IGFBP-3/transferrin/transferrin receptor 1 complexes as principal mediators of IGFBP-3 delivery to colon cells in non-cancer and cancer tissues.

PURPOSE: The aim of this work was to study the involvement of IGFBP-3/Tf complexes in the pathology of colorectal carcinoma (CRC), quantify them, investigate their relation to iron concentration and binding to transferrin receptor (TfR) in colon tissue (non-cancer and cancer), and to assess the priority of this pathway for internalization of IGFBP-3. METHODS: The presence of IGFBP-3/Tf complexes was analyzed in sera from healthy persons and patients with CRC, and in colon tissue by immunoblotting. Complexes were immunoprecipitated, quantified by immunoassay and structurally characterized by immunoblotting, lectin blotting and mass spectrometry. Complexes which interacted with colon cells were immunoprecipitated with anti-TfR1 antibody and studied. Colon tissue slides were subjected to immunohistochemical analysis. RESULTS: The concentration of IGFBP-3/Tf complexes was three times lower in patients with CRC. They were increasingly carbonylated, sialylated, contained more Galß4GlcNAc units, expressed altered charge density and increased affinity for metal ions. Immunoprecipitation experiments revealed more TfR1 on membranes than in cytosol of colon cells, also more in cancer than non-cancer tissue. TfR1 on membranes were less occupied with IGFBP-3/Tf complexes than in cytosol. Immunofluorescent staining indicated a remarkable degree of co-localization of IGFBP-3 and TfR1, evenly distributed in non-cancer tissue and both evenly and cell surface concentrated in cancer tissue. CONCLUSIONS: Increased expression of TfR1 on colon cell membranes in patients with CRC compensates for the reduced extracellular availability of IGFBP-3/Tf and TfR1 is the principal binding partner of extracellular IGFBP-3. IGFBP-3/Tf complexes in patients with CRC exhibit increased affinity for iron ions.

Molecular forms of the insulin-like growth factor-binding protein-2 in patients with colorectal cancer.

The components of the insulin-like growth factor (IGF) system and molecules with which they interact are associated with the neoplastic transformation of cells in colorectal cancer. The IGF-binding protein-2 (IGFBP-2) plays a significant role in mitotic stimulation of the cancer cells and its concentration is significantly elevated in tumor states. Little is known about IGFBP-2 at the molecular level and the purpose of this study was to examine the interactions between IGFBP-2 and some other proteins, the fragmentation pattern and posttranslational modifications that might have occurred due to a disease. Results have shown that the amount of monomer IGFBP-2 was 20-30% greater in patients with cancer and the amount of fragmented IGFBP-2 was doubled compared to healthy people, whereas the portion of IGFBP-2 in complex with α2 macroglobulin (α2M) was 2.5 times lower in cancer patients. According to this distribution, IGFBP-2 was not only increasingly synthetized in patients with cancer, but also the amount involved in complexes with α2M was reduced favoring the existence of binary IGFBP-2/IGF complexes, free to leave the circulation. Both IGFBP-2 and α2M were significantly more oxidized in patients with colon cancer than in healthy individuals and α2M was additionally sialylated. It can be speculated that the formation of IGFBP-2/α2M complexes is part of the control mechanism involved in the regulation of IGFBP-2 and, consequently, IGF availability. It also seems that posttranslational modifications are more important factors in determining the amount of IGFBP-2/α2M complexes than the actual quantity of these two proteins.

Detection and identification of oxidized insulin-like growth factor-binding proteins and receptors in patients with colorectal carcinoma.

