The clinicopathological characteristics and survival outcomes of primary expansile vs. infiltrative mucinous ovarian adenocarcinoma: a retrospective study sharing the experience of a tertiary centre.

Background: Mucinous ovarian carcinomas (MOCs) are rare ovarian tumours accounting for 3% of all epithelial ovarian carcinomas (EOCs). They are either expansile or infiltrative, based on the tumour's histological pattern of invasion. MOCs have a distinct molecular profile, natural history, chemo-sensitivity, and prognosis compared to other EOCs. The aim of this study was to describe patient and tumour characteristics, as well as survival outcomes of expansile and infiltrative primary MOCs. Methods: This was a retrospective cohort study conducted at a tertiary cancer centre. Patients had surgery for primary MOC between Jul 1, 2010 and Oct 28, 2022. All patients discussed at the Oxford multidisciplinary team (MDT) meeting with a diagnosis of MOC were included. We excluded patients with mucinous metastatic carcinoma (MMC), dual histological diagnoses, those who died before treatment was initiated, and patients with incomplete records. Results: A total of 47 patients were identified and 14 were excluded. Out of the remaining 33 MOCs, 23 (70.6%) were expansile and 10 (30.4%) were infiltrative. The median follow-up was 37 months (95% CI: 14.1-69.8). Patients with infiltrative tumours were older than those with expansile tumours (median age 62 vs. 55 years, P=0.049). Infiltrative tumours were diagnosed at a more advanced International Federation of Gynaecology and Obstetrics (FIGO) stage compared to expansile tumours: FIGO stage II/III 50% vs. 8.2% (P=0.002). We found paired-box gene 8 (PAX8) more frequently expressed in expansile tumours (75% vs. 37.5%, P=0.099). Adjuvant treatment was administered in 50% of patients with infiltrative disease, compared to only 13% of those with expansile disease (P=0.036). 80% of patients who have relapsed had received adjuvant chemotherapy, compared to 17.2% of patients without relapse (P=0.012). At 3 years, there was a statistically significant difference in progression-free survival (PFS) (94.7% vs. 65.6%, P=0.02) between the expansile and infiltrative groups, but no difference in overall survival (OS) (88.8% vs. 90%, P=0.875). Conclusions: Patients with infiltrative tumours were older, more likely to have bilateral tumours and more likely to have an advanced FIGO stage at diagnosis. Adjuvant treatment was more likely to be administered to patients with infiltrative tumours, however, this did not prevent relapse. PFS at 3 years was significantly higher in patients with expansile tumours. PAX8 was more frequently expressed by expansile tumours.

Neuropeptide S receptor 1 is a nonhormonal treatment target in endometriosis.

Endometriosis is a common chronic inflammatory condition causing pelvic pain and infertility in women, with limited treatment options and 50% heritability. We leveraged genetic analyses in two species with spontaneous endometriosis, humans and the rhesus macaque, to uncover treatment targets. We sequenced DNA from 32 human families contributing to a genetic linkage signal on chromosome 7p13-15 and observed significant overrepresentation of predicted deleterious low-frequency coding variants in NPSR1, the gene encoding neuropeptide S receptor 1, in cases (predominantly stage III/IV) versus controls (P = 7.8 × 10-4). Significant linkage to the region orthologous to human 7p13-15 was replicated in a pedigree of 849 rhesus macaques (P = 0.0095). Targeted association analyses in 3194 surgically confirmed, unrelated cases and 7060 controls revealed that a common insertion/deletion variant, rs142885915, was significantly associated with stage III/IV endometriosis (P = 5.2 × 10-5; odds ratio, 1.23; 95% CI, 1.09 to 1.39). Immunohistochemistry, qRT-PCR, and flow cytometry experiments demonstrated that NPSR1 was expressed in glandular epithelium from eutopic and ectopic endometrium, and on monocytes in peritoneal fluid. The NPSR1 inhibitor SHA 68R blocked NPSR1-mediated signaling, proinflammatory TNF-α release, and monocyte chemotaxis in vitro (P < 0.01), and led to a significant reduction of inflammatory cell infiltrate and abdominal pain (P < 0.05) in a mouse model of peritoneal inflammation as well as in a mouse model of endometriosis. We conclude that the NPSR1/NPS system is a genetically validated, nonhormonal target for the treatment of endometriosis with likely increased relevance to stage III/IV disease.

