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.

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The expression of two discrete cell properties related to the host natural effector mechanisms, i.e., resistance to damage by H2O2, a cytotoxic product of activated macrophages, and the ability to secrete PGE, which inhibits NK-cell cytotoxicity, has been examined in parental Syrian hamster embryo cells spontaneously transformed in vitro (STHE strain) and in 18 in vivo selected sublines. In all cell variants, resistance to H2O2 and PGE-releasing activity were either both expressed, or not expressed at all. Parental STHE cells and 5 variants selected in vivo, which were equally highly susceptible to H2O2-induced damage, did not release any detectable amount of PGE upon contact with NK cells. In contrast, 13 other STHE variants selected in vivo and characterized by their resistance to H2O2, all released PGE upon contact with NK cells. Thus, these two biochemically unrelated cell phenotypic characteristics are likely to be either simultaneously selected in vivo, or united in cluster which pre-exist or appear in rare cell variants of the parental cell population in the conditions of in vivo natural selection pressure.

The content of matrix metalloproteinases 7 and 9 was significantly increased, while the content of metalloproteinase 2 was reduced in ovarian cancer tissue compared to benign tumors. In blood serum from patients with ovarian cancer, the concentrations of matrix metalloproteinases 7 and 9 and their type 1 tissue inhibitor were significantly elevated, while the concentration of matrix metalloproteinase 2 was reduced compared to the corresponding parameters in healthy women. After chemotherapy, tissue and serum concentrations of metalloproteinases and their inhibitor in patients practically returned to normal. A significant positive correlation between serum levels of matrix metalloproteinases 7 and 9 and tissue inhibitor of metalloproteinases-1 in patients with ovarian cancer and the size of primary tumor (ultrasound examination) and a positive correlation between these parameters and the concentration of classical ovarian cancer marker CA-125 were demonstrated.

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