn can induce a variety of metastatic characterization changes such as EMT in PaCa cells. PaCa -derived exosomes can recruit and stimulate PSCs to proliferate, migrate and secrete more fibronectin, thereby creating a metastasis microenvironment. PaCa cells may additionally produce exosomes to deregulate the body metabolism, impairing the functions of ICs, IECs, SGCs and SKMs. PaCa-derived exosomes can stimulate the proliferation and migration of VECs, thus forming new blood vessels, inducing KC and HSC activation to form a distant metastasis microenvironment in the liver, as well as targeting immune cells (including DCs) to promote immunosuppression