Littérature scientifique sur le sujet « ION CHANNELS hERG1 COLORECTAL CANCER BREAST CANCER »

Cancer can be viewed as a "tissue", where neoplastic cells are immersed into a peculiar microenvironment (the "tumor microenvironment", TME) which modulates tumor cell behaviour during multistep tumorigenesis. Based on this concept, antineoplastic therapy should be tuned to target not only tumor cells but also the cellular constituents of the TME. Such necessity is well exemplified by considering tumor angiogenesis, a major aspect of cancer biology. Ion channels and transporters are increasingly recognized as relevant players in the tumor cell-TME cross-talk. For example, during tumor neo-angiogenesis, soluble factors as well as fixed components of the extracellular matrix (ECM) and membrane proteins determine signal exchange between the TME and the implicated cell types. The signalling network is coordinated by functional "hubs", which may be constituted by integrin receptors associated with other proteins to form macromolecular signalling platforms at the adhesive sites. These complexes often include ion channels. The K + channels encoded by the human ether-à-go-go related gene (Kv11.1, or hERG1) are frequently overexpressed in human cancers and regulate intracellular signalling by physically associating with integrin subunits and growth factor/chemokine receptors. In colorectal cancer (CRC) we recently identified a novel signalling pathway centered on hERG1 channels and integrins. This pathway involves the p53 protein, which is encoded by a tumor suppressor gene often mutated in human cancers. p53 controls angiogenesis, through a mechanism regulated by hERG1 K + channels. The central role played by hERG1 in CRC angiogenesis suggests that targeting hERG1 may be an effective therapeutic option in patients with advanced CRC. To better understand the above process, it is necessary to study the interlaced dynamics of the key microscopic actors by using dedicated mathematical models. We here review a simple model, of reductionist inspiration, that explores the intimate connections between apoptosis and hypoxia, passing through angiogenesis. We show that a dynamical switch takes place between the normoxia and cellular death conditions. When oxygen lacks, cells can cross the transition line and so gain their way towards the normoxia regime, by implementing point mutations that affect the p53 production and activation rate, with the involvement of K + ion homeostasis, in agreement with the experimental observations.

Surgical resection was the main approach to cancer therapy, often supplemented by radiation and chemotherapy. The effectiveness of such complex treatment in many cases remains low. In this regard, there is an urgent need to search for new compounds that have selective cytotoxic activity against tumor cells and do not damage normal tissues of the organism. The review discusses mechanisms of antitumor action of cationic antimicrobial peptides (AMPs) of the cathelicidin family - human α-helical cathelicidin (LL-37), and a peptide with β-hairpin conformation – protegrin-1 (PG-1) on lung, breast, pancreas, prostate, squamous skin cancer cells, oral cancer, stomach, ovarian, colorectal cancer, melanoma, leukemia, lymphoma, glioma and neuroblastoma cells. An opportunity of antitumor and pro-oncogenic actions of the peptides and an interplay of these effects with mmunomodulatory action of AMPs on tumor-associated macrophages, natural killer cells and T-lymphocytes is discussed. Possible mechanisms of LL-37 and PG-1 selective action upon tumor cells are presented, including the interaction of LL-37 with G-protein-coupled receptors: the N formylpeptide-2 receptor (FPR2), CXC chemokine-2 (CXCR2), Mas-related gene X2 (MrgX2), purinergic (P2Y11), epidermal (EGFR/ErbB1, ERBb2), insulin-like (IGF1R) growth factors, ligand-gated ion channels (LGIC) and Tolllike (TLR) receptors, with expression varying significantly in different types of tumors, as compared to normal tissues. An increase in the level of LL-37 secretion and expression of its CAMP gene are associated with progression of lung adenocarcinoma, breast, pancreas, and prostate cancer, ovarian cancer, melanoma, and squamous cell carcinoma of the skin. In contrast, CAMP expression and LL-37 secretion are significantly reduced in gastric cancer cells, oral squamous cell cancer, colorectal cancer, leukemia, lymphomas, gliomas, and SH-SY5Y neuroblastoma. Therefore, therapeutic effects of LL-37 can only be used for specific types of tumors. The mechanisms of action of PG-1 on tumor cells are still poorly understood, although the available data indicate that protegrin exhibits a more unidirectional effect, i.e., it damages cell membranes. Protegrin-1 and LL-37 can synergistically enhance the antitumor effects of chemotherapy drugs and have a more pronounced effect on tumor cells, than upon normal cells. Natural AMPs appear to be promising candidates for the role of new antitumor agents, which are also active against malignant metastatic, recurrent multidrug-resistant tumors. On the other hand, peptides such as LL-37, in some cases, exhibit properties that can be considered pro-oncogenic, which indicates a need for further detailed studies on the molecular mechanisms of their action on tumor cells.

