Limfoangiogeneza w guzach nowotworowych

Summary The lymphatic vasculature is essential for the maintenance of fluid homeostasis, immune surveillance and fat absorption. A role of the lymphatic vessels in the development of human diseases, such as inflammation and tumorigenesis, has proven to be both essential and active. The molecular mechanisms of lymphangiogenesis are not clear, but vascular endothelial growth factors (VEGF-C and VEGF-D) within tumours may simulate endothelial cells within tumour tissues to grow and generate new lymphatics. Recently, several markers specific for lymphatic endothelium and models for lymphatic vascular research have been characterized and many critical regulators of lymphatic vessel growth have been identified. This review focuses on the mechanisms of lymphangiogenesis in general, and especially on the role of lymphatic vessels in ovarian cancerStreszczenie Układ limfatyczny jest niezbędny do utrzymania homeostazy płynu tkankowego oraz odgrywa ważną rolę w regulacji funkcji układu immunologicznego. Naczynia limfatyczne maja istotny i aktywny udział w patofizjologii stanów zapalnych oraz rozwoju nowotworów. Mechanizmy molekularne regulujące limfangiogenezę pozostają jak dotąd słabo poznane chociaż wiadomo, że śródbłonkowe czynniki wzrostu naczyń (VEGF-C i VEGF-D) stymulują wzrost endoteliocytów i powstawanie nowych naczyń chłonnych. W ostatnich latach zidentyfikowano szereg markerów specyficznych dla śródbłonka naczyń limfatycznych oraz opisano nowe modele badawcze wzrostu naczyń chłonnych. Artykuł przedstawia poglądy dotyczące regulacji limfangiogenezy w guzach nowotworowych

Ekspresja wybranych markerów i modulatorów angiogenezy u chorych na raka jajnika w okresie przed-, około- i pomenopauzalnym

Summary Introduction: One of the most commonly assessed angiogenesis markers is microvessel density which is determined on the bases of specific endothelial antigen expression (CD34, CD105). Angiogenesis modulators include growth factors and their receptors (EGFR), proteases and their inhibitors, oncogenes and suppressor genes (p53). Objective: The aim of the study was to evaluate whether there are any differences in selected angiogenesis markers and modulators expressions in ovarian cancer patients with different menopause status. Material and methods: The study included 100 women, age 30-70, who underwent surgical treatment due to ovarian cancer. As far as their menopause status was concerned, the women were divided into three groups: pre-, peri-, and postmenopausal. Microvessel density was assessed on the basis of CD34 (MVDCD34) and CD105 (MVDCD105) expression. Additionally, tumor tissue p53 protein and EGFR expression were investigated. Active EGFR form in blood serum samples of cancer patients was assessed before the surgery. Results: Microvessel density, assessed on the basis of CD34 and CD105 expression, as well as p53 and EGFR expression were similar in all three groups of patients. Active EGFR serum concentration in women with ovarian cancer did not prove to be significantly different and did not depend on the menopause status. Conclusion: Intensity of the angiogenesis process does not depend on the menopausal status of women and is similar in pre-, peri- and postmenopausal patients.Streszczenie Wstęp: Jednym z najczęściej ocenianych markerów angiogenezy jest gęstość mikronaczyń określana na podstawie ekspresji antygenów swoistych dla komórek śródbłonkowych (CD34, CD105). Modulatorami angiogenezy są m.in. czynniki wzrostu i ich receptory (np. EGFR), proteazy i ich inhibitory, onkogeny i geny supresorowe (p53). Cel pracy: Celem pracy była ocena, czy u pacjentek z rakiem jajnika o różnym statusie menopauzalnym występują różnice w ekspresji wybranych markerów i modulatorów angiogenezy. Materiał i metody: Do badania włączono 100 kobiet w wieku 30-70 lat, które zostały poddane leczeniu operacyjnemu z powodu raka jajnika. Chore w zależności od statusu menopauzalnego podzielono na trzy grupy: pacjentki w okresie przed-, około- i pomenopauzalnym. Gęstość mikronaczyń oceniano na podstawie ekspresji antygenu CD34 (MVDCD34) oraz antygenu CD105 (MVDCD105). Analizowano immunohistochemiczna ekspresję białka p53 i EGFR w tkance guza. W surowicy krwi pobranej od pacjentek przed zabiegiem operacyjnym oceniano stężenie aktywnej formy EGFR. Wyniki: Gęstość mikronaczyń oceniana na podstawie ekspresji CD34 i CD105, a także ekspresja białka p53 oraz EGFR była podobna we wszystkich trzech badanych grupach. Nie stwierdzono również istotnych różnic w stężeniu aktywnej formy EGFR w surowicy krwi chorych na raka jajnika w zależności od ich statusu menopauzalnego. Wnioski: Proces angiogenezy zachodzącej w raku jajnika wydaje się być niezależny od statusu menopauzalnego pacjentek. Jego tempo i nasilenie są prawdopodobnie zbliżone u chorych w okresie przed-, około- i pomenopauzalnym

