Identification of Biomarkers Associated with Liver Metastasis Progression from Colorectal Cancer Using Exosomal RNA Profiling

SIMPLE SUMMARY: Exosomes are a class of extracellular vesicles released by cancer cells that play important roles in cancer progression and therapy resistance. Using RNA sequencing in plasma exosomes from patients with metastatic colorectal cancer (mCRC), we investigated exosomal RNA expression profiles between initial recurrence and cancer progression after metastasectomy. The differential expression level of the exosome RNA was enriched in samples from patients with metastases to the liver, multiple metastatic sites and large tumor burden. In terms of liver metastasis, the interferon-α response gene set was enriched in a tumor burden of ≥1 cm(3), and CXCL10, CXCL11 and SAMD 9 were highly expressed in the exosomal RNA which was validated using GSEA. High CXCL10 expression was associated with shorter progression-free survival (PFS), but CXCL11 and SAMD 9 were not correlated with PFS. Exosomal CXCL10 RNA could be a novel biomarker for liver metastasis from mCRC and a potential target for the prevention and treatment of these patients. ABSTRACT: This study aimed to identify novel biomarkers for metastatic colorectal cancer progression using exosomal RNA expression profiling. The exosomal RNA expression profiles of 54 patients with mCRC were investigated. Exosomal RNA profiling was performed at the time of relapse immediately before metastasectomy and cancer recurrence or progression after metastasectomy. The up- and down-regulated RNA expression profiles were screened and analyzed using H-cluster, principle component analysis and gene ontology. The tissue expression profile of the liver metastases was compared with the GSE 41258 set using GSEA tools. We identified two distinctive biological process gene sets (IFNA and PCDB families) related to metastatic progression. The interferon-α response gene set was enriched, especially when the tumor volume was ≥1 cm(3). CXCL10, CXCL11 and SAMD 9 mRNA were highly expressed in the plasma exosome samples of patients with mCRC to the liver. Furthermore, high expression of CXCL10 but not CXCL11 or SAMD9 was associated with a poor prognosis and shorter progression-free survival. Conclusions: Cancer-derived exosomal CXCL10 may be a novel biomarker for liver metastasis of mCRC and a potential target for the prevention and treatment of mCRC with liver metastasis.