The malignant progression of gynecologic tumors is determined by their potential for invasion and metastasis. Specifically, epithelial tumor cells need to leave the primary tumor mass to invade the environment and/or metastasize to distant regions. To do so, these tumor cells undergo distinct changes from an epithelial to amesenchymal phenotype, a process called epithelial-to-mesenchymal transition (EMT). In this article, we review the significance of EMT-related mechanisms in gynecologic malignancies. For the cancers considered here - breast, ovarian and cervical carcinomas - a multitude of EMT events have been described, including the loss of epithelial markers (E-cadherin, cytokeratines) and an increase in mesenchymal markers (e. g. N-cadherin, vimentin). In addition, the expression of the EMT transcription factors Snail and Twist has been observed in different malignancies. EMT can be induced by several stimuli, e. g. growth factors, WNT and notch signaling as well as tumor hypoxia, a common feature of solid tumors. Characteristic EMT-related changes can be detected in gynecologic cancers, suggesting a role for EMT in triggering invasion, metastasis and, therefore, malignant progression in these tumor entities. Further investigation of EMT pathways will result in the identification of new targets for tailored cancer therapies.

Hypoxie beeinflusst die maligne Progression von Tumoren, indem sie deren Invasions- und Metastasierungspotenial erhöht und zu Therapieresistenz führt. Viele Gene, die in vitro unter hypoxischen Bedingungen induziert werden, werden im Kontext des klinischen Tumors unabhängig vom aktuellen Grad der Hypoxie exprimiert. Daher lautet unsere Hypothese, dass chronisch intermittierende Hypoxie zur Fixierung des hypoxischen Genexpressionsmusters führt unabhängig vom aktuellen Oxygenierungsstatus. CSRP2 ist eines der 'hypoxie-fixierten' Gene, welches wir in einem Langzeit-Experiment mit zyklischen Hypoxie- und Reoxygenierungsphasen identifiziert haben. Dieses Gen spielt eine Rolle bei zellulären Differenzierungsprozessen. Ziel der aktuellen Studie war es, die Expression von CSRP2 in der Zervixkarzinom-Zelllinie Siha und in klinischen Zervixkarzinomen zu analysieren. Ausserdem wurde der Effekt von Doxorubicin, einem starken DNA-Interkalator, auf die CSRP2-Expression in Siha-Zellen untersucht.

Purpose: Intratumoral hypoxia contributes to neovascularisation by angiogenic factors. Angiogenesis can be examined by evaluation of microvessel density using immunohistochemistry. VEGF-1 is mainly involved in angiogenesis by binding a 180 kD transmembrane protein receptor, the VEGFR-1 (ftl-1). Alternative splicing produces are a shorter soluble form (soluble FLT-1, s-VEGFR-1), which can be measured in the serum and plasma of tumor patients.

Fragestellung: Hypoxie spielt eine wichtige Rolle bei der malignen Progression von Tumoren, indem sie deren Invasions- und Metastasierungspotential erhöht. Die Aussagekraft bisheriger In-vitro-Modelle der Tumorhypoxie ist aufgrund ihrer kurzen Versuchsdauer und des Fehlens von Reoxygenierungsphasen beschränkt. Hier beschreiben wir den Einfluss wiederholter Hypoxie/Reoxygenierungs-Zyklen auf die Genexpression in Zervixkarzinomzellen.

Fragestellung: Klinische und experimentelle Daten belegen eine Beziehung zwischen Tumorhypoxie und maligner Progression. Um dieses Verhältnis weiter zu charakterisieren, wurde die Gewebeoxygenierung von benignen und malignen Neoplasien mittels invasiver pO2-Messung bestimmt.

Purpose: About on fifth of patients with breast cancer represent metastatic disease in the bones (Oka H et al. 2006). In ductal carcinomain situ, the expression of COX-2 is associated with an aggressive disease (Bolan GP et al. 2004). Evaluating the expression of COX-2, histologic proven bone metastases of breast cancer were investigated immunohistochemically.

