Magdalena Chechlinska - Academia.edu (original) (raw)

Papers by Magdalena Chechlinska

Research paper thumbnail of The role of cytokines in carcinogenesis

Nowotwory, 2003

Cytokiny sà bia∏kowymi mediatorami mi´dzykomórkowymi, odgrywajàcymi kluczowà rol´ w procesach pro... more Cytokiny sà bia∏kowymi mediatorami mi´dzykomórkowymi, odgrywajàcymi kluczowà rol´ w procesach proliferacji, ró˝nicowania, migracji i apoptozy komórek. Sà regulatorami reakcji odpornoÊciowych i zapalnych, procesów rozwoju, regeneracji i utrzymania homeostazy tkanek. Ich êród∏em sà ró˝ne typy komórek. Charakteryzuje je plejotropowoÊç dzia∏ania. Produkcja, uwalnianie i oddzia∏ywanie cytokin tworzy skomplikowanà sieç wzajemnych zale˝noÊci, które determinujà efekty biologiczne ich dzia∏ania. Wiele dowodów wskazuje na udzia∏ cytokin w patogenezie nowotworów. Cytokiny uczestniczà we wszystkich etapach nowotworzenia. Zmieniona ekspresja wielu cytokin oraz receptorów powierzchniowych i komponentów wewnàtrzkomórkowych szlaków sygnalizacyjnych cytokin w komórkach nowotworowych powoduje, ˝e ró˝nego typu cytokiny stajà si´ autokrynnymi i parakrynnymi czynnikami wzrostu i prze˝ycia tych komórek. Ponadto cytokiny indukujà zmiany w mikroÊrodowisku guza, sprzyjajàce jego rozwojowi, biorà udzia∏ w inwazji i tworzeniu przerzutów odleg∏ych. Sà wa˝nymi mediatorami typowej w nowotworach immunosupresji. Niniejszy artyku∏ przeglàdowy przedstawia udzia∏ cytokin w wielostopniowym procesie rozwoju nowotworów. Omówiono ich rol´ jako autokrynnych i parakrynnych czynników wzrostu, nieaktywnych czynników antyproliferacyjnych i czynników prze˝ycia komórek nowotworowych oraz mediatorów angiogenezy, inwazji, rozsiewu nowotworów i immunosupresji. Szczególnà uwag´ poÊwi´cono wyst´pujàcym w miar´ progresji nowotworów zmianom uwalniania cytokin w Êrodowisku nowotworów oraz zmianom ich aktywnoÊci w kierunku oddzia∏ywaƒ promujàcych procesy nowotworowe. Badania nad cytokinami stanowià wa˝ny element w zrozumieniu mechanizmów procesu nowotworzenia i pokazujà, ˝e wszelkie próby interwencji klinicznej z u˝yciem cytokin powinny byç oparte o g∏´bokie rozeznanie promujàcych i hamujàcych oddzia∏ywaƒ cytokin na wzrost nowotworów. The role of cytokines in carcinogenesis Cytokines comprise a large family of protein intercellular mediators that play key roles in cell proliferation, differentiation, migration and apoptosis. These molecules regulate development, immunity, inflammation and repair, as well as general tissue homeostasis. Cytokines can be produced by virtually all cell types. Pleiotropy and redundancy characterise their effects. The complicated network of interactions between different cytokines and responding cells determines their biological effect. A large body of evidence points to the important role of cytokines in the pathogenesis of cancer. Cytokines contribute to all stages of carcinogenesis. Due to the altered expression of cytokines and cytokine receptors, as well as the disruption of intracellular signalling pathways in cancer cells, many different cytokines became autocrine and paracrine growth and survival signals for these cells. In addition, cytokines induce changes in the tumour microenvironment favouring tumour growth and invasion, and contribute to metastasis and host immunosuppression. This review will outlines the action of some endogenous cytokines in the multistep process of tumour development, namely their role as autocrine and paracrine growth factors, ineffective antiproliferative factors, survival factors, and mediators of angiogenesis, invasion, metastatic spread and immunosuppression. Particular emphasis will be placed on the loss of cytostatic/cytotoxic/anti-neoplastic cytokine activities in favour of tumour-promoting capabilities, with the progression of cancer. Cytokine research has generated a rich body knowledge regarding mechanisms of oncogenesis and has shown that clinical applications of cytokines require a profound recognition of their effects in vivo.

Research paper thumbnail of Sera of lung cancer patients affect the release of Th1, Th2 and monocyte-derived cytokines, and the expression of IL-2Rα by normal, stimulated mononuclear cells

Cellular & Molecular Biology Letters

Abbreviations used: IL -interleukin; IFN -interferon; TNF -tumour necrosis factor; IL-1ra -IL-1 r... more Abbreviations used: IL -interleukin; IFN -interferon; TNF -tumour necrosis factor; IL-1ra -IL-1 receptor antagonist; IL-2Rα -IL-2 receptor α; ConA -concanavalin A; CP -lung cancer patients' sera; AB -pooled normal human AB serum.

Research paper thumbnail of Chechlinska M, Kaminska J, Markowska J, Kramar A, Steffen JPeritoneal fluid cytokines and the differential diagnosis of benign and malignant ovarian tumors and residual/recurrent disease examination. Int J Biol Markers 22: 172-180

The International journal of biological markers

ABSTRACT

Research paper thumbnail of 741 microRNA-34 expression and the status of TP53 in the primary ovarian cancer

European Journal of Cancer Supplements, 2010

Background: Cervical cancer is the second most common malignancy of women worldwide. Recently, ab... more Background: Cervical cancer is the second most common malignancy of women worldwide. Recently, aberrant miRNA expression has been demonstrated in human cervical cancer, however the functional role of miRNAs in cervical cancer remains unclear. We previously observed a significant overexpression of miR-205 in human cervical cancer tissues as compared to their matched normal cervical tissues in a sequencing-based miRNA profiling analysis. In this study, we further explore the role of miR-205 in cervical cancer.