Colorectal cancer (CRC) is one of the most prevalent cancers worldwide and also the one with the highest mortality rate. Tumor growth is assisted by various growth factors, and insulin-like growth factors (IGFs) are among the most important. A majority of the IGFs are bound to IGF-binding proteins (IGFBPs) and their release is dependent on the rate of IGFBP proteolysis. The action of free IGFs is exerted and controlled by binding to cell membrane receptors (IGF-Rs). The objective of this work was to connect two determinants of the CRC pathology: oxidation as a process that underlies tumor development and the members of the IGF system that control it. Carbonyl groups (CO) on IGFBP-2, IGFBP-3, IGF-1R, and IGF-2R were determined in samples obtained from patients with CRC, and IGF-binding properties of these proteins were analyzed. According to our results, IGFBP-2 and IGFBP-3 in serum had increased content of CO groups due to CRC. Oxidation of IGFBP-2 increased its affinity for IGF molecules, whereas oxidation of IGFBP-3 reduced it. As for receptors, only intact CO-IGF-2R was detected on solubilized colon membranes, whereas CO-IGF-1R was degraded into fragments. Oxidative changes in the IGF axis may be regarded as part of the mechanism of its action. IGFs bound to IGFBP-3 remain in the circulation, whereas those bound to IGFBP-2 freely reach target tissues. Therefore, oxidation supports IGF distribution toward tissues and, consequently, promotes tumor growth.

[Functional effects of preserving the intercostobrachial nerve and the lateral thoracic vein during axillary dissection in breast cancer conservative surgery].

BACKGROUND/AIM: Conventional axillary dissection in breast cancer surgery implicates the section of the neurovascular elements passing through the dissected tissue: the intercostobrachial nerve (ICBN) and lateral thoracic vein (LTV). Preservation of the ICBN during axillary dissection is well documented in the literature, with slightly contradictory results of its influence to postoperative pain. There is no published data, as far as we know, on the functional effects of preserving the LTV. We supposed that ligation of the LTV contributes to the emergence of postoperative breast edema, which is common in breast cancer conservative surgery. The preservation of venous drainage could diminish the frequency of this undesired occurrence. METHODS: In a prospective study, 126 patients undergoing axillary node clearance for breast cancer of stages I and II were randomly selected for preservation of ICBN and LTV (n=65), or for conventional dissection (n=61). Sensory deficit, pain and breast edema as a dichotomized characteristics were examined in the first two weeks after the surgery. RESULTS: No difference in the number of dissected nodes was seen between the two groups (p = 0.7). The loss of sensitivity was significantly less common in the group randomized for ICBN preservation (16/65 vs. 30/61,p < 0.005), while there was no difference in the pain intensity and duration (49/65 vs 44/61, p > 0.05). LTV was preserved in 22 patients in the group for preservation, and in none of the control group. Breast edema was registered in 33 patients from the group for preservation (51%) and in 37 patients from the control group (61%). The difference in distribution was not significant, and the same results were obtained when the frequency of breast edema in the group with preserved LTV (22 patients, 10 of them without breast edema) was compared with the all others (p > 0.05). CONCLUSION: The preservation of the ICBN significantly improved the functional effect of the axillary dissection for breast cancer by reducing sensory loss, while there was no difference in pain intensity and duration. Although we did not prove that the preservation of LTV prevents breast edema after conservative surgery for breast cancer, we think that more complex analysis, including parameters such as the extent of resection of breast tissue, the dimension and constitutional characteristics of the breast, tumor location, obesity, and further developments in surgical technique, would reveal at least discrete improvements in the functional results of this surgical approach.

[Rene Favaloro--a surgeon who has changed the history of coronary disease].

Rene Favaloro was one of the most distinguished surgeons of the 20th century. He was the first to introduce the original technique of aortocoronary bypass grafting, entering the new era of coronary artery disease treatment. Working at the Cleveland Clinic, together with Mason Sones and Effler, he became a member of the medical team which performered the first aortocoronary bypass grafting and showed the functional competence of the new graft. Although today percutaneous coronary interventions and coronary artery stents have a very important role in coronary artery disease treatment, five years after his death aortocoronary bypass grafting is the method of choice in selected groups of patients. Nowadays, when urgent percutaneous coronary interventions are an important treatment option in our country, it is good to remember that this also was the idea of Rene Favaloro and Mason Sones, who discussed agressive treatment in the first hours of myocardial infarction, and to remember his tremendous contributions and life dedicated to cardiosurgery.