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