Extracellular vesicle-miRNAs as liquid biopsy biomarkers for disease identification and prognosis in metastatic colorectal cancer patients

Abstract

Disseminated disease is present in ≈50% of colorectal cancer patients upon diagnosis, being responsible for most of cancer deaths. Addition of biological drugs, as Bevacizumab, to chemotherapy, has increased progression free survival and overall survival of metastatic colorectal cancer (mCRC) patients. However, these benefits have been only reported in a small proportion of patients. To date, there are not biomarkers that could explain the heterogeneity of this disease and would help in treatment selection. Recent findings demonstrated that microRNAs (miRNAs) play an important role in cancer and they can be encapsulated with high stability into extracellular vesicles (EVs) that are released in biological fluids. EVs can act as cell-to-cell communicators, transferring genetic information, such as miRNAs. In this context, we aimed to investigate serum EV associated miRNAs (EV-miRNAs) as novel non-invasive biomarkers for the diagnosis and prognosis of Bevacizumab-treated mCRC patients. We observed that baseline miRNA-21 and 92a outperformed carcinoembryonic antigen levels in the diagnosis of our 44 mCRC patients, compared to 17 healthy volunteers. In addition, patients who died presented higher levels of miRNA-92a and 222 at 24 weeks. However, in the multivariate Cox analysis, higher levels of miRNA-222 at 24 weeks were associated with lower overall survival. Altogether, these data indicate that EV-miRNAs have a strong potential as liquid biopsy biomarkers for the identification and prognosis of mCRC. Colorectal cancer (CRC) is the second most common cancer in women and the third most in men worldwide. Moreover, it accounts for 8.9% of all tumour-related mortality and is the second most common cause of cancer death 1. Disseminated disease is present upon diagnosis in 50% of the patients [lymph nodes (35%) and distant organs (22%)] and half of the patients diagnosed as localized tumours will eventually develop it 2. In recent years, the application of new targeted therapies, including anti-angiogenic drugs, has contributed to largely increase the overall survival (OS) of metastatic colorectal cancer mCRC patients, reporting median survivals of ≈30 months 3. Bevacizumab, a humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF) has demonstrated benefits in progression-free survival (PFS) and OS in combination with chemotherapy 4,5 .

miR-552: an important post-transcriptional regulator that affects human cancer

“…The miR-552 expression was also significantly up-regulated in various CRC cell lines including HCT116, HT-29, HCT-15, and HT-29 [21][22][23][24]. Consistent with this, miR-552 was also found to be up-regulated in the serum of CRC patients [25]. Comparing miR-552 expression in 158 pairs of colon cancer (CC) adenocarcinoma tissues with proficient DNA mismatch repair (pMMR) and adjacent tissues found that miR-552 expression was significantly associated with CC risk [20].…”

Circulating extracellular vesicle‑encapsulated microRNA as screening biomarkers for intraductal papillary mucinous neoplasm

“…They can be loaded into exosomes or other extracellular vesicles (extracellular vesicle-encapsulated miRNA: EV-miRNA) or exist freely in the blood circulation (circulating miRNA). Among these two forms, EV-miRNA has several advantages over circulating miRNA: i) It can be specifically released for cell-to-cell communication, and ii) lipid membrane coverage protects miRNA from RNase degradation ( 12 ).…”

The biomolecule corona of lipid nanoparticles contains circulating cell-free DNA

“…9 Therefore, the increased amount of nucleosomerelated proteins identified in ovarian cancer patients in this study is likely to extend to other cancer types and NP classes, as a general reflection of increased histone levels commonly seen in cancer. [61][62][63][64] In recent years, other cell-free nucleic acids, such as miRNAs, have received growing interest as disease biomarkers 65 and although extensive characterisation of the NP corona total nucleic acid content was beyond the scope of this study, it remains an important avenue of future research. Blood-circulating RNA molecules are commonly complexed with proteins, including those forming the RNA-induced silencing complex (RISC).…”