Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver

Abstract

Pancreatic ductal adenocarcinomas (PDAC) are highly metastatic with poor prognosis, mainly due to delayed detection. We hypothesized that intercellular communication is critical for metastatic progression. Here, we show that PDAC- derived exosomes induce liver pre-metastatic niche formation in naïve mice and consequently increase liver metastatic burden. Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor β secretion and upregulation of fibronectin production by hepatic stellate cells. This fibrotic microenvironment enhanced recruitment of bone marrow-derived macrophages. We found that macrophage migration inhibitory factor (MIF) was highly expressed in PDAC-derived exosomes, and its blockade prevented liver pre-metastatic niche formation and metastasis. Compared to patients whose pancreatic tumors did not progress, MIF was markedly higher in exosomes from stage I PDAC patients who later developed liver metastasis. These findings suggest that exosomal MIF primes the liver for metastasis and may be a prognostic marker for the development of PDAC liver metastasis.

Extracellular vesicles swarm the cancer microenvironment: from tumor–stroma communication to drug intervention

“…This chain of events increases the metastatic potential in melanoma and lung cancer 11 . In another chain of events pancreatic ductal adenocarcinomas cell-derived EVs can lead to pre-metastatic niche formation in sequential steps of induction of TGFβ signaling in Kupffer cells leading to extracellular matrix modification and subsequently an influx of bone marrow-derived macrophages to the liver, providing a favorable niche for liver metastasis 19 .…”

Cross-kingdom inhibition of breast cancer growth by plant miR159

“…miRNAs can be secreted through extracellular vesicles (EVs), such as exosomes, shedding vesicles, and apoptotic bodies, or in complexes with protein or lipid-based carriers [9,10]. Accumulating evidence demonstrates that miRNAs can be transferred via EVs to neighboring or distant cells to modulate cell function [11][12][13][14][15][16][17][18][19]. Extracellular miRNAs are therefore emerging as a new group of messengers and effectors in intercellular communication.…”

Intimate cross-talk between cancer cells and the tumor microenvironment of B-cell lymphomas: The key role of exosomes

“…Pre-metastatic niches usually have been formed in the receptor organs before tumor-cell metastasis and in which exosomes might be involved. Costa-Silva et al 49 reported that pancreatic ductal adenocarcinomas-secreted exosomes induced pre-metastatic niche formation due to the exosomal cargo macrophage migration inhibitory factor (MIF). Besides, their subsequent study found that a variety of tumor-derived exosomes uptaken by organ-specific recipient cells also established a favorable microenvironment that promoted the colonization and growth of disseminated tumor cells upon their arrival.…”

“…Multiple studies indicate that exosomes are actually involved in different phases of carcinogenesis and tumor development. [48][49][50][51][52][53][54][55] From the perspective of tumor-initiating property, Melo et al 17 demonstrated that the non-tumorigenic MCF10A cells formed tumor mass in nude mice when co-injected with cancer cell-derived exosomes, and Dicer blocking in these exosomes could reduce tumor formation. This oncogenic conversion of MCF10A cells attributes to precursor microRNAs (pre-miRNAs), along with Dicer, AGO2 (Argonaute2), and TRBP (HIV-1 TAR RNA binding protein) in exosomes of cancer cells.…”