Protocol for a longitudinal, prospective cohort study investigating the biology of uterine fibroids and endometriosis, and patients' quality of life: the FENOX study.

INTRODUCTION: Millions of women suffer from the consequences of endometriosis and uterine fibroids, with fibroids the cause for over 50% of hysterectomies in the USA, and direct costs for their treatment estimated at between US$4 and US$9 billion. Endometriosis commonly affects millions of women worldwide predominantly during reproductive age, with severe menstrual and non-menstrual pain and subfertility the main symptoms. Due to the 'unhappy triad' of endometriosis-lack of awareness, lack of clinically relevant biomarkers and the unspecific nature of symptoms-women wait on average for 8-12 years before the definitive endometriosis diagnosis is made. Treatment options for both conditions are not satisfactory at the moment, especially with a view to preserving fertility for the women and families affected. In the Fibroids and Endometriosis Oxford (FENOX) study, we combine the investigation of fibroids and endometriosis, and plan to collect high-quality tissue samples and medical data of participants over a time frame of 5 years after surgical intervention. METHODS AND ANALYSIS: Biological samples such as blood, saliva, urine, fat, peritoneal fluid and-if found-endometrial tissue or fibroids as well as detailed clinical and intraoperative data will be collected from women undergoing surgery and participating in the study after informed consent. We plan to recruit up to 1200 participants per disease arm (ie, endometriosis and uterine fibroids) over 5 years. Participants will fill in detailed and validated questionnaires on their medical history and quality of life, with follow-ups for 5 years. Enrolment started on 2 April 2018, and FENOX will close on 31 March 2028. We will analyse the biological samples using state-of-the-art molecular biology methods and correlate the findings with the medical records and questionnaire data. ETHICS AND DISSEMINATION: The findings will be published in high-ranking journals in the field and presented at national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN13560263.

Author Correction: Amine oxidase 3 is a novel pro-inflammatory marker of oxidative stress in peritoneal endometriosis lesions.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Characterization of exosomes in peritoneal fluid of endometriosis patients.

OBJECTIVE: To demonstrate the feasibility of studying exosomes directly from peritoneal fluid, we isolated exosomes from endometriosis patient samples and from controls, and characterized their cargo. DESIGN: Case-control experimental study. SETTING: Academic clinical center. PATIENT (S): Women with and without endometriosis who underwent laparoscopic surgery (n = 28 in total). INTERVENTION (S): None. MAIN OUTCOME MEASURE (S): Concentration of exosomes within peritoneal fluid and protein content of the isolated exosomes. RESULT (S): Peritoneal fluid samples were pooled according to the cycle phase and disease stage to form six experimental groups, from which the exosomes were isolated. Exosomes were successfully isolated from peritoneal fluid in all the study groups. The concentration varied with cycle phase and disease stage. Proteomic analysis showed specific proteins in the exosomes derived from endometriosis patients that were absent in the controls. Five proteins were found exclusively in the endometriosis groups: PRDX1, H2A type 2-C, ANXA2, ITIH4, and the tubulin α-chain. CONCLUSION (S): Exosomes are present in peritoneal fluid. The characterization of endometriosis-specific exosomes opens up new avenues for the diagnosis and investigation of endometriosis.

Amine oxidase 3 is a novel pro-inflammatory marker of oxidative stress in peritoneal endometriosis lesions.

