Relaxed fibronectin: a potential novel target for imaging endometriotic lesions.

BACKGROUND: Endometriosis is characterized by the ectopic occurrence of endometrial tissue. Though considered benign, endometriotic lesions possess tumor-like properties such as tissue invasion and remodeling of the extracellular matrix. One major clinical hurdle concerning endometriosis is its diagnosis. The diagnostic modalities ultrasound and MRI are often unable to detect all lesions, and a clear correlation between imaging and clinical symptoms is still controversial. Therefore, it was our aim to identify a potential target to image active endometriotic lesions. RESULTS: For our studies, we employed the preclinical radiotracer [111In]In-FnBPA5, which specifically binds to relaxed fibronectin-an extracellular matrix protein with key functions in homeostasis that has been implicated in the pathogenesis of diseases such as cancer and fibrosis. We employed this tracer in biodistribution as well as SPECT/CT studies in mice and conducted immunohistochemical stainings on mouse uterine tissue as well as on patient-derived endometriosis tissue. In biodistribution and SPECT/CT studies using the radiotracer [111In]In-FnBPA5, we found that radiotracer uptake in the myometrium varies with the estrous cycle of the mouse, leading to higher uptake of [111In]In-FnBPA5 during estrogen-dependent phases, which indicates an increased abundance of relaxed fibronectin when estrogen levels are high. Finally, immunohistochemical analysis of patient samples demonstrated that there is preferential relaxation of fibronectin in the proximity of the endometriotic stroma. CONCLUSION: Estrous cycle stages characterized by high estrogen levels result in a higher abundance of relaxed fibronectin in the murine myometrium. This finding together with a first proof-of-concept study employing human endometriosis tissues suggests that relaxed fibronectin could be a potential target for the development of a diagnostic radiotracer targeting endometriotic lesions. With [111In]In-FnBPA5, the matching targeting molecule is in preclinical development.

Effect of normal and preeclamptic plasma on superoxide-anion production of neutrophils from healthy non-pregnant women.

This study has examined whether production of superoxide-anion by granulocytes differs between non-pregnant, healthy pregnant and preeclamptic pregnant women. First, we assessed superoxide-anion production in 13 non-pregnant women, 11 healthy pregnant women and 14 preeclamptic pregnant women. Then, we examined the effect of plasma samples of healthy pregnant and preeclamptic pregnant women on superoxide production by neutrophils separated from healthy pregnant women. Superoxide generation was measured by ferricytochrome-c reduction. Phorbol-12,13-dibutyrate- and n-formyl-methionyl-leucyl-phenylalanine-stimulated superoxide-anion production was significantly decreased in healthy pregnant women's granulocytes compared with non-pregnant women. There was no significant difference between granulocyte superoxide-anion production in preeclamptic pregnant and non-pregnant women. When neutrophils from non-pregnant women were incubated in plasma from healthy pregnant women, the granulocyte phorbol-12,13-dibutyrate-stimulated superoxide-anion production was significantly inhibited. With the same stimulator, there were no significant differences between superoxide-anion production of neutrophils incubated in autologous, non-pregnant and preeclamptic pregnant plasma. If n-formyl-methionyl-leucyl-phenylalanine was used for stimulation, there were no significant differences in the superoxide-anion production of granulocytes in either group. Granulocyte superoxide-anion production decreases during pregnancy; this decrease does not occur in preeclampsia, and may cause endothelial damage. It is conceivable that there are unidentified factors in maternal circulation which inhibit superoxide-anion production by granulocytes in healthy pregnant women.

Superoxide anion production of granulocytes in patients with endometrial cancer at presentation and after treatment.

BACKGROUND: In current medical science the reactive oxygen intermediates play an ever more important role. METHODS: The authors analysed superoxide anion production of polymorphonuclear leukocytes (PMNLs) in 30 blood samples from endometrial carcinoma patients. They measured it before the complex treatment and in nine cases at least 1 year after finishing the treatment. The results were compared with healthy controls. Phorbol dibutyrate stimulated superoxide anion production was measured spectrophotometrically as superoxide dismutase inhibitable reduction of ferricytochrome-c absorbance. RESULTS: The mean superoxide anion production of PMNLs of the 31 healthy controls was 1.541 nM/min/10(5)cells (S.D.=0.201 nM/min/10(5)cells). Superoxide anion production of samples from endometrial cancer patients was much lower. The superoxide anion production of granulocytes in the early stage of endometrial cancer was lower (1.11 nM/min/10(5)cells) as in the controls. There was no essential difference in the superoxide production of patients with different depths of myometrial infiltration. After treatment, the superoxide anion production of the granulocytes of the clinically tumour-free patient had substantially progressed (1.357 nM/min/10(5)cells), but it was henceforth lower than the control. CONCLUSIONS: According to our results, damage to the non-specific immunity is already advanced at the earliest stage of endometrial cancer. Further examinations are needed to decide how to normalise the superoxide production of granulocytes, and whether it has any importance in prevention and therapy.