Identification of potential metabolic biomarkers of rectal cancer and of the effect of neoadjuvant radiochemotherapy

Abstract

We report a pilot study on the feasibility of determinations of circulating levels of paraoxonase-1 (PON1) and compounds related to energy metabolism as biomarkers for the evaluation of patients with rectal cancer (RC), and the effects produced by neoadjuvant radiochemotherapy (NRCT). We studied 32 patients treated with radiotherapy plus capecitabine concomitant chemotherapy and 48 control subjects. We identified pre-NRCT PON1 and α-ketoglutarate as the parameters that best discriminated between RC patients and the control group. Receiver operating characteristics analysis of the combination of the two parameters showed an area under the curve (AUC) of 0.918. Moreover, patients who presented a pathological complete response (pCR) to treatment had lower plasma pre-NRCT valine concentrations (AUC of 0.826). Patients who had a relapse had lower concentrations of succinate (AUC of 0.833). The results of the present study illustrate the usefulness of investigating alterations in oxidative stress and metabolism in RC. Due to the small number of patients studied, our results must be considered preliminary, but they suggest that the determination of circulating levels of PON1 and α-ketoglutarate might be a valuable tool for the early diagnosis of RC, while the determination of valine and succinate might effectively predict pCR and the appearance of relapse.

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

“…On the other hand, among DEP upregulated in exosomes of good responders was PON1, an important antioxidant enzyme, which elevated serum level was previously observed in rectal cancer patients in response to neoadjuvant radiochemotherapy [ 15 ]. Interestingly, signal transduction proteins S100A8 and S100A9 upregulated in exosomes of poor responders were previously proposed as CRC tumor-specific exosomal markers, involved in migration, leucocyte recruitment, tumor-promoting inflammation, and formation of premetastatic niches [ 18 ].…”

“…Most studies on the role of exosomes in response to radiation and RT concern changes in transcriptome and proteome, yet much less is known about the metabolome component of these vesicles [ 43 ]. In general, only a few studies addressed RT-induced changes in metabolic profiles of rectal cancer [ 14 , 15 , 44 ], and there is no data about the potential of small molecules to discriminate patients who responded differently to radiotherapy. Here, we observed that metabolites present in exosomes and plasma had some potential to discriminate patients with different responses to neo-RT, and a few differentially accumulated metabolites (DAMs) were observed in both specimens (though DEPs detected in exosomes were much more numerous).…”

“…Previous studies reported that extracellular vesicles are generally enriched in molecules involved in fatty acids transport and storage [ 51 ]. Paraoxonase-1 (PON1), upregulated in exosomes of good responders, is an important antioxidant enzyme linked to cellular mitochondria-associated membranes, and in high-density lipoproteins (HDL), protects the cell from oxidative stress [ 15 ]. On the other hand, two DEPs upregulated in exosomes of poor responders, fatty acid-binding protein 5 (FABP5) and CD5L, are also involved in lipid metabolism.…”

“…A few studies revealed proteomic profiles of tissue and plasma of rectal cancer patients with different responses to RT [ 11 , 12 , 13 ]. On the other hand, few reports concerning metabolomic changes induced by the treatment of locally advanced rectal cancer patients were limited to the effects of neo-chemoradiotherapy [ 14 , 15 ]. Furthermore, a systemic approach combining both omics modalities was not applied in this field.…”

A differential DNA methylome signature of pulmonary immune cells from individuals converting to latent tuberculosis infection

“…The Principal Component Analysis (PCA) was calculated using the factoExtra (v1.0.7) 60 and factoMineR (v2.4) 61 . To examine the correlation of DNA methylation and regulation of gene expression, the Spearman’s rank correlation coefficient was calculated between the scaled M-values 62 and normalized expression values for the 1,186 CpG-sites and corresponding genes using ggcorr function in GGally package in R 63 . Heatmaps were generated using ComplexHeatmap package (v 4.0.3).…”