Endometriosis is a common gynaecological disease of women in reproductive age, and is thought to arise from retrograde menstruation and implantation of endometrial tissue, mostly into the peritoneal cavity. The condition is characterized by a chronic, unresolved inflammatory process thereby contributing to pain as cardinal symptom in endometriosis. Elevated reactive oxygen species (ROS) and oxidative stress have been postulated as factors in endometriosis pathogenesis. We here set out for a systematic study to identify novel mechanisms and pathways relating to oxidative stress in ectopic peritoneal lesions. Using combined proteomic and transcriptomic approaches, we identified novel targets including upregulated pro-oxidative enzymes, such as amine oxidase 3/vascular adhesion protein 1 (AOC3/VAP1) as well as downregulated protective factors, in particular alkenal reductase PTGR1 and methionine sulfoxide reductase. Consistent with an altered ROS landscape, we observed hemoglobin / iron overload, ROS production and lipid peroxidation in ectopic lesions. ROS-derived 4-hydroxy-2-nonenal induced interleukin IL-8 release from monocytes. Notably, AOC3 inhibitors provoked analgesic effects in inflammatory pain models in vivo, suggesting potential translational applicability.

Mass cytometry analysis reveals a distinct immune environment in peritoneal fluid in endometriosis: a characterisation study.

BACKGROUND: Endometriosis is a gynaecological condition characterised by immune cell infiltration and distinct inflammatory signatures found in the peritoneal cavity. In this study, we aim to characterise the immune microenvironment in samples isolated from the peritoneal cavity in patients with endometriosis. METHODS: We applied mass cytometry (CyTOF), a recently developed multiparameter single-cell technique, in order to characterise and quantify the immune cells found in peritoneal fluid and peripheral blood from endometriosis and control patients. RESULTS: Our results demonstrate the presence of more than 40 different distinct immune cell types within the peritoneal cavity. This suggests that there is a complex and highly heterogeneous inflammatory microenvironment underpinning the pathology of endometriosis. Stratification by clinical disease stages reveals a dynamic spectrum of cell signatures suggesting that adaptations in the inflammatory system occur due to the severity of the disease. Notably, among the inflammatory microenvironment in peritoneal fluid (PF), the presence of CD69+ T cell subsets is increased in endometriosis when compared to control patient samples. On these CD69+ cells, the expression of markers associated with T cell function are reduced in PF samples compared to blood. Comparisons between CD69+ and CD69- populations reveal distinct phenotypes across peritoneal T cell lineages. Taken together, our results suggest that both the innate and the adaptive immune system play roles in endometriosis. CONCLUSIONS: This study provides a systematic characterisation of the specific immune environment in the peritoneal cavity and identifies cell immune signatures associated with endometriosis. Overall, our results provide novel insights into the specific cell phenotypes governing inflammation in patients with endometriosis. This prospective study offers a useful resource for understanding disease pathology and opportunities for identifying therapeutic targets.

Diaphragmatic peritonectomy vs. full thickness resection with pleurectomy during Visceral-Peritoneal Debulking (VPD) in 100 consecutive patients with stage IIIC-IV ovarian cancer: A surgical-histological analysis.

OBJECTIVE: To compare the surgical and histological outcomes of diaphragmatic peritonectomy vs. full thickness resection with pleurectomy during Visceral-Peritoneal Debulking. METHODS: Service evaluation protocol (Trust number 3265). All patients with stage IIIC-IV ovarian cancer who had diaphragmatic surgery between April 2009 and November 2013 were included. Clinical notes and histology reports were reviewed. Additional histology sections were undertaken. Patients were divided in Groups 1 (peritonectomy) and 2 (pleurectomy). The outcomes of interest were: surgical (intra- and post-operative morbidity, pulmonary morbidity, mortality, rate of complete resection) and histological (rate of diaphragmatic peritoneum, muscle and pleural involvement, rate of microscopic diaphragmatic free margins). RESULTS: Sixty four patients had diaphragmatic peritonectomy (Group 1), 36 patients full thickness diaphragmatic resection with pleurectomy (Group 2). There was no significant difference in the rate of mortality (3% in both groups), overall intra- and post-operative morbidity (32.8% vs. 38.8%), pulmonary morbidity (9.3% vs. 19%, P=0.14). Histology showed tumor invasion in the diaphragmatic peritoneum (96%), muscle (28%) and pleura (19.4%). Microscopic free margins were seen in 86% vs. 92% in Groups 1 and 2. CONCLUSIONS: Our study demonstrated that, in patients with ovarian cancer, diaphragmatic involvement extends to the muscle in almost 30% and to the pleura in 20% of the patients. Overall and specific morbidity was not significantly different when comparing peritonectomy vs. pleurectomy.

