Extracellular Vesicles from Metastatic Rat Prostate Tumors Prime the Normal Prostate Tissue to Facilitate Tumor Growth

Abstract

Accumulating data indicates that tumor-derived extracellular vesicles (EVs) are responsible for tumor-promoting effects. However, if tumor EVs also prepare the tumor-bearing organ for subsequent tumor growth, and if this effect is different in low and high malignant tumors is not thoroughly explored. Here we used orthotopic rat Dunning R-3327 prostate tumors to compare the role of EVs from fast growing and metastatic MatLyLu (MLL) tumors with EVs from more indolent and non-metastatic Dunning G (G) tumors. Prostate tissue pre-conditioned with MLL-EVs in vivo facilitated G tumor establishment compared to G-EVs. MLL-EVs increased prostate epithelial proliferation and macrophage infiltration into the prostate compared to G-EVs. Both types of EVs increased macrophage endocytosis and the mRNA expression of genes associated with M2 polarization in vitro, with MLL-EVs giving the most pronounced effects. MLL-EVs also altered the mRNA expression of growth factors and cytokines in primary rat prostate fibroblasts compared to G-EVs, suggesting fibroblast activation. Our findings propose that EVs from metastatic tumors have the ability to prime the prostate tissue and enhance tumor growth to a higher extent than EVs from non-metastatic tumors. Identifying these differences could lead to novel therapeutic targets and potential prognostic markers for prostate cancer.

Studying the Fate of Tumor Extracellular Vesicles at High Spatiotemporal Resolution Using the Zebrafish Embryo

“…These results are consistent with in vitro studies showing that EVs from breast cancer cells or oral squamous carcinoma cells stimulate an M1 macrophage inflammatory response (including TNF induction) (Xiao et al, 2018;Chow et al, 2014). Other studies, however, show that tumor EVs, for instance from prostate tumors, induce an M2 activation (Halin Bergströ m et al, 2016). Although the M1/M2 binary polarization model of macrophages has been challenged (Aras and Zaidi, 2017), pro-inflammatory macrophages have been reported to exert pro-or anti-tumoral effects depending on the context (Engblom et al, 2016).…”

Reduced number of CD169+ macrophages in pre‐metastatic regional lymph nodes is associated with subsequent metastatic disease in an animal model and with poor outcome in prostate cancer patients

“…One function of the subcapsular sinus‐macrophages is to capture lymph borne particles, including tumor‐derived antigens and exosomes . Antigens sampled by the CD169 + macrophages are presented to effector cells like T‐cells and NK‐cells, which migrate to the tumor where they promote an anti‐tumor immune response . In breast cancer, the density of CD169 + cells in regional LNs correlated with clinical stage, and also with numbers of cytotoxic CD8 + T cells in high grade tumors, but was not associated to cancer specific survival .…”

“…Effects of tumor‐derived exosomes on regional LNs have not been examined in our model system. However, MLL‐derived exosomes injected into the prostate precondition it for accelerated growth of low‐malignant prostate cancer cells implanted 3 days later . It is likely that MLL‐exosomes also could influence the tumor‐draining LNs in a similar tumor‐promoting way.…”

“…Metastatic prostate tumors secrete factors that precondition, not only the tumor stroma but also the remaining benign parts of the prostate, in ways that facilitate subsequent tumor growth and spread . If metastatic prostate tumors secrete factors that also prepare regional lymph nodes (LNs) for metastatic growth is only limitedly explored.…”

Highly aggressive rat prostate tumors rapidly precondition regional lymph nodes for subsequent metastatic growth

“…Implantation of Dunning rat prostate cancer cells into the prostate of immunocompetent and syngeneic rats resulted in adaptive changes in major parts of the non-malignant prostate tissue [ 8 , 10 , 11 ]. The nature and magnitude of these changes were related to tumor aggressiveness and metastatic capacity [ 9 , 11 , 12 ]. Similar changes in the benign parts of the prostate were associated with disease aggressiveness and outcome in prostate cancer patients [ 9 , 10 , 13 , 14 ].…”