Exosomal miRNA: Small Molecules, Big Impact in Colorectal Cancer

Abstract

Colorectal cancer (CRC) is one of the major causes of cancer-related deaths worldwide. Tumor microenvironment (TME) contains many cell types including stromal cells, immune cells, and endothelial cells. The TME modulation explains the heterogeneity of response to therapy observed in patients. In this context, exosomes are emerging as major contributors in cancer biology. Indeed, exosomes are implicated in tumor proliferation, angiogenesis, invasion, and premetastatic niche formation. They contain bioactive molecules such as proteins, lipids, and RNAs. More recently, many studies on exosomes have focused on miRNAs, small noncoding RNA molecules able to influence protein expression. In this review, we describe miRNAs transported by exosomes in the context of CRC and discuss their influence on TME and their potential as circulating biomarkers. This overview underlines emerging roles for exosomal miRNAs in cancer research for the near future.

Figure 1

Scheme of exosome biogenesis, composition, and major role in TME modification, in the context of CRC. The biogenesis of exosomes involves 4 different steps: (1) the membrane invagination; (2) endosome formation; (3) generation of the exosome precursors, called intraluminal vesicles (ILVs), by inward budding of endosomes (these accumulations of ILVs are termed as multivesicular bodies (MVBs)); and (4) the fusion of MVBs with the plasma membrane release the ILVs in the extracellular space by exocytosis and become exosomes. Composition: exosomes are composed of different types of enzymes and proteins involved in adhesion, intracellular signaling, immunostimulatory molecules, multivesicular body (MVB) formation, and heat shock proteins (HSPs). Exosomes contain nucleic acids, including miRNA, mRNA, DNA, and small noncoding RNA (snRNA and tRNA). In addition to direct interactions between CRC cells and TME, exosomes, especially exosomal miRNAs, play a key role in the cross talk between cells in TME. CRC cells can release exosomes that will modify TME cells and promote tumor growth, metastasis formation, and chemoresistance. Inversely, stromal cells can also release exosomes that influence tumor cell metabolism. Differential expression of miRNAs within exosomes could also be useful in CRC as biomarker for diagnosis and monitoring.

Figure 2

Proposed models for the role of exosomal miR-21 in CRC development. (a) Fibroblast-derived exosomes have an effect on CRC cells. The internalization of normal fibroblast- (NOF-) derived exosomes into CRC cells leads to an increase of cellular miR-21 and to the activation of phospho-Erk/Akt pathway, leading to oxaliplatin resistance. (b) CRC cells release miR-21-containing exosomes that are able to inhibit endothelial progenitor cell (EPC) IL6R mRNA transcription, leading to a reduced migration, proliferation, and invasion and favoring thrombosis in CRC. (c) Cancer-associated fibroblasts (CAFs) secrete miR-21-overexpressing exosomes which increase liver metastases. Tumor-associated macrophages (TAMs) also release miR-21-containing exosomes that can negatively regulate BRG1 mRNA in CRC cells and lead to an increased migration and proliferation.

Figure 3

Proposed models for the dual roles of exosomal miR-200 family members on TME in CRC. (a) Upon decitabine (DAC) treatment, CRC cells enter a MET process that stimulates the release of miR-141/miR-200c enriched exosomes. (b) In endothelial cells, exosomal miR-200c, -141, and -429 can also inhibit the expression of transcription factors belonging to the ZEB family, activators of EMT. (c) On the contrary, 5-FU-resistant CRC cells release exosomes without miR-200 family members, favoring EMT. (d) CRC cells exposed to TGF-β1 release miR-200b-enriched exosomes that inhibit p27/kip mRNA, leading to an increased proliferation.

Figure 4

Proposed models for the effects of exosomal miR-1246 on the TME. p53 mutations resulting in gain of function (GOF) in CRC cells induce the release miR-1246-overexpressing exosomes. Exosomal miR-1246 can induce a switch of macrophage phenotype towards a tumor-associated phenotype (TAM), modifying tumor inflammatory state. It leads to a decreased secretion of proinflammatory and increased secretion of anti-inflammatory cytokines. TAMs also present enhanced ECM degradation, migration, and invasion properties. Exosomes are represented as small orange circles.