Differentiating pelvic actinomycosis from advanced ovarian cancer: a report of two cases, management reflections and literature review.

Pelvic actinomycosis comprises a rare, subacute to chronic bacterial infection characterised by suppurative and granulomatous inflammation. Diagnosis is difficult as it may simulate pelvic malignancies. Laboratory and radiological findings are non-specific. We reported on 2 cases of pelvic actinomycosis mimicking ovarian malignancy with different management approaches that lead to opposite outcomes. We reviewed the literature on pelvic actinomycosis imitating ovarian cancer with a focus on its surgical management. Despite agreement on the duration of antibiotic therapy following surgical management, consensus regarding surgical approach was rather equivocal. We concluded that pelvic actinomycosis should be strongly suspected in women with presumed ovarian cancer of atypical presentation and a history of intrauterine devices (IUD).

Focal adhesion kinase (FAK) expression in normal and neoplastic lymphoid tissues.

Focal adhesion kinase (FAK) is a protein tyrosine kinase essential for intracellular regulatory events, such as cell growth, differentiation, migration and tumor metastasis. The aim of this study was to analyze the expression of FAK protein in a series of normal and neoplastic lymphoid tissues. An anti-FAK antibody was used to study the protein expression in paraffin-embedded samples of normal and neoplastic, hematolymphoid and non-hematolymphoid tissues by immunohistochemistry. In normal hematolymphoid tissue, the strongest expression of FAK was detected in germinal center and marginal-zone B cells; positive staining was also found in mantle zone B cells. In human lymphomas, FAK was expressed mostly in B-cell lymphomas and was predominantly negative in T-cell lymphoma. In Hodgkin lymphomas, FAK was found only in the neoplastic cells of lymphocyte predominant type, whereas the tumor cells of the classical form were FAK-negative. We demonstrate for the first time the expression of FAK in paraffin-embedded hematolymphoid tissue samples. Its differential expression in lymphomas may be of relevance for some B-cell neoplasms by using it as an additional marker to distinguish B- from T-lymphoblastic leukemia/lymphoma to further differentiate lymphocyte predominant from classical Hodgkin lymphoma.

Expression of terminally glycosylated calcitonin receptor-like receptor in uterine leiomyoma: endothelial phenotype and association with microvascular density.

PURPOSE: The role for the hypoxia-inducible angiogenic factor adrenomedullin (AM) in tumor growth and progression has been suggested. Calcitonin receptor-like receptor (CL) is a G protein-coupled receptor (GPCR) that mediates effects of AM, but little information is available on its expression and functional state in human tumors. The present study attempted to determine CL potential for antiangiogenic therapy of uterine leiomyoma. EXPERIMENTAL DESIGN AND RESULTS: GPCR CL is transported to the cell surface and recognized by AM only when terminally/mature glycosylated. The presence and localization of this form of the receptor in tumor and surrounding myometrial tissues obtained from leiomyoma-bearing uteri were examined using deglycosylation, immunoblotting, and immunofluorescence analysis. The mature CL glycoprotein was expressed in both tissues and localized exclusively in normal and tumor endothelium within leiomyoma-bearing uteri. The functionality of the receptor expressed in myometrial microvascular endothelial cells (MMVEC) was examined in vitro using receptor internalization and angiogenic assays. The mature CL glycoprotein expressed by primary MMVECs was functional because AM interacted with this GPCR and induced its internalization as well as angiogenic effects (proliferation and migration) in MMVECs in vitro. Finally, the levels of tissue-expressed mature CL glycoprotein as a functional form of this GPCR were analyzed by immunoblotting. The expression of this functional form of the receptor in vivo was significantly decreased (P = 0.01) in leiomyoma tissue, and this was concurrent with the decrease in microvascular density (measured by Chalkley counting) in tumor compared with surrounding myometrium (P = 0.031). CONCLUSIONS: Our findings suggest that GPCR CL mediates angiogenic effects of AM in myometrium and that further evaluation of the properties of the CL expressed in both normal and tumor endothelium in vivo may be essential before targeting this endothelial GPCR for antiangiogenic therapies.

