Molecular Composition of Serum Exosomes Could Discriminate Rectal Cancer Patients with Different Responses to Neoadjuvant Radiotherapy

Abstract

Identification of biomarkers that could be used for the prediction of the response to neoadjuvant radiotherapy (neo-RT) in locally advanced rectal cancer remains a challenge addressed by different experimental approaches. Exosomes and other classes of extracellular vesicles circulating in patients’ blood represent a novel type of liquid biopsy and a source of cancer biomarkers. Here, we used a combined proteomic and metabolomic approach based on mass spectrometry techniques for studying the molecular components of exosomes isolated from the serum of rectal cancer patients with different responses to neo-RT. This allowed revealing several proteins and metabolites associated with common pathways relevant for the response of rectal cancer patients to neo-RT, including immune system response, complement activation cascade, platelet functions, metabolism of lipids, metabolism of glucose, and cancer-related signaling pathways. Moreover, the composition of serum-derived exosomes and a whole serum was analyzed in parallel to compare the biomarker potential of both specimens. Among proteins that the most properly discriminated good and poor responders were GPLD1 (AUC = 0.85, accuracy of 74%) identified in plasma as well as C8G (AUC = 0.91, accuracy 81%), SERPINF2 (AUC = 0.91, accuracy 79%) and CFHR3 (AUC = 0.90, accuracy 81%) identified in exosomes. We found that the proteome component of serum-derived exosomes has the highest capacity to discriminate samples of patients with different responses to neo-RT when compared to the whole plasma proteome and metabolome. We concluded that the molecular components of exosomes are associated with the response of rectal cancer patients to neo-RT and could be used for the prediction of such response.

A Review of Circulating Tumor DNA as a Biomarker Guide for Total Neoadjuvant Therapy in Patients with Locally Advanced Rectal Cancer

“…This is further compounded by the wide variation of cfDNA/ctDNA detection strategies that limit generalization of the reported findings. Even so, other liquid biopsy technologies being developed (e.g., extracellular vesicles, cfRNA, circulating tumor cells) are still emerging, and cfDNA/ctDNA is currently the most advanced biomarker available to guide TNT for rectal cancer [77][78][79]. As technologies improve, and more rigorous trials are conducted, it is likely that non-operative management may be more comfortably employed if a validated cfDNA/ctDNA biomarker is readily available to optimize the identification of responding patients that would best benefit under the watchful waiting paradigm.…”

Metabolomics of Extracellular Vesicles: A Future Promise of Multiple Clinical Applications

“…For instance, metabolomic testing has been performed to screen for biomarkers in rectal cancer patients, aiming to assess the neoadjuvant chemotherapy response. 105 What is more, this research also compared the sensitivity of proteins and lipids as biomarkers. At present, there are numerous clinical studies screening differential markers, while only a few studies have been conducted to compare the effectiveness between a single omics and a combination of multiple omics.…”

“…Several proteins and metabolites relevant to the unexpected results have consequently been revealed, as well as the involved signaling pathway, such as immune response, complement activation cascade, and platelet functions. 105 Studies based on radiation therapy have been described to alter exosome content, thus affecting unirradiated cells and mediating radiation tolerance. 111 At the same time, through fecal microbial EVs, genomics and metabolomics were used to construct a colorectal cancer diagnostic model.…”

“…Metabolite analysis mainly depends on the distribution of species and the relative intensity of their content. [26][27][28] After these steps, EVs metabolomics can apply to diagnosis, [89][90][91][92][93][94][95][96][97][98] drug efficacy screening, [99][100][101][102][103][104] disease progression monitoring, 51,[105][106][107][108] identifying prognostic biomarkers 43,47,109,110 and cooperating with other omics. 83,111,112…”

Biomarkers for Predicting the Response to Radiation-Based Neoadjuvant Therapy in Rectal Cancer

“…The exosome levels of pentadecanoic acid and of sucrose were higher in poor responders. Proteome components of serumderived exosomes are also promising biomarkers, and the combination of proteomic and metabolomic biomarkers is likely to be a fruitful area of investigation [91].…”