Transcriptome reprogramming by cancer exosomes

Exosomes are extracellular vesicles released by almost all cell types, including cancer cells, into bodily fluids such as saliva, plasma, breast milk, semen, urine, cerebrospinal fluid, amniotic fluid, synovial fluid and sputum. Their key function being intercellular communication with both neighbouring as well as distant cells. Cancer exosomes have been shown to regulate organ-specific metastasis. However, little is known about the functional differences and molecular consequences of normal cells responding to exosomes derived from normal cells compared to those derived from cancer cells.

Here, researchers from Queen Mary University of London characterised and compared the transcriptome profiles of primary human normal oral keratinocytes (HNOK) in response to exosomes isolated from either primary HNOK or head and neck squamous cell carcinoma (HNSCC) cell lines.

In recipient HNOK cells, they found that regardless of normal or cancer derived, exosomes altered molecular programmes involved in matrix modulation (MMP9), cytoskeletal remodelling (TUBB6, FEZ1, CCT6A), viral/dsRNA-induced interferon (OAS1, IFI6), anti-inflammatory (TSC22D3), deubiquitin (OTUD1), lipid metabolism and membrane trafficking (BBOX1, LRP11, RAB6A). Interestingly, cancer exosomes, but not normal exosomes, modulated expression of matrix remodelling (EFEMP1, DDK3, SPARC), cell cycle (EEF2K), membrane remodelling (LAMP2, SRPX), differentiation (SPRR2E), apoptosis (CTSC), transcription/translation (KLF6, PUS7). The researchers have also identified CEP55 as a potential cancer exosomal marker.

Genome-wide gene expression analysis on normal primary human oral keratinocytes transfected by normal or cancer-derived exosomes

a OK113 cells were transfected by equal concentration (2 × 10¹⁰ particles/well) of each type of exosomes for 48 h prior to microarray analysis using Illumina Human HT-12 v4 Gene Expression BeadChip, exploring 47,231 genes. b Within the top 400 differentially expressed genes (P < 10^− 20), exosome (both normal and cancer) exposure led to larger proportion of downregulated genes (61.6%) compared with upregulated genes (38.4%) in recipient cells. c Within the top 400 differentially expressed genes (P < 10^− 2), cancer and normal exosomes induced almost equal proportion (50.3 vs 49.7%) of differentially expressed genes in recipient cells

In conclusion, both normal and cancer exosomes modulated unique gene expression pathways in normal recipient cells. Cancer cells may exploit exosomes to confer transcriptome reprogramming that leads to cancer-associated pathologies such as angiogenesis, immune evasion/modulation, cell fate alteration and metastasis. Molecular pathways and biomarkers identified in this study may be clinically exploitable for developing novel liquid-biopsy based diagnostics and immunotherapies.