Revelation of Proteomic Indicators for Colorectal Cancer in Initial Stages of Development.

Background: Colorectal cancer (CRC) at a current clinical level is still hardly diagnosed, especially with regard to nascent tumors, which are typically asymptotic. Searching for reliable biomarkers of early diagnosis is an extremely essential task. Identification of specific post-translational modifications (PTM) may also significantly improve net benefits and tailor the process of CRC recognition. We examined depleted plasma samples obtained from 41 healthy volunteers and 28 patients with CRC at different stages to conduct comparative proteome-scaled analysis. The main goal of the study was to establish a constellation of protein markers in combination with their PTMs and semi-quantitative ratios that may support and realize the distinction of CRC until the disease has a poor clinical manifestation. Results: Proteomic analysis revealed 119 and 166 proteins for patients in stages I-II and III-IV, correspondingly. Plenty of proteins (44 proteins) reflected conditions of the immune response, lipid metabolism, and response to stress, but only a small portion of them were significant (p < 0.01) for distinguishing stages I-II of CRC. Among them, some cytokines (Clusterin (CLU), C4b-binding protein (C4BP), and CD59 glycoprotein (CD59), etc.) were the most prominent and the lectin pathway was specifically enhanced in patients with CRC. Significant alterations in Inter-alpha-trypsin inhibitor heavy chains (ITIH1, ITIH2, ITIH3, and ITIH4) levels were also observed due to their implication in tumor growth and the malignancy process. Other markers (Alpha-1-acid glycoprotein 2 (ORM2), Alpha-1B-glycoprotein (A1BG), Haptoglobin (HP), and Leucine-rich alpha-2-glycoprotein (LRG1), etc.) were found to create an ambiguous core involved in cancer development but also to exactly promote tumor progression in the early stages. Additionally, we identified post-translational modifications, which according to the literature are associated with the development of colorectal cancer, including kininogen 1 protein (T327-p), alpha-2-HS-glycoprotein (S138-p) and newly identified PTMs, i.e., vitamin D-binding protein (K75-ac and K370-ac) and plasma protease C1 inhibitor (Y294-p), which may also contribute and negatively impact on CRC progression. Conclusions: The contribution of cytokines and proteins of the extracellular matrix is the most significant factor in CRC development in the early stages. This can be concluded since tumor growth is tightly associated with chronic aseptic inflammation and concatenated malignancy related to loss of extracellular matrix stability. Due attention should be paid to Apolipoprotein E (APOE), Apolipoprotein C1 (APOC1), and Apolipoprotein B-100 (APOB) because of their impact on the malfunction of DNA repair and their capability to regulate mTOR and PI3K pathways. The contribution of the observed PTMs is still equivocal, but a significant decrease in the likelihood between modified and native proteins was not detected confidently.

Human fetal and tumor alpha-fetoproteins differ in conformationally dependent epitope variants expression.

Expression of two conformationally dependent epitopes (cdes) designated as cdeD and cde106 of human alpha-fetoprotein (hAFP) was studied in hAFP of fetal and tumor origin. This was done by immunoaffinity electrochromatography on nitrocellulose membrane and by ELISA. Using anti-cdeD and anti-cde106 monoclonal antibodies (MoAbs), the relationship between the cde-positive and cde-negative hAFP fractions was evaluated in 75 samples with the above techniques. It was shown that hAFP consists of cde-positive and -negative variants irrespective of its tissue origin. In all the tested AFP samples, cde-negative variants were found to be predominant, while certain quantitative differences in the content of cde-positive variants were observed. Thus, in the amniotic fluid hAFP (irrespective of normal or pathological fetal development), the level of the cde-positive molecules was higher than in hAFP of other origin (cord blood serum, patients' sera with hepatocellular carcinoma, germ cell tumors, and the other hAFP-positive tumor cases). In all the tested samples, cdeD- and cde106-positive variants were revealed practically in parallel with each other.

Renal safety of intravenous ibandronic Acid in breast cancer patients with metastatic bone disease.

INTRODUCTION: Renal adverse events are a troublesome complication of bisphosphonate therapy. This study investigated the effect of intravenous ibandronic acid (ibandronate) treatment on renal function in breast cancer patients with metastatic bone disease. METHODS: 74 patients were randomised to double-blind (but not dose-blind) treatment with bolus injections of ibandronic acid 2mg (n = 23), 1-hour infusions of ibandronic acid 6mg (n = 28), or placebo injections or infusions (n = 23). According to randomisation, patients received either three injections or three infusions over the 3-month period, one at the start and two subsequent doses at 4-weekly intervals. Measurements of urinary excretion of total protein, albumin, alpha(1)-microglobulin, N-acetyl-beta-D-glucosaminidase, haematuria and serum creatinine were performed before, during and after treatment. RESULTS: Treatment with ibandronic acid was not associated with impairment of renal function; the renal safety profiles of ibandronic acid 2 and 6mg were similar to that of placebo. Assessments of proteinuria, haematuria, enzymuria and serum creatinine indicated that there were no statistically significant changes between pre- and post-treatment levels in patients receiving ibandronic acid 2 or 6mg or between patients receiving ibandronic acid or placebo. Urine parameters varied during treatment in the same range with approximately similar frequency in the ibandronic acid and placebo groups. CONCLUSIONS: Short-term administration of intravenous ibandronic acid did not impair renal function in breast cancer patients with metastatic bone disease. Because tolerability profiles vary between bisphosphonates, the lack of renal toxicity with ibandronic acid makes the drug an attractive treatment option for metastatic bone disease.

Autoantibodies against the Ca(2+)-binding protein recoverin in blood sera of patients with various oncological diseases.

In cancer, the retinal Ca(2+)-binding protein recoverin is a paraneoplastic antigen, the aberrant expression of which is capable of triggering the appearance of specific autoantibodies in the serum of patients with malignant tumors and the subsequent development of a paraneoplastic syndrome, cancer-associated retinopathy (CAR). The frequency of serum autoantibodies against recoverin (AAR), earlier determined at a rate of 15-20% in lung cancer, is much higher than the frequency of CAR syndrome, which is approximately 1%. In the present study, we estimated for the first time the frequencies of serum AAR in patients with various types of malignancies other than lung cancer. Patient biospecimens were collected to analyze for the presence of AAR. Additionally, various cell lines were cultivated and analyses were performed using Western blotting and RT-PCR. Results showed that in all cases tested, the AAR frequencies did not exceed 10%. Five AAR-positive patients with various types of cancer were available for ophthalmological investigation and only one of these patients had CAR syndrome. This result is consistent with the conclusion made in our previous studies of lung cancer that serum AAR do not necessarily trigger the development of CAR syndrome.