Katarzyna Walkiewicz

Clinical Significance and Prognostic Relevance of Microsatellite Instability in Sporadic Colorectal Cancer Patients

Microsatellite instability (MSI) is a marker of the replication error phenotype. It is caused by impaired DNA mismatch repair processes (MMR), resulting in ineffectiveness of the mechanisms responsible for the DNA replication precision and postreplicative DNA repair. MSI underlies the pathogenesis of 10%–20% of colorectal cancer (CRC) cases. The data about the potential value of MMR status as a predictive factor for 5-fluorouracil (FU)-based chemotherapy remain unclear. According to National Comprehensive Cancer Network updated guidelines, MSI testing is recommended for all patients with stage II CRC because patients with MSI-H (high-frequency MSI) tumour may have a good prognosis and obtain no benefit from 5-FU-based adjuvant chemotherapy. The significance of the MSI status as a predictive factor for patients with metastatic disease was not confirmed. The association between the MSI status and the efficacy of the therapy based on anti-programmed death-1 receptor inhibitors requires further studies.

Aflatoxins: characteristics and impact on human health

Some molds commonly occurring in the natural environment produce mycotoxins in the process of secondary metabolism. Aspergillus flavus and A. parasiticus are species of molds, which are responsible for the production of aflatoxins and are crucial in the pathogenesis of human diseases. Aspergillus species present in decaying plants, the soil and their spores are transferred via air currents and insects to crops and food storages. Aflatoxins B1, B2, G1, G2, M1 and M2 are the most common derivatives of aflatoxins. Ingestion of contaminated food is the main source of exposure to aflatoxins, which adversely affect the health of both humans and animals. The compounds can cause acute or chronic toxic effects of a teratogenic, mutagenic, carcinogenic, immunotoxic or hepatotoxic character. Molecular aflatoxins affect DNA mutations, postranslation peptids chains modification, proteins and nucleic acids methylation and the formation of free radicals. Due to aflatoxins carcinogenic features and frequent occurrence in food and forages they are routinely examinated in some groceries and agricultural products.

Expression of Migration-Related Genes in Human Colorectal Cancer and Activity of a Disintegrin and Metalloproteinase 17

Introduction. The ability to form metastases which depends on the mechanisms of cell migration is an important element of the progression of cancer. In the present study we analyzed the genes involved in the regulation of migration in colon cancer cells. Materials and Methods. A total of 20 pairs of surgically removed tumoral and healthy (marginal) tissues samples from colorectal cancer patients at clinical stages I-II and III-IV were analyzed. The isolation of RNA from CRC and normal tissues and its subsequent molecular analysis were performed according to manufacturers instructions. Microarray data analysis was performed using the GeneSpring 11.5 platform and Significance Analysis of Microarrays (SAM). In SAM analysis to identify significantly differentially expressed genes score and q-value parameters were used. Results. The largest increase in expression of genes was shown by MMP9, ADAM17, EphA2, and TIMP. Conclusions. Presented genes, especially ADAM17, MMP9, EphA2, TIMP1, ICAM 11, and CD4, may be used as prognostic markers of advanced stages of colorectal cancer, contributing to the development of new lines of therapy focused on reducing metastasis of the primary tumor.

Profile of gene expression of TLR-signaling pathways in colorectal cancer tissues:

Toll-like receptors (TLRs) are involved in transduction of molecular signals in immune process such as induction and regulation of immunity, production of cytokines, and recognition of specific molecular patterns on the surface of microorganisms, but also in cancer development—which was partially proven in previous studies. There is a lack of detailed research on differentiating levels of TLR expression in colorectal cancer at different stages of its advancement, so in our study we want to determine whether there is such a difference of TLRs and TLR-connected protein expression. In this study, 83 samples of colorectal adenocarcinoma (varying clinical degrees) and 40 slices of healthy colon tissue have been analyzed. The delivered material was subjected to homogenization and extraction of total RNA. The isolated RNA was subsequently purified and valued quantitatively and qualitatively. Quantification was performed using a spectrophotometer GeneQuant II. The RNA concentration in the tested samples was determined spectrophotometrically. A qualitative assessment was performed by performing electrophoresis on a 1% agarose gel stained with ethidium bromide. The expression profile of the genes encoding the TLRs was determined using oligonucleotide microarray HG-U133A. To determine the mRNA (messenger RNA), differentiate cancerous tissue from normal colon using PL-Grid Infrastructure. The results were analyzed statistically, taking a significance level P < 0.05. In the study were found three proteins, DUSP2, IFNγ, EIF4A1, associated with TLR system, that differentiate early stages of colorectal cancer of healthy tissue, moreover eleven, inter alia: vascular endothelial growth factor (VEGF), which differentiate high stage of cancer of healthy tissues. The results emphasize the role of pathways associated with TLR activation in the pathogenesis of colorectal cancer. In summary, molecular studies on the development of colorectal cancer will enable the introduction of minimally invasive genetic diagnosis of early forms of cancer. In addition, identification of new signaling pathways can provide the basis for developing new therapeutic methods.

The importance of ADAM family proteins in malignant tumors

Increasing numbers of reports about the role of adamalysins (ADAM) in malignant tumors are being published. To date, more than 30 representatives of this group, out of which about 20 occur in humans, have been described. The ADAM family is a homogeneous group of proteins which regulate, from the stage of embryogenesis, a series of processes such as cell migration, adhesion, and cell fusion. Half of them have proteolytic activity and are involved in the degradation of the extracellular matrix and the disintegration of certain protein complexes, thereby regulating the bioavailability of various growth factors. Many of these functions have a direct role in the processes of carcinogenesis and promoting the growth of tumor, which affect some signaling pathways, including those related to insulin-like growth factors (IGF1, IGF2), vascular growth factor (VEGF), tumor necrosis factor α (TNFα) and the EGFR/HER pathway. Another branch of studies is the evaluation of the possibility of using members of ADAM family proteins in the diagnosis, especially in breast, colon and non- small cell lung cancer. The detection of concentrations of adamalysin in serum, urine and pleural aspirates might contribute to the development of methods of early diagnosis of cancer and monitoring the therapy. However, both the role of adamalysins in the development and progression of tumors and their importance as a diagnostic and predictive further research still need to be checked on large groups of patients.

Praktyczne zalecenia żywieniowe w trakcie chemioterapii u chorych na nowotwory przewodu pokarmowego

Stan odzywienia chorych na nowotwory przewodu pokarmowego ściśle związany jest ze stosowanym leczeniem przeciwnowotworowym i wystepowaniem niepoządanych objawow związanych z terapią. Najcześciej u chorych w trakcie chemioterapii stwierdza sie zaburzenia w odczuwaniu smaku i zapachu, biegunki, zaparcia stolca oraz nudności i wymioty, co moze powodowac niechec do jedzenia, w konsekwencji prowadzic do niedozywienia chorego. Szacuje sie, ze niedozywienie wystepuje u okolo 80% chorych z rakiem przelyku, 60% – z rakiem zolądka i 10-15% – z rakiem jelita grubego. Stosowanie indywidualnych zalecen zywieniowych ma na celu lagodzenie niepoządanych objawow terapii oraz poprawiac stan odzywienia. Opieka dietetyczna powinna byc wlączona do planu opieki chorego i stanowic jego integralną cześc. W oddzialach szpitalnych, w ktorych nie funkcjonuje zespol terapeutyczny obowiązek zaznajomienia chorych z zaleceniami zywieniowymi spoczywa glownie na personelu pielegniarskim, dlatego upowszechnianie tego typu opracowan wydaje sie pomocne w codziennej pracy.

The role of some ADAM-proteins and activation of the insulin growth factor-related pathway in colorectal cancer

Colorectal cancer (CRC) is the third most common malignant neoplasm worldwide. In Poland, colorectal cancer ranks second in tumor incidence regardless of sex; moreover, there has been a steady increase in the incidence of CRC. CRC results from complex interactions between inherited susceptibility, clinical conditions and environmental/lifestyle-related risk factors such as physical inactivity, smoking, alcohol consumption, high-fat/low-fiber diet, and obesity/overweight. The activation of pathways associated with insulin resistance and insulin-like growth factors (IGF) appears to be the epidemiological link between the metabolic syndrome and the development of CRC, which is of particular importance. What is significantly associated with the pathway of IGF is ADAM12 and 28-protein, which belong to a broad family of the adamalysines. These proteins, by adjusting the bioavailability of growth factors, influence the process of carcinogenesis. The aim of this article is to analyze the role of selected adamalysines and activation of the IGF system associated with the formation of colon cancer.