Innate immunity was critical in insects defensive system and able to be induced by Janus kinase/signal transducer and activator of transcription cascade transduction (JAK/STAT) signaling pathway. Currently, it had been identified many JAK/STAT signaling pathway-related genes in silkworm, but little function was known on insect innate immunity. To explore the roles of JAK/STAT pathway in antifungal immune response in silkworm (Bombyx mori) against Beauveria bassiana infection, the expression patterns of B. mori C-type lectin 5 (BmCTL5) and genes encoding 6 components of JAK/STAT signaling pathway in silkworm challenged by B. bassiana were analyzed using quantitative real time PCR. Meanwhile the activation of JAK/STAT signaling pathway by various pathogenic micro-organisms and the affect of JAK/STAT signaling pathway inhibitors on antifungal activity in silkworm hemolymph was also detected. Moreover, RNAi assay of BmCTL5 and the affect on expression levels of signaling factors were also analyzed. We found that JAK/STAT pathway could be obviously activated in silkworm challenged with B. bassiana and had no response to bacteria and B. mori cytoplasmic polyhedrosis virus (BmCPV). However, the temporal expression patterns of JAK/STAT signaling pathway related genes were significantly different. B. mori downstream receptor kinase (BmDRK) might be a positive regulator of JAK/STAT signaling pathway in silkworm against B. bassiana infection. Moreover, antifungal activity assay showed that the suppression of JAK/STAT signaling pathway by inhibitors could significantly inhibit the antifungal activity in hemolymph and resulted in increased sensitivity of silkworm to B. bassiana infection, indicating that JAK/STAT signaling pathway might be involved in the synthesis and secretion of antifungal substances. The results of RNAi assays suggested that BmCTL5 might be one pattern recognition receptors for JAK/STAT signaling pathway in silkworm. These findings yield insights for better understand the molecular mechanisms of JAK/STAT signaling pathway in antifungal immune response in silkworm.

Aims: Finger-like and spray-like pattern of invasion represent the most common types of tumoral growth patterns in carcinoma of the cervix uteri (CX) invading host tissue (Horn et al. 2006). Infiltrative growth usually induce new matrix formation by activating the peritumoral stromal cells; that is, desmoplastic stromal reaction (DSR) at the front of invasion (juxtatumoral stroma). Infiltrative growth and peritumoral stromal remodelling might be involved by apoptosis of tumor cells. BNIP3 is a mitochondrial protein and a proapoptotic member of the Bcl-2 family and expressed in different types of human cancer. Nothing is known regarding the association of BNIP-3 expression in CX and parameters of infiltrative growth.

Fragestellung: Es ist nur wenig bekannt über die Cyclooxygenase-2 (Cox-2)-Expression im normalen Brustdrüsengewebe und über Veränderungen des Cox-2-Expressionsmusters vom Normalgewebe über DCIS-Läsionen bis hin zum invasiven Mammakarzinom. Ziel der Studie war es daher, die Cox-2-Expression in Normalgewebe, DCIS und invasivem Mammakarzinom der jeweils selben Patientin zu untersuchen und zu vergleichen.

OBJECTIVE:Cervical cancer is associated with infection of epithelial cells with the human papillomavirus (HPV) type 16 and HPV18. A functional signalling machinery in T-cells is required in order to successfully fight and eradicate HPV16+ transformed epithelial cells. One of the key signalling molecules associated with the T-cell receptor (TCR) is the homodimeric zeta chain molecule.MATERIAL AND METHODS:28 formalin fixed und paraffin embedded samples of cervical tissue with cervical intraepithelial lesions CIN I (n = 3), CIN III (n = 7), invasive cervical carcinoma (CC) (n = 13) and normal cervical tissue (n = 5) has been evaluated for HPV-PCR und zeta chain immunohistochemistry. For immunohistochemistry a monoclonal IgG1 anti TZR zeta chain-antibody (mAb) has been used (clone 6B 10.2, Santa Cruz, Heidelberg, Germany). According to the performed Western-Blot analysis on peripheral blood monocytes (PBMCs) the used mAb has specifically recognized TCR zeta chains.RESULTS:We show reduced protein zeta chain expression associated with invasive cervical cancer, but not with pre-invasive HPV16-positive lesions or HPV16-negative normal cervix tissue.CONCLUSIONS:Thus, reduced TCR zeta chain expression is not necessarily linked to a chronic viral infection, nor to the presence of transformed cells, but rather to the stromal invasion of the cancer lesion.

