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Altered Protein Profile and Impairment of Physiological Autophagic Flux in Myofibers Could Be Predictive of Relapse in Colorectal-Cancer Patients At an Early Stage of Disease
Mario Gruppo*1, Stefano Merigliano1, Valentina Beltrame1, Cosimo Sperti1, Mario Bernardo2, Gianfranco DA Dalt1, Gianpietro Zanchettin1, Ugo Carraro3, Eva Pigna4, Dario Coletti4, 5, Viviana Moresi4, Sandra Zampieri3
1Department of Surgery, Oncology and Gastroenterology, University Hospital of Padua, Padova, Italy; 2University of Tor Vergata, Rome, Italy; 3Department of Biomedical Sciences, University of Padua, Padua, Italy; 4DAHFMO Unit of Histology and Medical Embriology; Interuniversity Institute of Miology, Sapienza University, Rome, Italy; 5Department of Biological Adaptation and Ageing B2A, Pierre et Marie Curie University, Paris, France
Background
Skeletal muscle is the major reservoir of body proteins and it can be affected in conditions associated to altered protein turnover and metabolism such as cancer. Although severe wasting is seen primarily in patients with advanced malignancy, some of them present degree of wasting at the onset of disease. Autophagy has been recently described to play a relevant role in muscle wasting.
Materials and Methods
We performed morphometric studies and immunohistochemical analyses on intraoperative rectus abdominis muscle biopsies from 50 consecutive weight stable colorectal patients and 25 weight-stable patients operated for non-inflammatory benign diseases with no clinical signs of myopathies. Biochemical and molecular analyses have been performed in order to evaluate protein profile, the presence of autophagy induction and their correlation with clinical outcome.
Results
In cancer patients, we observed a subclinical myopathy characterized by an abnormal distribution of myonuclei relocated from the periphery inside the myofiber. The percentage of myofibers with abnormally located myonuclei was significantly higher in patients (median= 9%) compared to controls (median= 2.7%) (p=0.0002). Analyses on serum samples showed that, in the absence of systemic inflammation, in the prevalence of cancer patients the levels of albumin and prealbumin were below the normal range and the mean value was significantly lower compared to that detected in controls (albumin: 34.82 ± 5.8 g/L vs 45.2 ± 5.3, p< 0.01; prealbumin: 174.38±57.86 mg/L vs 264.00±69.73, p<0.001). Molecular analyses showed an accumulation of p62, a typical marker of autophagy induction, significantly higher in cancer patients compared to controls. Follow-up was 38 ± 12 months. Deceases in patients' group were 18% (9/50) and cancer relapse occurred in 32% (16/50) patients. We found an inverse correlation between the number of abnormally nucleated myofibers and the presence of lymph node metastasis (N+) (ñ)=-0.64 (p=0.002). Cancer relapse was correlated with low serum levels of prealbumin (156.59 ± 44.22 mg/L in cancer relapse vs 190.62 ± 57.23 mg/L in patients without relapse; p = 0.08) and high levels of p62 in myofibers of cancer patients (Tab.1).
Conclusions
Colorectal cancer patients have a subclinical myopathy characterized by myofibers with internally located myonuclei. In the absence of inflammation, cancer patients show low levels of prealbumin and albumin as markers of altered protein turnover and persistent high levels of p62 in myofibers as expression of autophagy induction with an impairment in physiological autophagic flux. Up to now our data indicate the presence of an altered protein turnover at an early stage of disease, with an impairment in the physiological autophagic flux, that could be predictive of cancer relapse and onset of cancer cachexia.
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