Endothelins and carcinogenesis.

Endothelins are a family of four endogenous peptides (ET-1, ET-2, ET-3, ET-4) secreted primarily in an inactive form by the endothelium. They are activated with the participation of converting enzyme. Numerous studies have described their pleiotropic biological activity. These peptides are involved, inter alia, in the regulation of processes such as cell proliferation, migration, angiogenesis and apoptosis. Their important role in the regulation of blood pressure, tissue perfusion (especially in the central nervous system), and myocardial systolic function is also known. Moreover, changes in transcriptional activity of endothelin and its receptors may be involved, with the participation of a number of signaling pathways, in carcinogenesis, and the pathogenesis of numerous diseases (heart, kidney, lung and skin disorders, especially with the component of fibrosis). Their role has been documented in the development of breast, prostatic, colorectal, ovarian, lung, kidney, and endometrial cancer, and in melanoma. In this article we present a brief description of the endothelin group and the participation of them and their receptors in carcinogenesis. We also try to show their role as prognostic and predictive factors in human malignant tumors. The article also refers to clinical trials on the use of preparations of endothelin receptor antagonists in the design of molecular therapeutic strategies in human malignancies.

PTEN – clinical significance in colorectal cancer

Phosphatase and tensin homolog deleted on chromosome ten (PTEN ) is a human suppressor gene. Its protein product is a bispecific phosphatase playing the complex role in the cell cycle regulating processes and apoptosis by the mechanism of signal transduction into the cell via tyrosine kinase B signaling pathway (PI3K/Akt/mTOR). Reduction or loss of PTEN function is implicated in the pathogenesis of many malignancies, including colorectal cancer. A gradual decrease in the function of PTEN in the sequence of transformations: normal tissue–polyp–adenocarcinoma – disseminated cancer was indicated. The relation between the PTEN loss and the higher clinical severity of colorectal cancer was observed, i.a. higher TNM status and higher tendency to form metastases, leading in some of the studies to shortened patients survival during the observation period. The potential predictive value of the PTEN function loss for the EGFR-targeted therapy in patients with advanced colorectal cancer is the subject of controversy. The potential application of PTEN assessment in clinical practice as a prognostic and/or predictive factor requires further well-designed prospective studies on larger patient population, using the unified methodology. The aim of the study is to summarize the current knowledge on the role of PTEN gene and PTEN protein in the pathogenesis of colorectal cancer and the role of PTEN in clinical practice. KEY WORDs: PTEN, colorectal cancer, EGFR-targeted therapy Correspondence: Angelika Copija, MD Department of Clinical Oncology, Regional Specialised Hospital No. 4 in Bytom 41-900 Bytom, al. Legionów 10 e-mail: ang.c@wp.pl Received: 25.02.2016. Accepted: 16.05.2016.

Statins and colorectal cancer

Statins are naturally occurring compounds that inhibit the enzyme 3-hydroxy-3-methyl-glutaryl-CoA reductase. Through their beneficial management of the body’s lipid metabolism, they are widely used medicinal drugs employed extensively in the primary and secondary prevention of cardiovascular disease. In addition, many studies to date have shown the therapeutic advantages derived from using statins in conditions such as endometriosis, osteoporosis, polycystic ovary syndrome and rheumatic disease. Due to the steady increase of cancer morbidity rates, as demonstrated by epidemiological data, the putative role of statins in treating or preventing cancer has been ever more frequently investigated; including for colorectal cancer. This paper attempts to bring together current knowledge/ evidence on statin therapy targeted at the development, disease course and treatment of colorectal cancer, both in terms of epidemiological findings and clinical observations. Because of the reported link between metabolic disorders and the development of colorectal cancer, particular focus is given to the effects of statins on signalling pathways involving insulin-like growth factors (IGFs).