Ewa Kopczyńska

Role of microRNAs in the resistance of prostate cancer to docetaxel and paclitaxel.

Taxanes, a group of cancer drugs that includes docetaxel and paclitaxel, have become a front-line therapy for a variety of metastatic cancers, but resistance can develop. There are several docetaxel resistance mechanisms in prostate cancer: unfavorable tumor microenvironment, drug efflux pump, alterations in microtubule structure and/or function, and apoptotic defects (e.g. up regulation of Bcl-2 and clusterin or activation of the PTEN/PI3K/mTOR pathway or activation of the MAPK/ERK pathway). MicroRNAs (miRNAs), small regulatory molecules, could also function as a contributor to the resistance of cancer cells to commonly used anti-cancer drugs. Aberrant expressions of miRNAs that can act as tumor suppressors or oncogenes are closely associated with the development, invasion and metastasis of various cancers including prostate cancer. Nearly 50 miRNAs have been reported to be differentially expressed in human prostate cancer so far, but knowledge concerning the effects of miRNAs on the sensitivity to anti-cancer drugs is still limited. The author of the review focus on probable impact of miRNAs on the resistance to docetaxel and paclitaxel. Overexpression of miR-21 increased the resistance of prostate cancer cells to docetaxel by targeting PDCD4, PTEN, RECK, and BTG2. Nevertheless, decreased expressions of tumor suppressors: miR-34a, miR-143, miR-148a and miR-200 family are involved in resistance of anti-cancer drugs by inhibition of apoptosis and activation of signaling pathways. Conclude miRNAs become very attractive target for potential therapeutic interventions.

Endoglin - a marker of vascular endothelial cell proliferation in cancer.

Endoglin (CD105) is an accessory receptor of transforming growth factor B. The highest synthesis, as well as expression, of endoglin has been found in vascular endothelial cells. The involvement of endoglin in angiogenesis and in angiogenesis-dependent processes has been observed. Endoglin promotes angiogenesis not only by activation of vascular endothelial cell proliferation but also by induction of the antiapoptotic pathway in hypoxic endothelial cells. The potential application of endoglin as a tumour angiogenesis marker, useful for cancer diagnostics and clinical application, is anticipated. Endoglin expression may be useful as an indicator of disease progression and helpful for estimation of recurrence and metastasis risk.

The comparison of serum vascular endothelial growth factor levels between patients with metastatic and non-metastatic thyroid cancer, and patients with nontoxic multinodular goiter

BACKGROUND One of the important proangiogenic factors involved in the growth of normal and neoplastic tissues is vascular endothelial growth factor (VEGF). AIM We hypothesized that serum VEGF concentration would differ between patients with metastatic and non-metastatic thyroid cancer, multinodular goiter, and healthy subjects. We also hypothesized that endogenous TSH stimulation would affect serum VEGF level. SUBJECTS AND METHODS The study group consisted of 71 patients (62 females and 9 males), aged 44.9 +/- 12.3 years, with differentiated thyroid cancer (50 papillary, 17 follicular, and 4 oxyphilic), treated in our department during the years 2003-2006. All patients had undergone total or near-total thyroidectomy and radioactive iodine treatment, that had resulted in remission in 59 patients and persistent/recurrent disease in 12 patients. The study included two control groups: 30 patients with nontoxic multinodular goiter and 30 healthy subjects. RESULTS Serum VEGF concentrations were significantly higher in patients with distant metastases than those in remission or healthy patients. (423.4 vs 217.6 vs 235.55 pg/ml respectively, P < 0.05). This was not observed in patients with locoregional metastases. During endogenous TSH stimulation, VEGF decreased significantly (215.3 vs 169.6 pg/ml, P < 0.05). Patients with multinodular goiter showed significantly lower VEGF concentrations than the remaining study groups. CONCLUSIONS Serum VEGF concentration might be used as an additional marker of thyroid cancer with distant metastases, but its interpretation should be undertaken very cautiously. Endogenous TSH stimulation decreases VEGF levels in patients either with or without thyroid tissue, suggesting that its regulatory effects are through receptors located outside the thyrocytes.

Visfatin concentrations in obese patients in relation to the presence of newly diagnosed glucose metabolism disorders.