Expression of lymphangiogenesis marker Prox-1 in ovarian cancer

Limfangiogeneza w raku jajnika jest mało poznana. Naczynia limfatyczne wspomagają wzrost guza, a jednocześnie są główną drogą przerzutów komórek nowotworowych. Ocena ekspresji wybranych markerów śródbłonka naczyń limfatycznych może być przydatna do oceny przebiegu procesu limfoangiogenezy, oceny zezłośliwienia guza oraz zdolności do powstawania przerzutów. Szczególnie obiecujące mogą być badania nad ekspresją białek specyficznych dla limfangiogenezy, takich jak Prox-1 czy jądrowy czynnik transkrypcyjny. Ocena tych markerów być może umożliwi ich wykorzystanie w roli czynników prognostycznych użytecznych przy przewidywaniu leczenia. W niniejszej pracy badano zależności pomiędzy ekspresją Prox-1, różnymi typami histologicznymi oraz różnym stopniem zróżnicowania histologicznego raka jajnika. Ekspresja Prox-1 występowała we wszystkich badanych typach histologicznych raka jajnika. Nie uzyskano jednak różnic istotnych statystycznie (p > 0,05) w odniesieniu do typu i stopnia zróżnicowania histologicznego. Dalsze badania uwzględniające większą grupę chorych, zakres zabiegu chirurgicznego oraz inne wykładniki limfangiogenezy prawdopodobnie pozwolą na wykrycie innych zależności.Lymphangiogenesis in ovarian cancer is not yet well characterised. Lymphatic vessels help tumor progression, and simultaneously represent the most important pathway for neoplastic cell dissemination. The estimation of the lymphatic endothelium markers expression can be useful in the evaluation of lymphangiogenesis, cancer progression and ability of metastatic spreading. It is especially interesting the research on specific lymphatic markers, such as Prox-1, nuclear transcription factor. We investigated correlation between expression of Prox-1, histological type and grading of ovarian cancer. Our studies show the expression of Prox-1 in all investigated histological types of ovarian cancer. We did not observe the statistis correlation (p > 0.05) with reference to type and grading. Further investigations taking into account bigger number of patients, spectrum of operation, and other exponents of limphangiogenesis, probably allow to discover different correlations

Neuropilin 1 in uterine leiomyosarcoma. Clinical and pathological analysis

Objectives: The role of angiogenesis in leiomyosarcomas still remains unclear. The aim of this study was to evaluate the NRP1 expression in the leiomyosarcoma tissues and to find the relations between its expression and the clinical features. Material and methods: The study group consisted of 50 patients with diagnosis of the uterine leiomyosarcoma. Clinical and follow up data were collected. Using immunohistochemical methods the expression of NRP1 was detected. Results: The lack of NRP1 expression was found in 14 cases, positive (weak or moderate) expression was noted in 36 cases. The significantly higher expression of NRP1 was observed in more severe clinical stages in comparison to lower stages of the disease. The significantly shorter survival of patients with the positive expression of NRP1 in leiomyosarcoma was observed. Conclusions: The expression of NRP1 is associated with clinical advancement and worse prognosis in uterine LMS. Neuropilin 1 can be widely used as a postoperative survival predictor for the patients suffering from uterine LMS

Does the patients age at cancer diagnosis affect microvessels density in uterine sarcoma tissues?