Research paper thumbnail of 752 Gene expression profile of spontaneously immortalised T lymphocytes

European Journal of Cancer Supplements, 2010

Research paper thumbnail of miR-7 Expression in Serous Ovarian Carcinomas

Anticancer research, 2015

miR-7 has recently been linked to cancer. Some miR-7 targets, including B-cell lymphoma 2 (BCL2) ... more miR-7 has recently been linked to cancer. Some miR-7 targets, including B-cell lymphoma 2 (BCL2) and epidermal growth factor receptor (EGFR), are involved in ovarian cancer (OC) pathogenesis. The majority of OCs display TP53 mutations, which are critically important for OC development. We aimed to study the expression level of miR-7 and of two of its postulated target genes, BCL2 and EGFR, in serous ovarian carcinomas of different TP53 status and tumour grade. Gene and miR expression was assessed by real-time reverse transcription polymerase chain reaction in 45 clinical samples of low- (G1+G2) and high- (G3) grade primary serous OC with wild-type (wt) or mutated TP53, as well as in three OC cell lines, each representing a different TP53 status. The results obtained in patients with OC were analysed against their disease-free survival (DFS). In high-grade OC with TP53 mutations, the level of miR-7 expression significantly exceeded (by several fold) that in wtTP53 cancer (p<0.01)....

Research paper thumbnail of miR expression in MYC-negative DLBCL/BL with partial trisomy 11 is similar to classical Burkitt lymphoma and different from diffuse large B-cell lymphoma

Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, Jan 13, 2015

Fast and reliable differential diagnosis of Burkitt lymphoma (BL) vs. diffuse large B cell lympho... more Fast and reliable differential diagnosis of Burkitt lymphoma (BL) vs. diffuse large B cell lymphoma (DLBCL) is of major importance for therapeutic decisions and patient outcome. Aggressive B cell non-Hodgkin lymphomas (B-NHLs) that do not belong to the abovementioned entities were categorized by the current WHO lymphoma classification as "B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL" (DLBCL/BL). We have recently described a DLBCL/BL subgroup with recurrent chromosome 11q aberrations, resembling BL (B-NHLs[11q]). Here, we analyzed 102 prospectively collected fine needle aspirates from patients with aggressive B-NHLs in order to investigate the potential of microRNA (miR)-155, its precursor BIC, as well as miR-21 and miR-26a to differentiate BL from DLBCL, and from DLBCL/BL that include B-NHLs[11q]. Both BL and DLBCL/BL cases, including B-NHLs[11q], demonstrated significantly lower expression levels of miR-155/BIC, miR-21, and miR-26a comp...

Research paper thumbnail of Carcinoembryonic antigen and cytokeratin 20 in peritoneal cells of cancer patients: are we aware of what we are detecting by mRNA examination?

British Journal of Cancer, 2008

Research paper thumbnail of Squamous cell carcinoma antigen 1 and 2 expression in cultured normal peripheral blood mononuclear cells and in vulvar squamous cell carcinoma

Tumor Biology, 2010

Squamous cell carcinoma antigen (SCCA) is expressed in normal squamous cell epithelia and in squa... more Squamous cell carcinoma antigen (SCCA) is expressed in normal squamous cell epithelia and in squamous cell carcinomas (SCC). Two nearly identical genes encode the inhibitory serpins SCCA1 (SERPINB3) and SCCA2 (SERPINB4). Serum levels of SCCA are elevated in patients with benign skin diseases and in patients with SCC. SCCA, used for the monitoring of SCC patients, presents no satisfactory diagnostic specificity. As we have shown previously, the reverse transcription polymerase chain reaction (RT-PCR)-based SCCA messenger RNA (mRNA) testing aimed at detecting disseminated cancer cells may be hampered by the false-positive results due to SCCA expression in activated peripheral blood mononuclear cells (PBMC). The aim of this study was to assess the expression of SCCA at mRNA and protein levels in cultured normal PBMC, compared to that in vulvar SCC (VSCC) samples. High SCCA concentrations were found in vulvar tumours and in metastatic lymph nodes, while negative inguinal lymph nodes from the same patients often presented significantly less SCCA. In normal activated PBMC, the level of SCCA protein was the lowest. At the mRNA level SCCA was detectable in normal PBMC even in cultures with no mitogen stimulation, but only by the nested RT-PCR, contrary to VSCC samples found to be SCCA positive already in one-step PCR. Both SCCA1 and SCCA2 transcripts were present in cultured PBMC; SCCA1 was expressed at a higher level than SCCA2. In conclusion, both SCCA forms are detectable in normal

Research paper thumbnail of A survey of prognostic value of serum factors in multiple myeloma patients before treatment: macrophage-colony stimulating factor (M-CSF) is a powerful predictor of survival

Medical Oncology, 2009

Cytokines are involved in the pathogenesis of multiple myeloma (MM) and other cancers. The aim of... more Cytokines are involved in the pathogenesis of multiple myeloma (MM) and other cancers. The aim of this study was to evaluate a range of cytokines of diverse activity in patients with multiple myeloma for a possible prognostic value. Concentrations of the following cytokines and cytokine receptors were measured by ELISA in the sera of 64 untreated MM patients: IL-6, IL-8, IL-10, TNFα, sTNF R I and II, sIL-2Rα, IL-1ra, M-CSF, G-CSF, VEGF, and bFGF. Serum levels of sTNF RI, IL-6, and bFGF were elevated in over 50% of patients. There was an inverse relationship between sTNF RII, TNFα, IL-1ra, and albumin levels. There was no significant relationship between cytokines/cytokine receptors and other serum correlates of myeloma. In a univariate survival analysis, β2-microglobulin, LDH, sIL-2Rα, sTNF RI, and M-CSF were significant variables. In a multivariate analysis, only M-CSF and β2-microglobulin retained a significant influence on survival. Serum M-CSF may be considered another independent and clinically useful prognostic factor in multiple myeloma.

