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

Diego De Miguel Pérez,José Exposito Hernandez,Agustín Robles Remacho,Jose Luis Garcia Puche,Jose Antonio Lorente Acosta,Ma Jose Serrano,Mayte Delgado Ureña,Alba Rodriguez Martínez,Alba Ortigosa Palomo,Francisco Gabriel Ortega Sánchez

doi:10.1038/s41598-020-60212-1

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.

Highlights

Disseminated disease is present in ≈50% of colorectal cancer patients upon diagnosis, being responsible for most of cancer deaths
According to the recommendations of the International Society of Extracellular Vesicles (ISEV), there are minimal requirements to claim a proper isolation of EVs26
In order to assess the population heterogeneity, the ISEV recommends that the employment of electron or atomic force microscopy be paired with a single tracking method

Summary

Introduction

Disseminated disease is present in ≈50% of colorectal cancer patients upon diagnosis, being responsible for most of cancer deaths. As Bevacizumab, to chemotherapy, has increased progression free survival and overall survival of metastatic colorectal cancer (mCRC) patients. These benefits have been only reported in a small proportion of patients. Circulating tumour cells (CTCs), considered to be responsible for disease relapse, have been evaluated as prognosis biomarker for mCRC patients under Bevacizumab therapy[14,15,16], more evidence is needed for clinical application. The use of liquid biopsy provides potential clinically-relevant non-invasive genomic and epigenomic signatures for cancer monitoring Due to their high abundance and their role as regulators of gene expression, circulating microRNAs (miRNAs), small non-coding RNAs (19–24 nucleotides long), have been proposed as potential markers in several cancer types[18]. MiRNAs play two different roles that appear to be context specific, acting as onco-miRNAs when they inhibit the expression of tumour suppressor genes accelerating tumorigenesis or as tumour-suppressors when they prevent tumour progression by blocking oncogene expression[19]

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