Exosomal MicroRNAs in Pregnancy Provides Insight into a Possible Cure for Cancer

Abstract

The biological links between cancer and pregnancy are of recent interest due to parallel proliferative, immunosuppressive and invasive mechanisms between tumour and trophoblast development. Therefore, understanding “cancer-like” mechanisms in pregnancy could lead to the development of novel cancer therapeutics, however, little is understood on how tumour and trophoblast cells recapitulate similar molecular mechanisms. Based on our observations from a previous study, it was not only evident that exosomal miRNAs are involved in the pathophysiology of preeclampsia but also contained cancer-specific miRNAs, which suggested that “pseudo-malignant-like” exosomal-mediated mechanisms exist in pregnancy. The presented study therefore aimed to identify exosomal miRNAs (exomiR) in pregnancy which can be repurposed towards preventing tumour metastasis and immunosuppression. It was identified that exomiR-302d-3p, exomiR-223-3p and exomiR-451a, commonly associated with cancer metastasis, were found to be highly expressed in pregnancy. Furthermore, computational merging and meta-analytical pathway analysis (DIANA miRPath) of significantly expressed exomiRs between 38 ± 1.9 vs. 30 ± 1.11 weeks of gestation indicated controlled regulation of biological pathways associated with cancer metastasis and immunosuppression. Therefore, the observations made in this study provide the experimental framework for the repurposing of exosomal miRNA molecular mechanisms in pregnancy towards treating and preventing cancer.

Specific and Aspecific Molecular Checkpoints as Potential Targets for Dismantling Tumor Hierarchy and Preventing Relapse and Metastasis Through Shielded Cytolytic Treatments

“…The above inductive process could occur through EV contents ( Sheu and Shih, 2010 ; da Silva Nardi et al, 2016 ; Rebmann et al, 2016 ; Naito et al, 2017 ; Jurj et al, 2020 ; Pillay et al, 2020 ) and be similar to the embryonic inductions occurring between mesenchymal and epithelial cells from early gastrula to organogenesis, during which the embryo structures progressively develop ( Balinsky, 1970 ). It is known that embryonic inductions require a direct contact between mesenchymal and epithelial cells ( Balinsky, 1970 ), as described in the SCID mouse model, between meta-nephric mesenchymal (MM) cells and ureteric bud (UB) epithelial progenitor cells in a three-dimensional co-culture, allowing for a direct cell–cell contact ( Ratajczak et al, 2006 ; Valadi et al, 2007 ; Velagapudi et al, 2012 ).…”

“…Tumor-suppressor miRNAs, loaded in exosomes and delivered, can inhibit pro-angiogenic mRNAs or knockdown specific genes for inhibiting tumor growth (Dilsiz, 2020); the exosome-formed synthetic miRNA-143 transferred to osteosarcoma cells inhibits their migration (Shimbo et al, 2014;Jurj et al, 2020). Notably, consistent with the paraembryonic nature of cancer, miRNAs have been shown in pregnancy, which may provide insights into a possible cure for cancer (Pillay et al, 2020). Cancer cell exosomes depend on cell surface heparan sulfate proteoglycans for their internalization and functional activity (Christianson et al, 2013;Vader et al, 2014), and heparin blocks EV transfer between donor and recipient cells (Atai et al, 2013;Vader et al, 2014).…”

“…Tumor progression necessarily requires the control and the overexploitation of the host surrounding microenvironment. To this end, tumor cells can dictate tumor functional phenotypes to surrounding cells through molecules for intercellular communications, such as HLA-G and exosomal miRNAs, as embryonic cells also do ( da Silva Nardi et al, 2016 ; Rebmann et al, 2016 ; Dilsiz, 2020 ; Pillay et al, 2020 ). These molecules could induce such phenotypes by activating or silencing defined genic systems in the recipient cells.…”

“…The level of realization of a defined IGC within the induced cells of a tumor would be responsible for their differentiation degree and, thus, for the different malignancy levels. I think that a crucial mechanism for the inductions in tumor progression is based on the cargoes of EVs (exosomes in particular) ( Sheu and Shih, 2010 ; da Silva Nardi et al, 2016 ; Rebmann et al, 2016 ; Naito et al, 2017 ; Jurj et al, 2020 ; Pillay et al, 2020 ). In the recipient cancer and normal cells, exosomes deliver their contents modulating cell signaling pathways.…”

“…In mice lacking the S100A4 gene, tumor development and metastasis formation are suppressed ( Grum-Schwensen et al, 2005 ; Lukanidin and Sleeman, 2012 ; Hoshino et al, 2015 ). Silencing of S100A10 blocks the chemotherapy-induced enrichment of breast CSCs, impairs tumor initiation, and delays recurrence ( Pillay et al, 2020 ). In three-dimensional culture and in vivo , reversion of the malignant phenotype of human breast cancer cells occurs by ITG blocking antibodies ( Weaver et al, 1997 ; Hoshino et al, 2015 ).…”