Research paper thumbnail of Serum macrophage colony-stimulating factor (M-CSF) in patients with Hodgkin lymphoma

Medical Oncology, 2011

Macrophage colony-stimulating factor (M-CSF) was recently implicated by in vitro studies as a sur... more Macrophage colony-stimulating factor (M-CSF) was recently implicated by in vitro studies as a survival and proliferation factor for Hodgkin/Reed-Sternberg cells. We evaluated pre-treatment serum M-CSF levels in 66 patients with histopathologic diagnosis of classical Hodgkin lymphoma (HL) and looked for possible correlations with baseline clinical characteristics. Significantly higher M-CSF serum concentrations were found in patients with bulky mediastinal mass, systemic symptoms, and elevated ESR but not LDH. There was no significant association between M-CSF level and sex, clinical stage, number of lymph node areas involved, and histopathological subtype of HL. We conclude that serum M-CSF levels are frequently elevated in HL patients and are significantly related to the presence of bulky mediastinal mass and systemic symptoms. These observations may indicate a pathogenetic role of M-CSF in Hodgkin lymphoma.

Research paper thumbnail of Cytokines as potential tumour markers

Expert Opinion on Medical Diagnostics, 2008

Cytokines and cytokine receptors contribute importantly to each step of cancer development and pr... more Cytokines and cytokine receptors contribute importantly to each step of cancer development and progression, and deregulated levels of cytokines and cytokine receptors can be detected in cancer patients locally and systemically. This review aims to outline and discuss the current status of cytokines and their receptors as potential diagnostic, prognostic, predictive and risk indicators, exemplified in cervical, ovarian, breast, prostate, colorectal, gastric, and non-small cell lung cancers and in sarcomas. The Medline database was searched for articles on the relevant cancers, published in the English language, using combinations of the following keywords: cytokine, interleukin, growth factor, diagnostic, prognostic, predictive, serum, ascitic and expression. The searches yielded over 2000 papers, and an arbitrary selection of the cited literature was made to present the developments in the field. Cytokines, unspecific by definition, present certain patterns of deregulation, often related to clinical characteristics of cancer patients. Some cytokines, most often VEGF, IL-6 and EGFR, present a value of independent prognostic indicators. So far, only local EGFR and HER2 expression assessment in a few cancer types has been accepted for routine use, to qualify patients for a targeted therapy. The authors believe that cytokines may contribute importantly to cancer management in the future; to more likely to indicate prognosis, to identify patients who might benefit from a particular treatment, to monitor treatment response and disease recurrence, and, finally, possibly as part of a larger panel of tumour markers, to improve diagnosis.

Research paper thumbnail of microRNAs in uterine sarcomas and mixed epithelial–mesenchymal uterine tumors: a preliminary report

Tumor Biology, 2013

Uterine sarcomas and mixed epithelial-mesenchymal uterine tumors are a heterogeneous group of rar... more Uterine sarcomas and mixed epithelial-mesenchymal uterine tumors are a heterogeneous group of rare tumors for which there are very few diagnostic markers available. As aberrant microRNA (miRNA) expression patterns represent putative diagnostic cancer markers, we aimed to identify miRNA expression profiles of the major uterine sarcoma subtypes and mixed epithelial-mesenchymal tumors of the uterus. Eighty-eight miRNAs were assessed by quantitative RT-PCR in cancerous and noncancerous tissue samples collected from 29 patients with endometrial sarcoma, leiomyosarcoma, and mixed epithelial-mesenchymal tumors. Tumor and control samples significantly (P<0.05) differed in the expression of miR-23b, miR-1, let-7f, and let-7c in endometrial sarcomas, and miR-1, let-7c, miR-133b, let-7b, miR-143, let-7a, let-7d, let-7e, let-7g, miR-222, let-7i, and miR-214 in mixed epithelialmesenchymal tumors. All the significantly changed miRNAs were down-regulated in the malignant tissues as compared to their normal counterparts. This may suggest their tumor suppressor role in these malignancies. No statistically significant changes in miRNA expression levels were found between leiomyosarcoma tumors and controls. The identified miRNAs warrant further studies as valuable candidate markers for the differential diagnosis of uterine sarcomas from benign uterine lesions and between uterine sarcoma subtypes.

Research paper thumbnail of Discriminant analysis involving serum cytokine levels and prediction of the response to therapy of patients with Hodgkin lymphoma

Tumor Biology, 2012

Current standard diagnostic methods do not identify patients with Hodgkin lymphoma (HL), who are ... more Current standard diagnostic methods do not identify patients with Hodgkin lymphoma (HL), who are at high risk of failure after the first-line treatment. In HL patients, serum cytokine levels are frequently elevated and correlate with clinical and pathological features of the disease as well as with disease-free survival and overall survival. The aim of this study was to investigate if pretreatment serum cytokine and cytokine receptor concentrations evaluated by discriminant analysis could be predictive of response to standard first-line treatment in HL. The study involved 48 previously untreated patients with histologically confirmed classical HL and no EBV infection. Treatment included chemotherapy and involved field radiotherapy or radiotherapy alone. At the end of treatment, 71 % of patients reached complete response (CR), and 29 %, in partial response. To identify parameters predictive of nonachievement of CR after the first-line treatment, the discriminant analysis was used. The following variables were included in the analysis: clinical stage, sex, age, histologic subtype, bulky mediastinal mass, systemic symptoms and the number of involved nodal areas, lactate dehydrogenase (LDH) activity, and serum levels of 12 cytokines/cytokine receptors. The resulting classifying function assigned a discriminant power to the following variables: the levels of vascular endothelial growth factor, interleukin-8, macrophage colony stimulating factor, basic fibroblast growth factor, soluble tumor necrosis factor receptor I, and LDH activity. The accuracy of predicting CR and non-CR was 94 and 43 %, respectively.

