A biomarker based detection and characterization of carcinomas exploiting two fundamental biophysical mechanisms in mammalian cells

Abstract

BackgroundBiomarkers allowing the characterization of malignancy and therapy response of oral squamous cell carcinomas (OSCC) or other types of carcinomas are still outstanding. The biochemical suicide molecule endonuclease DNaseX (DNaseI-like 1) has been used to identify the Apo10 protein epitope that marks tumor cells with abnormal apoptosis and proliferation. The transketolase-like protein 1 (TKTL1) represents the enzymatic basis for an anaerobic glucose metabolism even in the presence of oxygen (aerobic glycolysis/Warburg effect), which is concomitant with a more malignant phenotype due to invasive growth/metastasis and resistance to radical and apoptosis inducing therapies.MethodsExpression of Apo10 and TKTL1 was analysed retrospectively in OSCC specimen (n = 161) by immunohistochemistry. Both markers represent independent markers for poor survival. Furthermore Apo10 and TKTL1 have been used prospectively for epitope detection in monocytes (EDIM)-blood test in patients with OSCC (n = 50), breast cancer (n = 48), prostate cancer (n = 115), and blood donors/controls (n = 74).ResultsPositive Apo10 and TKTL1 expression were associated with recurrence of the tumor. Multivariate analysis demonstrated Apo10 and TKTL1 expression as an independent prognostic factor for reduced tumor-specific survival. Apo10+/TKTL1+ subgroup showed the worst disease-free survival rate in OSCC.EDIM-Apo10 and EDIM-TKTL1 blood tests allowed a sensitive and specific detection of patients with OSCC, breast cancer and prostate cancer before surgery and in after care. A combined score of Apo10+/TKTL1+ led to a sensitivity of 95.8% and a specificity of 97.3% for the detection of carcinomas independent of the tumor entity.ConclusionsThe combined detection of two independent fundamental biophysical processes by the two biomarkers Apo10 and TKTL1 allows a sensitive and specific detection of neoplasia in a noninvasive and cost-effective way. Further prospective trials are warranted to validate this new concept for the diagnosis of neoplasia and tumor recurrence.

A multianalyte PCR blood test outperforms single analyte ELISAs (chromogranin A, pancreastatin, neurokinin A) for neuroendocrine tumor detection

“…The authors suggest this could accompany routine assays of metanephrine levels for the diagnosis of pheochromocytoma. A further example is provided by the use of combinations of epitope detection in monocytes where measures of Apo10 and TKTL1 exhibited significantly better performance metrics than a single measure alone in oral squamous cell carcinoma, breast cancer and prostate cancer (average single analyte sensitivity: 93 vs 95%; specificity: 90 vs 97%) (Grimm et al 2013). Thus, the combined detection of two independent fundamental biophysical processes allows for the sensitive and specific detection of neoplasia in a noninvasive and cost-effective way.…”

“…NETs may therefore be considered 'functional' or 'nonfunctional', though such terminology is archaic and of little scientific value except as a clinical descriptor of utility in diagnosis . The advantages of developing multianalyte assays with algorithmic analytic (MAAA) methodology to accurately assess a tumor group arising from many different cells and with numerous biological profiles has been described by a number of authors (Engels et al 2013, Grimm et al 2013. Coupling the integral aspects of disease represented by individual markers referable to a specific disease produces a significantly greater degree of quantification (Engels et al 2013).…”

“…Coupling the integral aspects of disease represented by individual markers referable to a specific disease produces a significantly greater degree of quantification (Engels et al 2013). Thus for example, examining two deeply conserved process of malignancy such as apoptosis and anaerobic glucose metabolism represented respectively by Apo10 and TKTL1 (key proteins facilitating invasion and metastasis), provides key information about tumor cell behavior not available through measurement of a single marker (Grimm et al 2013). It is therefore clear that a MAAA strategy, if appropriately configured to interrogate a specific neoplastic process, will mathematically encompass numerous different biological integers inaccessible to a monoanalyte approach.…”

Blood and tissue neuroendocrine tumor gene cluster analysis correlate, define hallmarks and predict disease status

“…The current scientific paradigm for biomarker development has focused on the advancement of multianalyte technologies (Engels et al 2013, Grimm et al 2013). …”

Expression patterns of CD168 correlate with the stage and grade of squamous cell carcinoma of head and neck

“…Several reports (9,10) have demonstrated that the overexpression of hypoxia-associated proteins, such as hypoxia-inducible factor-α and glucose transporter 1, is associated with poor prognosis and resistance to radiotherapy in the oral SCCs (OSCCs). Similarly, the expression of transketolase-like protein 1 and the Apo10 protein epitope of the endonuclease, DNAseX, in OSCC in tissue or in peripheral blood has been successfully used for monitoring these tumors.…”