Objectives: The objective of the study was to retrospectively evaluate the density of vessels exhibiting positive glycoprotein CD34 expression in the uterine leiomyosarcoma tissues and their correlation with the age of patients at the time of tumor diagnosis. Material and methods: The archival paraffin blocks with the cancer tissues collected from 50 patients suffering from uterine leiomyosarcoma were used together with their clinical and demographic data. The immunohistochemical peroxidase-de­pendent methods were used to detect microvessels with positive CD34 expression. The glycoprotein CD34 expression was evaluated as a density of microvessel showing the positive immunohistochemical reaction (MVDCD34). Results: The negative, statistically significant correlation between the age of patients (at the moment diagnosis) and the MVDCD34+ (R = –0.289, p = 0.042) was found. Conclusions: The study’s findings may suggest that the tissues of younger people constitute a permissive environment for pro-angiogenic factors

Ekspresja podoplaniny w raku jasnokomórkowym jajnika

Abstract Introduction: Podoplanin is a transmembrane glycoprotein expressed in endothelial lymphatic cells. It was proven to be a predictive marker in a variety of cancers e.g. mesothelioma and head and neck squamous-cell carcinoma. Ovarian clear cell carcinoma (OCCC) is a rare and unique histopathologic subtype of epithelial ovarian cancer (EOC). The molecular basis of that phenomenon remains unknown. Objectives: The aim of our study was to assess podoplanin expression on the protein level in OCCC. Material and Methods: Immunohistochemistry was performed on paraffin-embedded tissues from 19 patients with diagnosed OCCC. Results: Podoplanin expression was present (moderate or strong) in 52% of OCCC cases (10/19). Nine of eleven (81,2%) postmenopausal and one of eight (12,5%) premenopausal women were podoplanin positive. No differences in podoplanin expression were found in relation to clinical features of the tumor. Conclusion: The incidence of podoplanin expression is higher in ovarian clear cell adenocarcinoma in postmenopausal patients.Streszczenie Wstęp: Podoplanina jest przezbłonową glikoproteiną występującą w komórkach śródbłonka naczyń limfatycznych. Swoje zastosowanie jako marker predykcyjny znalazła w diagnostyce międzybłoniaka czy też w raku głowy i szyi. Jasnokomórkowy rak jajnika (OCCC) jest rzadko występującym i odmiennym histopatologicznym podtypem nabłonkowego raka jajnika. Molekularne podłoże tego zjawiska nadal nie jest znane. Cel: Celem badań była ocena ekspresji podoplaniny na poziomie białka w jasnokomórkowym raku jajnika. Materiał i metody: Ekspresję podoplaniny oceniono metodą immunohistochemiczną z zastosowaniem techniki macierzy tkankowych (TMA) u 19 pacjentek z OCCC. Wyniki: Ekspresja podoplaniny była obecna (średnia lub wysoka) w 52% przypadków OCCC (10/19). Jej ekspresję wykazano u jednej Spośród ośmiu pacjentek przed menopauzą (12,5%) i u 9 spośród 11 (81,2%) po menopauzie. Nie wykryto różnic w ekspresji podoplaniny w odniesieniu do cech klinicznych nowotworu. Wnioski: Częsta ekspresja podoplaniny jest charakterystyczna dla kobiet po menopauzie ze zdiagnozowanym rakiem jasnokomórkowym jajnika

Effects of active form of EGFR on disease-free survival in ovarian cancer women

BackgroundStandard procedure in cases of ovarian cancer includes surgical treatment and complementary chemotherapy based on taxanes and platinum compounds. The results of such a procedure in advanced forms of cancer are still unsatisfactory. More accurate determination of the duration of remission with cancer patients is possible through the identification of prognostic factors. Currently adopted and extensively used prognostic factors include, among others, the age of the patient at the moment of the disease being diagnosed, the degree of clinical advancement, the size of the tumour remaining after surgery, the histological type of the neoplasm, and the volume of fluid in the peritoneal cavity. Among neoplasm markers the greatest importance is attributed to the CA 125 antigen, but continued efforts are being made in the search for new, more specific and sensitive markers.AimThe objective of the study presented herein was estimation of the prognostic significance of the active form of EGFR in the serum of women with ovarian cancer in relation to their disease-free survival time.Materials/MethodsThe study was performed on 100 women treated for ovarian cancer in the course of four years. The concentration of the active form of EGFR was determined in the blood serum, prior to treatment, using commercial immunoenzymatic sets. Disease-free survival was defined as the time elapsed from the completion of complementary first-line chemotherapy till the appearance of clinical and/or biochemical (CA 125>30 U/ml) symptoms of relapse of the neoplastic disease.ResultsThe concentration of the active form of EGFR fell within the range of 0.093–0.475 fmol/ml and did not show statistical significance with relation to disease-free time: the duration of the remission period was similar in patients with low as well as with high concentration of the active form of that receptor.ConclusionsExamination of concentration of the active form of EGFR in blood serum prior to surgery does not display prognostic significance for prediction of the length of the period of remission or of disease-free survival