Research paper thumbnail of Pretreatment Serum Levels of Cytokines and Cytokine Receptors in Patients with Non-Small Cell Lung Cancer, and Correlations with Clinicopathological Features and Prognosis

Oncology, 2006

Cytokines are potential new serum markers, especially desirable for malignancies with poor progno... more Cytokines are potential new serum markers, especially desirable for malignancies with poor prognosis like non-small cell lung cancer (NSCLC). Cytokines, tumor necrosis factor alpha (TNFalpha), interleukin (IL)-6 and IL-8, soluble TNF (sTNF) RI, sTNF RII, soluble IL-2 receptor-alpha, IL-1 receptor antagonist (IL-1ra), IL-10, vascular endothelial growth factor, basic fibroblast growth factor, and macrophage (M-CSF) and granulocyte colony-stimulating factor, as well as tumor markers - carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC) and CYFRA 21.1 - were assessed in the sera of 103 untreated NSCLC patients, and these cytokines and tumor markers were referred to clinical parameters of the disease and to the overall survival of patients evaluated during a 6-year follow-up. Most of the factors analyzed were found to be elevated in the sera of NSCLC patients, and increases in IL-6, IL-8 and sTNF RI were noted in the greatest proportion of stage I patients. Most cytokine/cytokine receptor levels revealed higher sensitivity than the standard tumor markers; IL-6 and IL-1ra levels were significantly different in patients with squamous cell versus adenocarcinoma; IL-6 and IL-10 were related to the tumor size, while IL-6 and M-CSF levels significantly increased with disease progression. A significant prognostic value of pretreatment serum M-CSF and CEA levels in NSCLC patients has been shown, but only M-CSF proved to be an independent prognostic factor. Increased pretreatment serum M-CSF level is a significant independent predictor of poor survival in patients with NSCLC.

Research paper thumbnail of Systemic inflammation as a confounding factor in cancer biomarker discovery and validation

Nature Reviews Cancer, 2010

Research paper thumbnail of The relevance of RT-PCR detection of disseminated tumour cells is hampered by the expression of markers regarded as tumour-specific in activated lymphocytes

European Journal of Cancer, 2006

markers Carbonic anhydrase 9 (CA9) Epidermal growth factor receptor (EGFR) Mammaglobin (hMAM) Sma... more markers Carbonic anhydrase 9 (CA9) Epidermal growth factor receptor (EGFR) Mammaglobin (hMAM) Small breast epithelial mucin (SBEM) Squamous-cell carcinoma antigen (SCCA) A B S T R A C T Marker genes, commonly used to detect circulating tumour cells in RT-PCR-based tests: squamous-cell carcinoma antigen, epidermal growth factor receptor, mammaglobin, small breast epithelial mucin, but not carbonic anhydrase 9, were shown to be expressed in normal, mitogen-stimulated peripheral blood mononuclear cells (PBMNC). Thus, considering the inflammatory reactions often accompanying cancer development, to reduce false-positive results of the metastatic tumour cell tests, molecular markers should be validated not against normal peripheral blood, but against activated lymphoid cells, such as in vitro mitogen-stimulated PBMNC.

Research paper thumbnail of Serum soluble tumour necrosis factor receptor type I concentrations independently predict prognosis in patients with breast cancer

Clinical Chemistry and Laboratory Medicine, 2000

The aim of this study was to exploit the potential clinical use of circulating cytokine assessmen... more The aim of this study was to exploit the potential clinical use of circulating cytokine assessment in patients with breast cancer. The following circulating cytokines were measured in 210 histopathologically confirmed, untreated breast cancer patients: interleukin 6 (IL-6), tumour necrosis factor-α (TNFα), interleukin 8 (IL-8), soluble tumour necrosis factor receptor type I (sTNF RI), sTNF RII, interleukin 1 receptor antagonist (IL-1ra), interleukin 10 (IL-10), macrophage colony-stimulating factor, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). The patients have been followed-up for 10 years. bFGF and VEGF showed the highest diagnostic sensitivity. Only IL-6 concentrations were related to the clinical stage. A high percentage of patients in clinical stage I showed increased serum sTNF RII, VEGF and bFGF concentrations, of which only sTNF RII was found to be increased in a smaller percentage of patients with more advanced disease compared with patients with early stage disease. Patients aged 50 years and more presented with significantly higher concentrations of sTNF RI, IL-10, IL-6 and VEGF compared with younger patients. In multivariate analysis, a significant value of pretreatment serum sTNF RI concentrations, next to stage and oestrogen receptors status, was its utility as an independent prognostic factor of the overall survival in patients with breast cancer. Serum sTNF RI may be considered an additional, independent and clinically useful factor of poor prognosis in patients with breast cancer.

Research paper thumbnail of Procollagen I amino-terminal propeptide as a potential marker for multiple myeloma

Clinical Biochemistry, 2010

Investigating relationship between bone markers, cytokines and conventional prognostic parameters... more Investigating relationship between bone markers, cytokines and conventional prognostic parameters in patients with multiple myeloma (MM) and to assess the clinical application of bone turnover markers. Sixty-four patients with MM were examined before treatment and followed for survival for over 7 years. Serum concentrations of bone markers and cytokines were determined by the Roche and R&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;D kits, respectively. Standard deviation scores (SDS) were employed to normalize values. Collagen fragments (beta-CTX) were elevated in 47%, procollagen I amino-terminal propeptide (PINP)-in 28%, and osteocalcin (OC) in 11% of patients. The values of the SDS of PINP and OC, but not beta-CTX significantly decreased with MM stage. beta-CTX inversely correlated with vascular endothelial growth factor (VEGF) and albumin, and directly correlated with serum macrophage colony-stimulating factor (M-CSF). OC values correlated with albumin and beta2-microglobulin. PINP inversely correlated with LDH. The SDS values of PINP were significantly lower in MM patients with advanced bone disease. Circulating PINP concentration may be a useful marker for monitoring of treatment of multiple myeloma patients with bone lytic lesions, in particular, of patients treated with preoteasome inhibitors.

Research paper thumbnail of Implications of cancer-associated systemic inflammation for biomarker studies

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2010

Highly sensitive molecular technologies provide new capacities for cancer biomarker research, but... more Highly sensitive molecular technologies provide new capacities for cancer biomarker research, but with sensitivity improvements marker specificity is significantly decreased, and too many false-positive results should disqualify the measurement from clinical use. Hence, of the thousands of potential cancer biomarkers only a few have found their way to clinical application. Differentiating false-positive results from truepositive (cancer-specific) results can indeed be difficult, if validation of a marker is performed against inadequate controls.

