Mutant epidermal growth factor receptor in benign, borderline, and malignant ovarian tumors.

PURPOSE: Dysfunction of the epidermal growth factor (EGF) complex is essential to the growth and development of many human tumors. Overexpression of the EGF receptor (EGFR) is a characteristic finding in a considerable number of solid tumors and often signalizes poor prognosis. There is a major disagreement among researchers about both the frequency and possible clinical importance of EGFR overexpression in ovarian cancer. The type III variant of EGFR (EGFRvIII) is a mutant with a deletion. Contrary to the wild-type, it is constitutively active. EGFRvIII has not been found in normal tissue, and consequently, it is an attractive tumor-specific candidate for molecular targeted treatment. The literature dealing with this mutation in ovarian cancer has been very sparse. EXPERIMENTAL DESIGN: Tissue from 225 patients who underwent surgery for a pelvic mass was collected consecutively. The samples included 99 ovarian/peritoneal/tuba cancers, 17 ovarian borderline tumors, 66 benign ovarian tumors, 15 other cancer types, 24 normal ovarian biopsies, and 4 miscellaneous. The presence of EGFRvIII was investigated both by PCR analyses for EGFRvIII gene expression and with protein analysis by Western blots. RESULTS: None of the tissue samples was positive for the EGFRvIII mutation neither at the mRNA level nor at the protein level. CONCLUSIONS: The EGFRvIII mutation seems to be very rare in ovarian tissue. Our data indicate that EGFRvIII is not a part of the malignant phenotype in ovarian cancer and should not be pursued as a therapeutic target for treatment of this disease.

Protein levels and gene expressions of the epidermal growth factor receptors, HER1, HER2, HER3 and HER4 in benign and malignant ovarian tumors.

The epidermal growth factor receptors, HER1, HER2, HER3 and HER4 play a key role in the growth of malignant tumors. The receptors of the EGF receptor family are not cancer-specific proteins since these receptors are expressed to some extent in both normal and benign tissue, but this is not elucidated in detail in ovarian tissue. High tumor-to-normal-tissue concentration ratios would be favorable for molecular targeted anti-cancer treatment. The primary aim of the study was to analyze the potential differential protein content and gene expression of the four receptors in benign and malignant ovarian tumors. Tissue from 207 patients (101 malignant, 19 borderline, 64 benign ovarian tumors and 23 normal ovaries) were analyzed by quantitative ELISA for HER1-HER4 protein concentrations and by real-time PCR for HER1-HER4 gene expression. HER2 was also analyzed by immunohistochemistry. The HER2-4 receptor protein content and the median gene expression level was significantly higher in ovarian cancer patients compared to patients with benign ovarian tumors and normal ovaries (p<0.0000001). The protein content of the HER1 receptor was significantly lower in ovarian cancer compared to borderline tumors (p=0.012), benign ovarian tumors (p=0.049) and to normal ovaries (p=0.000069). A sound correlation between the protein levels and gene expressions was documented. In conclusion, decreased concentration of HER1 protein and increased HER2, HER3 and HER4 protein concentration were observed, as also elevated HER2-HER4 gene expression levels in ovarian cancer patients with barely any overlap of the HER3 and HER4 expression in malignant ovarian tumors compared to benign ovarian tissues.

Interleukin-1 is the initiator of Fallopian tube destruction during Chlamydia trachomatis infection.

Chlamydia trachomatis infection is associated with severe Fallopian tube tissue damage leading to tubal infertility and ectopic pregnancy. To explore the molecular mechanisms behind infection an ex vivo model was established from human Fallopian tubes and examined by scanning electron microscopy and immunohistochemistry. Extensive tissue destruction affecting especially ciliated cells was observed in C. trachomatis infected human Fallopian tube organ culture. Interleukin-1 (IL-1) produced by epithelial cells was detected after infection. Addition of IL-1 receptor antagonist (IL-1RA) completely eliminated tissue destruction induced by C. trachomatis. The anti-inflammatory cytokine IL-10 reduced the damaging effect of C. trachomatis infection, however, to a lesser extent than IL-1RA. Furthermore, IL-1 was found to induce IL-8, a neutrophil attractant, using a signal transduction pathway involving p38 MAP kinase. Consequently, IL-1 has the potential to generate a cellular infiltrate at the site of infection in vivo. Blocking the IL-1 receptors by IL-1RA eliminated tissue destruction and cytokine production. Hence, these studies show the importance of IL-1 in initiating the tissue destruction observed in the Fallopian tube following C. trachomatis infection. Because leukocytes are absent in the ex vivo model, this study strongly indicates that IL-1 is the initial proinflammatory cytokine activated by C. trachomatis infection.

Morphology of human Fallopian tubes after infection with Mycoplasma genitalium and Mycoplasma hominis--in vitro organ culture study.

BACKGROUND: Female infertility can be caused by scarring and occlusion of the Fallopian tubes. Sexually transmitted bacteria can damage the delicate epithelial layer of human Fallopian tubes (HFT). Genital mycoplasmas are associated with human reproductive failure. Yet, there is not enough evidence that mycoplasmas can cause tubal factor infertility. We analysed the effects of infections with Mycoplasma hominis and Mycoplasma genitalium on the HFT epithelium and compared them with the effects of infections with genital pathogens: Chlamydia trachomatis and Neisseria gonorrhoeae. METHODS: We used an in vitro model in which pieces of normal HFT were infected with different bacteria, and the outcome of the infections was analysed by scanning electron microscopy (SEM) and confocal microscopy. RESULTS: The presence of M. hominis did not cause any morphological changes of the epithelium of HFT. Noticeable changes in the morphology of the ciliated cells were observed in M. genitalium-infected tissue. Five days post-infection, the cilia were abnormally swollen and some of the ciliated cells fell off the epithelium. These effects could be inhibited by pre-incubation of M. genitalium with antibody directed against the C-terminal part of the adhesion protein MgPa before infection of HFT organ culture. CONCLUSION: We have shown that the presence of M. genitalium, but not M. hominis, in the HFT organ culture affected the epithelium and resulted in cilia damage. The effect of infection with M. genitalium on the HFT was, however, very moderate when compared with the extensive damage of the epithelium caused by N. gonorrhoeae or C. trachomatis.