Expression of lymphangiogenesis marker neuropilin-1 in different types of ovarian cancer

Background: Neuropilin (NRP) may be used as a marker of lymphangiogenesis in malignant tumors. Significant correlations of the expression of NRP with tumor progression and overall survival prognosis were found in several cancer types. However, its potential role in epithelial ovarian cancer (EOC) has not been clarified. AIMS: The aim of the work was to study a possible correlation of neuropilin-1 (NRP-1) expression with selected clinical and histological features of EOC. Material and Methods: The study included 53 women (aged 23 to 81, mean 56.6+/-4.4yrs), 38 of which were postmenopausal (71.7%). Immunohistochemical staining with a specific anti-NRP-1 antibody was performed in representative tumor tissue samples of patients with EOC. Both, percentage of stained lymphatic cells and intensity of staining were assessed under 200x magnification. The results were correlated with the menopausal status, FIGO stage, histological type and histological grade of EOC. Results: Histological examination revealed that there were 27 cases of serous cancers (50%), 15 cases of mucinous cancer (28.3%) and 11 endometrioid cancers (20.7%). In 41.5% (n=22) cases of EOC no NRP-1 staining was found, a weak (+) or strong (++) staining were found in 13 (24.5%) and 18 tumors, respectively. There were no significant differences between neuropilin-1 expression and both menopausal status of women and histological type of EOC. Except for stage II, clinical EOC patients’ FIGO stage was not correlated with the lack of expression (38.8% for stage I, 71.4% for stage II and 35.7% for stage III). Conclusion: We believe that neuropilin-1 expression is probably not related to clinical and histological features of epithelial ovarian cancer

Isobolographic analysis demonstrates the additive and synergistic effects of gemcitabine combined with fucoidan in uterine sarcomas and carcinosarcoma cells

Background: Uterine sarcomas and carcinosarcoma are associated with unfavorable prognosis. The regimens that are used in chemotherapy are associated with high incidence of side effects and usually do not significantly increase patients’ survival rates. In this study we investigated the activity and interactions between gemcitabine and fucoidan, the natural compound known for its anti-tumor properties, in human sarcomas and carcinosarcoma cell models. Methods: SK-UT-1, SK-UT1-B (carcinosarcoma), MES-SA (leiomyosarcoma), and ESS-1 (endometrial stromal sarcoma) cell lines were used for the experiments. Cells were incubated in the presence of gemcitabine, fucoidan, and mixtures, after the incubation the MTT tests were performed. In order to assess the interactions between tested compounds isobolographic analysis was performed. Additional assessments of apoptosis and cell cycle were done. Results: Additive effect of combined treatment with gemcitabine and fucoidan was observed in ESS-1 and SK-UT-1 cell line. Although the supra-additive (synergistic) effect noticed in SK-UT-1B cell line. It was not possible to determine the interactions of fucoidan and gemcitabine in MES-SA cell line due to insuffcient response to treatment. Addition of fucoidan to gemcitabine enhances its proapoptotic activity, what was observed especially in ESS-1 and SK-UT-1B cell lines. The arrest of cell cycle induced by mixture of gemcitabine and fucoidan, superior comparing gemcitabine alone was observed in SK-UT-1B. Conclusions: Obtained data showed that a combination of fucoidan and gemcitabine in uterine endometrial stromal sarcoma and carcinosarcoma cell lines has additive or even synergistic effect in decreasing cell viability. Furthermore, this drug combination induces apoptosis and arrest of cell cycle. The resistance of uterine leiomyosarcoma cell line, justifies searching for other drugs combinations to improve therapy effcacyThe research was founded by Medical University of Lublin (grants No. DS 120, DS 121 and MNmd129)