Research paper thumbnail of The role of cytokines in carcinogenesis

Nowotwory, 2003

Cytokiny sà bia∏kowymi mediatorami mi´dzykomórkowymi, odgrywajàcymi kluczowà rol´ w procesach pro... more Cytokiny sà bia∏kowymi mediatorami mi´dzykomórkowymi, odgrywajàcymi kluczowà rol´ w procesach proliferacji, ró˝nicowania, migracji i apoptozy komórek. Sà regulatorami reakcji odpornoÊciowych i zapalnych, procesów rozwoju, regeneracji i utrzymania homeostazy tkanek. Ich êród∏em sà ró˝ne typy komórek. Charakteryzuje je plejotropowoÊç dzia∏ania. Produkcja, uwalnianie i oddzia∏ywanie cytokin tworzy skomplikowanà sieç wzajemnych zale˝noÊci, które determinujà efekty biologiczne ich dzia∏ania. Wiele dowodów wskazuje na udzia∏ cytokin w patogenezie nowotworów. Cytokiny uczestniczà we wszystkich etapach nowotworzenia. Zmieniona ekspresja wielu cytokin oraz receptorów powierzchniowych i komponentów wewnàtrzkomórkowych szlaków sygnalizacyjnych cytokin w komórkach nowotworowych powoduje, ˝e ró˝nego typu cytokiny stajà si´ autokrynnymi i parakrynnymi czynnikami wzrostu i prze˝ycia tych komórek. Ponadto cytokiny indukujà zmiany w mikroÊrodowisku guza, sprzyjajàce jego rozwojowi, biorà udzia∏ w inwazji i tworzeniu przerzutów odleg∏ych. Sà wa˝nymi mediatorami typowej w nowotworach immunosupresji. Niniejszy artyku∏ przeglàdowy przedstawia udzia∏ cytokin w wielostopniowym procesie rozwoju nowotworów. Omówiono ich rol´ jako autokrynnych i parakrynnych czynników wzrostu, nieaktywnych czynników antyproliferacyjnych i czynników prze˝ycia komórek nowotworowych oraz mediatorów angiogenezy, inwazji, rozsiewu nowotworów i immunosupresji. Szczególnà uwag´ poÊwi´cono wyst´pujàcym w miar´ progresji nowotworów zmianom uwalniania cytokin w Êrodowisku nowotworów oraz zmianom ich aktywnoÊci w kierunku oddzia∏ywaƒ promujàcych procesy nowotworowe. Badania nad cytokinami stanowià wa˝ny element w zrozumieniu mechanizmów procesu nowotworzenia i pokazujà, ˝e wszelkie próby interwencji klinicznej z u˝yciem cytokin powinny byç oparte o g∏´bokie rozeznanie promujàcych i hamujàcych oddzia∏ywaƒ cytokin na wzrost nowotworów. The role of cytokines in carcinogenesis Cytokines comprise a large family of protein intercellular mediators that play key roles in cell proliferation, differentiation, migration and apoptosis. These molecules regulate development, immunity, inflammation and repair, as well as general tissue homeostasis. Cytokines can be produced by virtually all cell types. Pleiotropy and redundancy characterise their effects. The complicated network of interactions between different cytokines and responding cells determines their biological effect. A large body of evidence points to the important role of cytokines in the pathogenesis of cancer. Cytokines contribute to all stages of carcinogenesis. Due to the altered expression of cytokines and cytokine receptors, as well as the disruption of intracellular signalling pathways in cancer cells, many different cytokines became autocrine and paracrine growth and survival signals for these cells. In addition, cytokines induce changes in the tumour microenvironment favouring tumour growth and invasion, and contribute to metastasis and host immunosuppression. This review will outlines the action of some endogenous cytokines in the multistep process of tumour development, namely their role as autocrine and paracrine growth factors, ineffective antiproliferative factors, survival factors, and mediators of angiogenesis, invasion, metastatic spread and immunosuppression. Particular emphasis will be placed on the loss of cytostatic/cytotoxic/anti-neoplastic cytokine activities in favour of tumour-promoting capabilities, with the progression of cancer. Cytokine research has generated a rich body knowledge regarding mechanisms of oncogenesis and has shown that clinical applications of cytokines require a profound recognition of their effects in vivo.

Research paper thumbnail of Sera of lung cancer patients affect the release of Th1, Th2 and monocyte-derived cytokines, and the expression of IL-2Rα by normal, stimulated mononuclear cells

Cellular & Molecular Biology Letters

Abbreviations used: IL -interleukin; IFN -interferon; TNF -tumour necrosis factor; IL-1ra -IL-1 r... more Abbreviations used: IL -interleukin; IFN -interferon; TNF -tumour necrosis factor; IL-1ra -IL-1 receptor antagonist; IL-2Rα -IL-2 receptor α; ConA -concanavalin A; CP -lung cancer patients' sera; AB -pooled normal human AB serum.

Research paper thumbnail of Chechlinska M, Kaminska J, Markowska J, Kramar A, Steffen JPeritoneal fluid cytokines and the differential diagnosis of benign and malignant ovarian tumors and residual/recurrent disease examination. Int J Biol Markers 22: 172-180

The International journal of biological markers

ABSTRACT

Research paper thumbnail of 741 microRNA-34 expression and the status of TP53 in the primary ovarian cancer

European Journal of Cancer Supplements, 2010

Background: Cervical cancer is the second most common malignancy of women worldwide. Recently, ab... more Background: Cervical cancer is the second most common malignancy of women worldwide. Recently, aberrant miRNA expression has been demonstrated in human cervical cancer, however the functional role of miRNAs in cervical cancer remains unclear. We previously observed a significant overexpression of miR-205 in human cervical cancer tissues as compared to their matched normal cervical tissues in a sequencing-based miRNA profiling analysis. In this study, we further explore the role of miR-205 in cervical cancer.