INTRODUCTION Visfatin, protein secreted by visceral adipose tissue, exerts insulin-mimetic actions. Visfatin concentration increases in patients with longer-standing diabetes type 2 with progressive b-cell dysfunction. Data about the role of visfatin in newly diagnosed glucose metabolism abnormalities are limited. Evaluation of visfatin concentration in patients with obesity, in relation to the presence of newly diagnosed glucose metabolism disorders. MATERIAL AND METHODS The study included 68 subjects with obesity, without a previous diagnosis of abnormal glucose metabolism. In all subjects we performed an oral glucose tolerance test, and according to the results the group was divided into the subgroups: A (n = 31), with glucose metabolism disorders (impaired fasting glucose, impaired glucose tolerance and type 2 diabetes); and B (n = 37), without abnormalities. In all subjects serum lipids, uric acid, C-peptide, glycated haemoglobin (HbA1c), creatinine, and serum visfatin concentrations were measured. The control group comprised 30 lean, healthy individuals with normal glucose tolerance. RESULTS We found elevated visfatin levels in obese individuals versus the control group (50.0 ± 48 vs. 26.7 ± 22.1 ng/mL; p = 0.01). Visfatin concentrations in both subgroups, A and B, did not differ (40.86 ± 27.84 vs. 57.7 ± 59.79 ng/mL; p = 0.19). In subgroup A visfatin concentration correlated significantly with triglycerides (r = 0.37, p = 0.038), HbA1c (r = -0.43, p = 0.02), C-peptide (r = -0.38,p = 0.048), and waist-hip ratio (r = -0.41, p = 0.036). CONCLUSIONS The presence of newly diagnosed glucose metabolism abnormalities in obese subjects had no influence on the visfatin level, probably due to preserved endogenous insulin secretion and relatively short exposure to hyperglycaemia in patients with prediabetes or at early stage of type 2 diabetes.

Angiogenesis and lymphangiogenesis as prognostic factors after therapy in patients with cervical cancer

Aim of the study This retrospective study attempts to evaluate the influence of serum vascular endothelial growth factor C (VEGF-C), microvessel density (MVD) and lymphatic vessel density (LMVD) on the result of tumour treatment in women with cervical cancer. Material and methods The research was carried out in a group of 58 patients scheduled for brachytherapy for cervical cancer. All women were patients of the Department and University Hospital of Oncology and Brachytherapy, Collegium Medicum in Bydgoszcz of Nicolaus Copernicus University in Toruń. VEGF-C was determined by means of a quantitative sandwich enzyme immunoassay using a human antibody VEGF-C ELISA produced by Bender MedSystem, enzyme-linked immunosorbent detecting the activity of human VEGF-C in body fluids. The measure for the intensity of angiogenesis and lymphangiogenesis in immunohistochemical reactions is the number of blood vessels within the tumour. Statistical analysis was done using Statistica 6.0 software (StatSoft, Inc. 2001). The Cox proportional hazards model was used for univariate and multivariate analyses. Univariate analysis of overall survival was performed as outlined by Kaplan and Meier. In all statistical analyses p < 0.05 (marked red) was taken as significant. Results In 51 patients who showed up for follow-up examination, the influence of the factors of angiogenesis, lymphangiogenesis, patients’ age and the level of haemoglobin at the end of treatment were assessed. Selected variables, such as patients’ age, lymph vessel density (LMVD), microvessel density (MVD) and the level of haemoglobin (Hb) before treatment were analysed by means of Cox logical regression as potential prognostic factors for lymph node invasion. The observed differences were statistically significant for haemoglobin level before treatment and the platelet number after treatment. The study revealed the following prognostic factors: lymph node status, FIGO stage, and kind of treatment. No statistically significant influence of angiogenic and lymphangiogenic factors on the prognosis was found. Conclusion Angiogenic and lymphangiogenic factors have no value in predicting response to radiotherapy in cervical cancer patients.

The potential therapeutic applications and prognostic significance of metastasis associated in colon cancer 1 (MACC1) in cancers

The metastasis-associated in colon cancer-1 (MACC1) gene was identified in 2009. Expression of MACC1 was found to be significantly upregulated in primary and metastatic colon carcinomas compared to normal tissues or adenomas. The induction of MACC1 occurs at the crucial step of transition from a benign to a malignant phenotype. The aim of this review was to summarise current results of non-clinical and clinical studies on the role of MACC1 in the carcinogenesis and progression of cancer, as well its potential therapeutic and prognostic significance. The gene encoding the HGF receptor MET is a transcriptional target of MACC1. In addition to promoting the proliferation, invasion, and migration of colon cancer cells in cell culture and tumour growth and metastasis in mouse models, MACC1 also contributes to carcinogenesis and progression of colorectal cancer through the β-catenin signalling pathway and mesenchymal-epithelial transition. MACC1 knockdown with si/sh RNA was investigated in cell lines of different types of cancer. MACC1 is a promising therapeutic target for antitumour and antimetastatic intervention strategies for cancers. Here, it is presented as a potential independent prognostic indicator of reduced overall survival as well as of the occurrence of distant metastasis in patients with different types of cancer.

