Transcriptome reprogramming by cancer exosomes: identification of novel molecular targets in matrix and immune modulation

Abstract

BackgroundExosomes 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.MethodsHere, we 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.ResultsIn recipient HNOK cells, we 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). We have also identified CEP55 as a potential cancer exosomal marker.ConclusionsIn 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.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0846-5) contains supplementary material, which is available to authorized users.

KISS1/KISS1R and Breast Cancer: Metastasis Promoter

“…85 A recent study found using transcriptome analysis that fibulin-3 was expressed in cancer exosomes, which are extracellular vesicles released by cancer cells known to regulate organ-specific metastasis. 86 The fibulin-3 gene, EFEMP1, was found to be amplified in TNBC in contrast to other breast subtypes and plasma fibulin-3 levels were found to be elevated in TNBC patients compared with healthy subjects. 75 Furthermore, KISS1R signaling was found to induce fibulin-3 mRNA and protein expression as well as fibulin-3 secretion by TNBC cells.…”

Extracellular Vesicles in Oral Squamous Cell Carcinoma and Oral Potentially Malignant Disorders: A Systematic Review

“…HOC313-LM exosomes transferred oncogenic miR-343-3p and miR-1246 to HOC313-P cells and resulted in increase in cell motility and invasive ability [30] Cisplatin resistant OSCC cell lines (HSC3, SCC9) Parental OSCC (HSC3 and SCC9) EVs released from cisplatin-resistant OSCC cells transmit miR-21 to induce cisplatin resistance of OSCC cells [31] OSCC line (HSC3) Oral keratinocytes (RT7) OSCC derived EGFR-containing EVs were able to transform RT7 cells, effects of which were largely blocked by cetumixab [32] OSCC lines (Ca1 CALH2, SQCC/Y1) Premalignant buccal oral keratinocyte (SVpgC2a)…”

Exosomes: Biological Couriers with Transformative Messages

“…CEP55, a protein associated with ALIX and the ESCRT complex and a known downstream target of the oncogene FOXM1, was exclusively found to be membrane-localized in exosomes derived from malignant head and neck squamous cell carcinoma cells [56]. Moreover, these exosomes were demonstrated to reprogram the transcriptome of recipient human normal oral keratinocytes.…”