Research paper thumbnail of 752 Gene expression profile of spontaneously immortalised T lymphocytes

European Journal of Cancer Supplements, 2010

Research paper thumbnail of miR-7 Expression in Serous Ovarian Carcinomas

Anticancer research, 2015

miR-7 has recently been linked to cancer. Some miR-7 targets, including B-cell lymphoma 2 (BCL2) ... more miR-7 has recently been linked to cancer. Some miR-7 targets, including B-cell lymphoma 2 (BCL2) and epidermal growth factor receptor (EGFR), are involved in ovarian cancer (OC) pathogenesis. The majority of OCs display TP53 mutations, which are critically important for OC development. We aimed to study the expression level of miR-7 and of two of its postulated target genes, BCL2 and EGFR, in serous ovarian carcinomas of different TP53 status and tumour grade. Gene and miR expression was assessed by real-time reverse transcription polymerase chain reaction in 45 clinical samples of low- (G1+G2) and high- (G3) grade primary serous OC with wild-type (wt) or mutated TP53, as well as in three OC cell lines, each representing a different TP53 status. The results obtained in patients with OC were analysed against their disease-free survival (DFS). In high-grade OC with TP53 mutations, the level of miR-7 expression significantly exceeded (by several fold) that in wtTP53 cancer (p<0.01)....

Research paper thumbnail of miR expression in MYC-negative DLBCL/BL with partial trisomy 11 is similar to classical Burkitt lymphoma and different from diffuse large B-cell lymphoma

Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, Jan 13, 2015

Fast and reliable differential diagnosis of Burkitt lymphoma (BL) vs. diffuse large B cell lympho... more Fast and reliable differential diagnosis of Burkitt lymphoma (BL) vs. diffuse large B cell lymphoma (DLBCL) is of major importance for therapeutic decisions and patient outcome. Aggressive B cell non-Hodgkin lymphomas (B-NHLs) that do not belong to the abovementioned entities were categorized by the current WHO lymphoma classification as "B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL" (DLBCL/BL). We have recently described a DLBCL/BL subgroup with recurrent chromosome 11q aberrations, resembling BL (B-NHLs[11q]). Here, we analyzed 102 prospectively collected fine needle aspirates from patients with aggressive B-NHLs in order to investigate the potential of microRNA (miR)-155, its precursor BIC, as well as miR-21 and miR-26a to differentiate BL from DLBCL, and from DLBCL/BL that include B-NHLs[11q]. Both BL and DLBCL/BL cases, including B-NHLs[11q], demonstrated significantly lower expression levels of miR-155/BIC, miR-21, and miR-26a comp...

Research paper thumbnail of Carcinoembryonic antigen and cytokeratin 20 in peritoneal cells of cancer patients: are we aware of what we are detecting by mRNA examination?

British Journal of Cancer, 2008

Research paper thumbnail of Squamous cell carcinoma antigen 1 and 2 expression in cultured normal peripheral blood mononuclear cells and in vulvar squamous cell carcinoma

Tumor Biology, 2010

Squamous cell carcinoma antigen (SCCA) is expressed in normal squamous cell epithelia and in squa... more Squamous cell carcinoma antigen (SCCA) is expressed in normal squamous cell epithelia and in squamous cell carcinomas (SCC). Two nearly identical genes encode the inhibitory serpins SCCA1 (SERPINB3) and SCCA2 (SERPINB4). Serum levels of SCCA are elevated in patients with benign skin diseases and in patients with SCC. SCCA, used for the monitoring of SCC patients, presents no satisfactory diagnostic specificity. As we have shown previously, the reverse transcription polymerase chain reaction (RT-PCR)-based SCCA messenger RNA (mRNA) testing aimed at detecting disseminated cancer cells may be hampered by the false-positive results due to SCCA expression in activated peripheral blood mononuclear cells (PBMC). The aim of this study was to assess the expression of SCCA at mRNA and protein levels in cultured normal PBMC, compared to that in vulvar SCC (VSCC) samples. High SCCA concentrations were found in vulvar tumours and in metastatic lymph nodes, while negative inguinal lymph nodes from the same patients often presented significantly less SCCA. In normal activated PBMC, the level of SCCA protein was the lowest. At the mRNA level SCCA was detectable in normal PBMC even in cultures with no mitogen stimulation, but only by the nested RT-PCR, contrary to VSCC samples found to be SCCA positive already in one-step PCR. Both SCCA1 and SCCA2 transcripts were present in cultured PBMC; SCCA1 was expressed at a higher level than SCCA2. In conclusion, both SCCA forms are detectable in normal

Research paper thumbnail of A survey of prognostic value of serum factors in multiple myeloma patients before treatment: macrophage-colony stimulating factor (M-CSF) is a powerful predictor of survival

Medical Oncology, 2009

Cytokines are involved in the pathogenesis of multiple myeloma (MM) and other cancers. The aim of... more Cytokines are involved in the pathogenesis of multiple myeloma (MM) and other cancers. The aim of this study was to evaluate a range of cytokines of diverse activity in patients with multiple myeloma for a possible prognostic value. Concentrations of the following cytokines and cytokine receptors were measured by ELISA in the sera of 64 untreated MM patients: IL-6, IL-8, IL-10, TNFα, sTNF R I and II, sIL-2Rα, IL-1ra, M-CSF, G-CSF, VEGF, and bFGF. Serum levels of sTNF RI, IL-6, and bFGF were elevated in over 50% of patients. There was an inverse relationship between sTNF RII, TNFα, IL-1ra, and albumin levels. There was no significant relationship between cytokines/cytokine receptors and other serum correlates of myeloma. In a univariate survival analysis, β2-microglobulin, LDH, sIL-2Rα, sTNF RI, and M-CSF were significant variables. In a multivariate analysis, only M-CSF and β2-microglobulin retained a significant influence on survival. Serum M-CSF may be considered another independent and clinically useful prognostic factor in multiple myeloma.