Time-Dependent Changes of Plasma Concentrations of Angiopoietins, Vascular Endothelial Growth Factor, and Soluble Forms of Their Receptors in Nonsmall Cell Lung Cancer Patients Following Surgical Resection

Even when patients with nonsmall cell lung cancer undergo surgical resection at an early stage, recurrent disease often impairs the clinical outcome. There are numerous causes potentially responsible for a relapse of the disease, one of them being extensive angiogenesis. The balance of at least two systems, VEGF VEGFR and Ang Tie, regulates vessel formation. The aim of this study was to determine the impact of surgery on the plasma levels of the main angiogenic factors during the first month after surgery in nonsmall cell lung cancer patients. The study group consisted of 37 patients with stage I nonsmall cell lung cancer. Plasma concentrations of Ang1, Ang2, sTie2, VEGF, and sVEGF R1 were evaluated by ELISA three times: before surgical resection and on postoperative days 7 and 30. The median of Ang2 and VEGF concentrations increased on postoperative day 7 and decreased on day 30. On the other hand, the concentration of sTie2 decreased on the 7th day after resection and did not change statistically later on. The concentrations of Ang1 and sVEGF R1 did not change after the surgery. Lung cancer resection results in proangiogenic plasma protein changes that may stimulate tumor recurrences and metastases after early resection.

Potential applications of tenascin C for cancer diagnosis and therapy

Tenascyny są rodziną czterech wielodomenowych glikoprotein macierzy zewnątrzkomorkowej: tenascyna C, X, R i W. Pierwszym poznanym przedstawicielem tej rodziny byla tenascyna C. Bialko to spotykane jest rowniez pod innymi nazwami, takimi jak antygen macierzy zewnątrzkomorkowej glejaka, myotendinous antigen, heksabrachion, glikoproteina J1220/200 czy neuronektyna. Tenascyna C jest heksamerem; kazde ramie heksabrachionu zawiera: aminokoncową domene oligomeryzacji, powtorzenia podobne do naskorkowego czynnika wzrostu, domeny typu fi bronektyny III oraz homologiczną do fi brynogenu domene globularną. Wzor ekspresji tenascyny C zalezy od fazy rozwoju organizmu, a ekspresja zmienia sie znacząco w wielu roznych stanach patologicznych. W czasie embriogenezy tenascyna C jest obecna zwlaszcza w rozwijającym sie ośrodkowym ukladzie nerwowym, w mezenchymie w miejscach przejścia mezenchymalno-epitelialnego, a takze w rozwijających sie tkankach lącznych. W dojrzalych tkankach ekspresja tenascyny C jest slabsza, natomiast jest indukowana podczas gojenia ran, regeneracji nerwow, inwolucji tkanek, a takze w stanach patologicznych, takich jak choroby naczyniowe, nowotworzenie i przerzutowanie. Ekspresja tenascyny C zarowno podczas rozwoju organizmu, jak i w przebiegu choroby jest indukowana przez cytokiny pro- i przeciwzapalne, czynniki wzrostu, a takze przez wolne rodniki tlenowe, hipoksje i stres mechaniczny. Udzial tenascyny C w rozwoju nowotworow polega na: 1) bezpośredniej stymulacji komorek nowotworowych do proliferacji i migracji, 2) promocji angiogenezy przez wplyw na komorki endotelialne. Tenascyna C bierze udzial nie tylko w rozwoju guza pierwotnego, ale takze uczestniczy w procesie przerzutowania i w ucieczce spod nadzoru immunologicznego. Jest ona przedstawiana jako niekorzystny czynnik rokowniczy, miedzy innymi w nowotworach piersi, nerek, pecherza moczowego, wewnątrzwątrobowych drog zolciowych, pluca, krtani i gardla dolnego oraz mozgu. Z kolei w raku szyjki macicy wysoka ekspresja koreluje z dobrą prognozą. Poza tym ekspresja tenascyny C moze zostac wykorzystana do wykrywania wznowy nowotworow mozgu, a fragmenty tenascyny C — do wykrywania raka pluca. Tenascyna C moze byc nie tylko narzedziem diagnostycznym, badane jest rowniez jej zastosowanie w obrazowaniu i leczeniu nowotworow. Nowe strategie bazują na przeciwcialach, oligonukleotydach antysensownych, rybozymach, aptamerach oraz w zastosowaniu interferencji RNA.