Abstract Relationship between LDH and Mg in Monitoring of Hematological and Non-Hematological Malignant Disease Aurelian Udristioiu, Titu Maiorescu University of Bucharest, Faculty of Medicine, Department of Molecular Biology ABSTRACT Background Magnesium, which is the second most abundant into-cellular cation after potassium, plays a key role in regulating many cellular functions and enzymes, including ion channels, metabolic cycles, and signaling pathways. Aim of this study was to evaluate the correlation between the serum levels of lactate dehydrogenase (LDH) and magnesium (Mg) in patients diagnosed with hematological and non-hematological malignant diseases. Method We analyzed a cohort of patients (n = 75) comprising males (n = 36) and females (n =39) with a mean age of 57 years, who had cancer and were admitted to the oncology department. The biochemical parameters were measured running a Vitros 250 dry chemistry analyzer (Johnson & Johnson, USA) using the slides for multi-layer spectro-photometry measurements. These patients were closely monitored twice a week during treatment with specific cytostatic drugs and once a week during consolidation therapy, using specific tests for different types of cancer. In addition, with the cooperation of physicians and patients, they were performed along with hematological and biochemical tests, CBC with differential count and LDH and serum Mg levels, which can serve as markers for monitoring the progression of malignancies. Among the patients, 5 patients were diagnosed with lung cancer, 11 patients were diagnosed with breast cancer, 14 patients were diagnosed with colorectal cancer, 43 patients were diagnosed with chronic lymphocytic leukemia (CLL), 1 patient was diagnosed with acute promyelocytic leukemia (LAM-3) and 1 patient was diagnosed with chronic monocytic leukemia (CML). The CBC with the differential count, biochemistry samples, body radiography, ultrasound and computed tomography (CT) were used for the patient to establish the type of cancer diseases. An initial panel of monoclonal antibodies was used to determine the immune phenotypes of the subgroups of differentiated T cells and B cells. The diagnosis of LAM-3 was made based on blood smears, the examination of bone marrow (BM) aspirates, the evaluation of promyelocytes, (greater than 30% in BM), and the presence of a specific immune phenotype. Results The results were interpreted for each patient based on medical history, clinical and para-clinical examinations and other signs of malignant diseases. Among the patients in this study, 55 patients (73%) exhibited normal serum levels of Mg (normal range value = 1.60-2.3 mg/dL; mean value = 2.2 mg/dL; SD = 0.2; p = 0.02) following cancer therapy. Six patients (8%) exhibited low levels of Mg (range = 0.60-1.50 mg/dL; mean value = 1.05 mg/dL). However, 12 patients (16%) displayed high levels of serum Mg (range =2.6-3.27 mg/dL; mean value = 2.89 mg/dL). The levels of serum lactic dehydrogenase (LDH) were also evaluated in patients newly diagnosed with cancer and in patients with unfavorable responses to the cancer therapy (range = 240-1330 U/L; mean value = 787 U/L; SD =1.33; p = 0.002; normal values 135-225 U/L), (Table 1). Discussions The serum Mg level is increased via Mg²+ release from malignant tissues in patients with malignant disease prior to treatment with cytostatic drugs. In the different malignant diseases, the serum Mg values were high, normal or low, independent of the serum LDH values. The LDH levels remained elevated after initial cytostatic treatment until cancer remission. The number of chromosome copies in malignant tumors can be correlated with the total serum LDH values. LDH levels in cancer patients are elevated due to high levels of LDH-3 isoenzyme in patients with malignancies and high levels of LDH-4 and LDH-5 isoenzymes, elevated patients with cancer of liver, muscle, lung and tissue tissues. conjunctive. High concentrations of serum LDH damage the cell membrane. Thereafter, malignant cells become invasive and metastasizes. Conclusions Normal levels of Mg with moderately increased LDH levels were observed in all patients who had cancer that was in the regression phase following good responses to a specific cancer therapy. Low levels of Mg with high levels of serum LDH were observed in all patients with poor prognosis and metastases. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Ion Channels and Transporters (ICTs) are progressively emerging as a novel class of membrane proteins expressed in several types of human cancers and regulating the different aspects of cancer cell behavior. One of the ion channels dysregulated in cancers is hERG1 potassium channel and we investigated the role of hERG1 and other ICTs in colorectal and breast cancer. We started with the analysis of a pro-angiogenic signalling pathway involving hERG1 and β1-integrin (reported earlier in vitro) in primary samples from mCRCa (metastatic Colorectal Cancer) patients treated with Bevacizumab (BV). We found that this pro-angiogenic pathway interacts also in mCRC patients and that hERG1 is a positive prognostic biomarker for mCRCa patients treated with BV. Then we studied the role of hERG1 and Kca3.1 potassium channels in pH regulation mechanisms in colorectal cancer cells. It emerged that there is a cross talk among β1-integrins, hERG1, Kca3.1 and sodium-hydrogen exchanger 1 (NHE1) in cells and primary samples of CRCa. So we started to investigate the expression of hERG1, Kca3.1 and NHE1 in breast cancer. For the first time, hERG1 expression was found in primary breast cancer tissues and it emerged that hERG1 expression is associated with molecular subtype group. Since the nNaV1.5 channel has a principle role in breast tumor progression and we found that hERG1 is expressed in breast cancer tissues and in vitro data demonstrated that there is a networking between hERG1 and nNaV1.5 channels, we performed analysis for nNaV1.5. We found that hERG1 and nNaV1.5 are expressed in primary breast cancer samples and they are positively associated. It occured particulary in Basal Like/triple negative samples and the co-expression was found in the some tumor cells. These data encourage us to develop a monoclonal antibody (mAb) capable to recognise the nNaV1.5 channel. Thus 24 mAb clones were produced and screened and we validated putative mAbs and isolated one mAb with promising high specificity for nNaV1.5, with significant oncological therapeutic potential.