Research paper thumbnail of Serum macrophage colony-stimulating factor (M-CSF) in patients with Hodgkin lymphoma

Medical Oncology, 2011

Macrophage colony-stimulating factor (M-CSF) was recently implicated by in vitro studies as a sur... more Macrophage colony-stimulating factor (M-CSF) was recently implicated by in vitro studies as a survival and proliferation factor for Hodgkin/Reed-Sternberg cells. We evaluated pre-treatment serum M-CSF levels in 66 patients with histopathologic diagnosis of classical Hodgkin lymphoma (HL) and looked for possible correlations with baseline clinical characteristics. Significantly higher M-CSF serum concentrations were found in patients with bulky mediastinal mass, systemic symptoms, and elevated ESR but not LDH. There was no significant association between M-CSF level and sex, clinical stage, number of lymph node areas involved, and histopathological subtype of HL. We conclude that serum M-CSF levels are frequently elevated in HL patients and are significantly related to the presence of bulky mediastinal mass and systemic symptoms. These observations may indicate a pathogenetic role of M-CSF in Hodgkin lymphoma.

Research paper thumbnail of Cytokines as potential tumour markers

Expert Opinion on Medical Diagnostics, 2008

Cytokines and cytokine receptors contribute importantly to each step of cancer development and pr... more Cytokines and cytokine receptors contribute importantly to each step of cancer development and progression, and deregulated levels of cytokines and cytokine receptors can be detected in cancer patients locally and systemically. This review aims to outline and discuss the current status of cytokines and their receptors as potential diagnostic, prognostic, predictive and risk indicators, exemplified in cervical, ovarian, breast, prostate, colorectal, gastric, and non-small cell lung cancers and in sarcomas. The Medline database was searched for articles on the relevant cancers, published in the English language, using combinations of the following keywords: cytokine, interleukin, growth factor, diagnostic, prognostic, predictive, serum, ascitic and expression. The searches yielded over 2000 papers, and an arbitrary selection of the cited literature was made to present the developments in the field. Cytokines, unspecific by definition, present certain patterns of deregulation, often related to clinical characteristics of cancer patients. Some cytokines, most often VEGF, IL-6 and EGFR, present a value of independent prognostic indicators. So far, only local EGFR and HER2 expression assessment in a few cancer types has been accepted for routine use, to qualify patients for a targeted therapy. The authors believe that cytokines may contribute importantly to cancer management in the future; to more likely to indicate prognosis, to identify patients who might benefit from a particular treatment, to monitor treatment response and disease recurrence, and, finally, possibly as part of a larger panel of tumour markers, to improve diagnosis.

Research paper thumbnail of microRNAs in uterine sarcomas and mixed epithelial–mesenchymal uterine tumors: a preliminary report

Tumor Biology, 2013

Uterine sarcomas and mixed epithelial-mesenchymal uterine tumors are a heterogeneous group of rar... more Uterine sarcomas and mixed epithelial-mesenchymal uterine tumors are a heterogeneous group of rare tumors for which there are very few diagnostic markers available. As aberrant microRNA (miRNA) expression patterns represent putative diagnostic cancer markers, we aimed to identify miRNA expression profiles of the major uterine sarcoma subtypes and mixed epithelial-mesenchymal tumors of the uterus. Eighty-eight miRNAs were assessed by quantitative RT-PCR in cancerous and noncancerous tissue samples collected from 29 patients with endometrial sarcoma, leiomyosarcoma, and mixed epithelial-mesenchymal tumors. Tumor and control samples significantly (P<0.05) differed in the expression of miR-23b, miR-1, let-7f, and let-7c in endometrial sarcomas, and miR-1, let-7c, miR-133b, let-7b, miR-143, let-7a, let-7d, let-7e, let-7g, miR-222, let-7i, and miR-214 in mixed epithelialmesenchymal tumors. All the significantly changed miRNAs were down-regulated in the malignant tissues as compared to their normal counterparts. This may suggest their tumor suppressor role in these malignancies. No statistically significant changes in miRNA expression levels were found between leiomyosarcoma tumors and controls. The identified miRNAs warrant further studies as valuable candidate markers for the differential diagnosis of uterine sarcomas from benign uterine lesions and between uterine sarcoma subtypes.

Research paper thumbnail of Discriminant analysis involving serum cytokine levels and prediction of the response to therapy of patients with Hodgkin lymphoma

Tumor Biology, 2012

Current standard diagnostic methods do not identify patients with Hodgkin lymphoma (HL), who are ... more Current standard diagnostic methods do not identify patients with Hodgkin lymphoma (HL), who are at high risk of failure after the first-line treatment. In HL patients, serum cytokine levels are frequently elevated and correlate with clinical and pathological features of the disease as well as with disease-free survival and overall survival. The aim of this study was to investigate if pretreatment serum cytokine and cytokine receptor concentrations evaluated by discriminant analysis could be predictive of response to standard first-line treatment in HL. The study involved 48 previously untreated patients with histologically confirmed classical HL and no EBV infection. Treatment included chemotherapy and involved field radiotherapy or radiotherapy alone. At the end of treatment, 71 % of patients reached complete response (CR), and 29 %, in partial response. To identify parameters predictive of nonachievement of CR after the first-line treatment, the discriminant analysis was used. The following variables were included in the analysis: clinical stage, sex, age, histologic subtype, bulky mediastinal mass, systemic symptoms and the number of involved nodal areas, lactate dehydrogenase (LDH) activity, and serum levels of 12 cytokines/cytokine receptors. The resulting classifying function assigned a discriminant power to the following variables: the levels of vascular endothelial growth factor, interleukin-8, macrophage colony stimulating factor, basic fibroblast growth factor, soluble tumor necrosis factor receptor I, and LDH activity. The accuracy of predicting CR and non-CR was 94 and 43 %, respectively.