Zielstellung: Primäre Peritonealcarcinome (PPC) sind seltene, aber aggressive Malignome. In dieser Studie wurden Primäre Peritonealcarcinome hinsichtlich der Expression therapeutisch relevanter Faktoren untersucht.

Background and aims: To compare transperitoneal, extraperitoneal and laparoscopic pelvic lymphadenectomy in terms of feasibility and morbidity in patients affected by cervical cancer undergoing radical hysterectomy. Methods: Consecutive patients, affected by stage IB-IIB cervical carcinoma scheduled for radical surgery entered the study. Patients were randomly assigned to transperitoneal (TPL), extraperitoneal (EPL) or laparoscopic pelvic lymphadenectomy (LPL). All patients underwent classical radical hysterectomy. Perioperative data were recorded. Follow up examinations were performed at 15th, 30th and 60th day after surgery. Results: 168 patients entered the study. The mean operative time were: 63 1 7.6, 54 1 6.7 and 75 1 8.4 minutes (TPL vs EPL p,0.001; EPL vs LPL p , 0.001; TPL vs LPL p , 0.001) for TPL, EPL and LPL respectively. The Feasibility of the procedures, analyzed on an intention-to-treat basis, was 96%, 93% and 95% for TPL, EPL and LPL group respectively (p 1⁄4 ns). The average hospitalization were: 5.6 1 0.9, 3.2 1 0.4 and 3.1 1 0.3 days (TPL vs EPL p , 0.001; TPL vs LPL p , 0.001) for TPL, EPL and LPL respectively. Conclusions: EPL and LPL are as feasible and effective as TPL and can be adequately performed with a reasonable complication rate. LPL showed a statistically significant longer operative time. However both EPL and LPL can minimize some postoperative complications reducing length of stay.

Fragestellung: Unter physiologischen Umständen stellt Hypoxie einen Stimulus für Apoptose dar. Allerdings konnten wir zeigen, dass es in hypoxischen Zervixkarzinomen offensichtlich zu einer Apoptoseresistenz mit niedrigen Apoptoseraten kommen kann. Diese Karzinome waren klinisch aggressiver und bedeuteten eine schlechtere Prognose als alle anderen Zervixkarzinome. Da der Mechanismus der hypoxie-induzierten Apoptoseresistenz weitestgehend ungeklärt ist, untersuchten wir die Expression des Apoptosemediators Apaf-1 im Zervixkarzinom und seine Beziehung zu Apoptoserate und intratumoraler Hypoxie.

5046 Background: Clinical observations suggest that intratumoral hypoxia may increase the aggressiveness of tumors through clonal selection of cancer cells that have lost their apoptotic potential. We have shown previously that patients with hypoxic cervical cancers displaying a low apoptosis rate had a significantly worse prognosis compared to all other patients. The aim of this study, therefore, was to investigate the expression of the proapoptotic protein Apaf-1 in cervical cancers and to analyze its relation to intratumoral hypoxia and apoptosis. Methods: 56 patients with cervical cancer (FIGO stage IB to IV) were subjected to pretherapeutical intratumoral pO2 measurement with the Eppendorf electrode after informed written consent was given by each patient. The study was approved by the Ethics Committee of the University of Leipzig. Cervical cancer tissue from these patients was taken by needle core biopsy and analyzed by TUNEL assays as well as by immunohistochemistry with an anti-Apaf-1-antibody. For statistical analysis, Fisher’s exact test was used. Results: Apaf-1 was expressed in 86% of cervical cancers. The median apoptosis rate was 1.0% (range: 0.3– 3.4%). There was no direct correlation between Apaf-1 expression and intratumoral hypoxia. However, in the group of hypoxic cervical cancers (pO2 <10 mmHg) with a low apoptosis rate (<1.0%), 43.8 % (95% CI: 19.8–70.1%) of tumors showed a negative Apaf-1 expression compared to only 2.5% (95% CI: 0.06–13.1%) in non-hypoxic cancers and hypoxic cancers with a high apoptosis rate (p = 0.0003, Fisher’s exact test). Conclusions: While Apaf-1 is expressed in the vast majority of cervical cancers, a significant proportion of tumors with low apoptosis rates despite intratumoral hypoxia showed a loss of Apaf-1 expression. This finding suggests a mechanism by which hypoxic cervical cancers acquire resistance to apoptosis. No significant financial relationships to disclose.