Research paper thumbnail of Pretreatment Serum Levels of Cytokines and Cytokine Receptors in Patients with Non-Small Cell Lung Cancer, and Correlations with Clinicopathological Features and Prognosis

Oncology, 2006

Cytokines are potential new serum markers, especially desirable for malignancies with poor progno... more Cytokines are potential new serum markers, especially desirable for malignancies with poor prognosis like non-small cell lung cancer (NSCLC). Cytokines, tumor necrosis factor alpha (TNFalpha), interleukin (IL)-6 and IL-8, soluble TNF (sTNF) RI, sTNF RII, soluble IL-2 receptor-alpha, IL-1 receptor antagonist (IL-1ra), IL-10, vascular endothelial growth factor, basic fibroblast growth factor, and macrophage (M-CSF) and granulocyte colony-stimulating factor, as well as tumor markers - carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC) and CYFRA 21.1 - were assessed in the sera of 103 untreated NSCLC patients, and these cytokines and tumor markers were referred to clinical parameters of the disease and to the overall survival of patients evaluated during a 6-year follow-up. Most of the factors analyzed were found to be elevated in the sera of NSCLC patients, and increases in IL-6, IL-8 and sTNF RI were noted in the greatest proportion of stage I patients. Most cytokine/cytokine receptor levels revealed higher sensitivity than the standard tumor markers; IL-6 and IL-1ra levels were significantly different in patients with squamous cell versus adenocarcinoma; IL-6 and IL-10 were related to the tumor size, while IL-6 and M-CSF levels significantly increased with disease progression. A significant prognostic value of pretreatment serum M-CSF and CEA levels in NSCLC patients has been shown, but only M-CSF proved to be an independent prognostic factor. Increased pretreatment serum M-CSF level is a significant independent predictor of poor survival in patients with NSCLC.

Research paper thumbnail of Systemic inflammation as a confounding factor in cancer biomarker discovery and validation

Nature Reviews Cancer, 2010

Research paper thumbnail of The relevance of RT-PCR detection of disseminated tumour cells is hampered by the expression of markers regarded as tumour-specific in activated lymphocytes

European Journal of Cancer, 2006

markers Carbonic anhydrase 9 (CA9) Epidermal growth factor receptor (EGFR) Mammaglobin (hMAM) Sma... more markers Carbonic anhydrase 9 (CA9) Epidermal growth factor receptor (EGFR) Mammaglobin (hMAM) Small breast epithelial mucin (SBEM) Squamous-cell carcinoma antigen (SCCA) A B S T R A C T Marker genes, commonly used to detect circulating tumour cells in RT-PCR-based tests: squamous-cell carcinoma antigen, epidermal growth factor receptor, mammaglobin, small breast epithelial mucin, but not carbonic anhydrase 9, were shown to be expressed in normal, mitogen-stimulated peripheral blood mononuclear cells (PBMNC). Thus, considering the inflammatory reactions often accompanying cancer development, to reduce false-positive results of the metastatic tumour cell tests, molecular markers should be validated not against normal peripheral blood, but against activated lymphoid cells, such as in vitro mitogen-stimulated PBMNC.

Research paper thumbnail of Serum soluble tumour necrosis factor receptor type I concentrations independently predict prognosis in patients with breast cancer

Clinical Chemistry and Laboratory Medicine, 2000

The aim of this study was to exploit the potential clinical use of circulating cytokine assessmen... more The aim of this study was to exploit the potential clinical use of circulating cytokine assessment in patients with breast cancer. The following circulating cytokines were measured in 210 histopathologically confirmed, untreated breast cancer patients: interleukin 6 (IL-6), tumour necrosis factor-α (TNFα), interleukin 8 (IL-8), soluble tumour necrosis factor receptor type I (sTNF RI), sTNF RII, interleukin 1 receptor antagonist (IL-1ra), interleukin 10 (IL-10), macrophage colony-stimulating factor, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). The patients have been followed-up for 10 years. bFGF and VEGF showed the highest diagnostic sensitivity. Only IL-6 concentrations were related to the clinical stage. A high percentage of patients in clinical stage I showed increased serum sTNF RII, VEGF and bFGF concentrations, of which only sTNF RII was found to be increased in a smaller percentage of patients with more advanced disease compared with patients with early stage disease. Patients aged 50 years and more presented with significantly higher concentrations of sTNF RI, IL-10, IL-6 and VEGF compared with younger patients. In multivariate analysis, a significant value of pretreatment serum sTNF RI concentrations, next to stage and oestrogen receptors status, was its utility as an independent prognostic factor of the overall survival in patients with breast cancer. Serum sTNF RI may be considered an additional, independent and clinically useful factor of poor prognosis in patients with breast cancer.

Research paper thumbnail of Procollagen I amino-terminal propeptide as a potential marker for multiple myeloma

Clinical Biochemistry, 2010

Investigating relationship between bone markers, cytokines and conventional prognostic parameters... more Investigating relationship between bone markers, cytokines and conventional prognostic parameters in patients with multiple myeloma (MM) and to assess the clinical application of bone turnover markers. Sixty-four patients with MM were examined before treatment and followed for survival for over 7 years. Serum concentrations of bone markers and cytokines were determined by the Roche and R&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;D kits, respectively. Standard deviation scores (SDS) were employed to normalize values. Collagen fragments (beta-CTX) were elevated in 47%, procollagen I amino-terminal propeptide (PINP)-in 28%, and osteocalcin (OC) in 11% of patients. The values of the SDS of PINP and OC, but not beta-CTX significantly decreased with MM stage. beta-CTX inversely correlated with vascular endothelial growth factor (VEGF) and albumin, and directly correlated with serum macrophage colony-stimulating factor (M-CSF). OC values correlated with albumin and beta2-microglobulin. PINP inversely correlated with LDH. The SDS values of PINP were significantly lower in MM patients with advanced bone disease. Circulating PINP concentration may be a useful marker for monitoring of treatment of multiple myeloma patients with bone lytic lesions, in particular, of patients treated with preoteasome inhibitors.

Research paper thumbnail of Implications of cancer-associated systemic inflammation for biomarker studies

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2010

Highly sensitive molecular technologies provide new capacities for cancer biomarker research, but... more Highly sensitive molecular technologies provide new capacities for cancer biomarker research, but with sensitivity improvements marker specificity is significantly decreased, and too many false-positive results should disqualify the measurement from clinical use. Hence, of the thousands of potential cancer biomarkers only a few have found their way to clinical application. Differentiating false-positive results from truepositive (cancer-specific) results can indeed be difficult, if validation of a marker is performed against inadequate controls.