Aberrant expression of apoptosis proteins and ultrastructural aberrations in uterine leiomyomas from patients with hereditary leiomyomatosis and renal cell carcinoma.

OBJECTIVE: To examine differences between sporadic and familial uterine leiomyomata related to expression of apoptosis-related proteins and tumor ultrastructure. DESIGN: Expression of apoptosis-related proteins was measured by immunohistochemistry. Tumor ultrastructure was evaluated by transmission electron microscopy. SETTING: Human genetics laboratory. PATIENT(S): Patients confirmed for hereditary leiomyomatosis and renal cell carcinoma (HLRCC), and anonymous archival sporadic leiomyoma patients. INTERVENTION(S): Samples for electron microscopy were collected from myomectomy and hysterectomy with informed consent. Other samples were archival. MAIN OUTCOME MEASURE(S): Intensity of immunohistochemistry staining and evaluation of electron micrographs. RESULT(S): Immunohistochemistry revealed increases in expression of antiapoptotic Bcl-2 and the proliferation factor proliferating cell nuclear antigen (PCNA) in both sporadic and HLRCC uterine leiomyomata. Furthermore, we observed an increase in antiapoptotic Bcl-x and a concurrent decrease in proapoptotic Bak solely in HLRCC leiomyomas. We also observed ultrastructural alterations in HLRCC and sporadic leiomyomas, particularly pertaining to extracellular matrix and intermediate filament aggregation. CONCLUSION(S): The observed alterations in expression of apoptosis-related proteins indicate a shift in both HLRCC and sporadic leiomyomas to increased resistance to apoptosis compared with myometrium, which appears to be stronger in HLRCC leiomyomas. The changes observed in HLRCC leiomyomas appear to be related to activation of the hypoxia pathways. The results suggest not only a partial overlap in the pathogenic mechanism of the two tumor types, but also intriguing differences.

Mitotic count is not predictive of clinical behavior in hidradenoma papilliferum of the vulva: a clinicopathologic study of 19 cases.

Although it is generally recognized that some benign sweat gland neoplasms may show appreciable mitotic activity, there are few reports of its quantitative analysis in specific tumor types or of its correlation with clinical behavior. The presence of a large number of mitoses in a sweat gland tumor for which the histologic criteria of malignancy are not well defined, particularly in association with nuclear abnormalities, may produce a considerable diagnostic challenge. We recently encountered such a problem in a putative case of hidradenoma papilliferum. Therefore, we have undertaken a retrospective clinicopathologic study of 19 cases originally diagnosed as hidradenoma papilliferum or probable hidradenoma papilliferum, with a particular emphasis on the relationship of the mitotic index to clinical behavior. The age range of the cases was 41 to 92 years (mean 56.8 years). In all cases in which the margins could be evaluated, the tumors were well circumscribed (15/15), but in 4 cases circumscription could not be assessed because the specimen was fragmented. All showed focal mild nuclear pleomorphism. Mitoses were present in both epithelial and myoepithelial cells. The mitotic index varied from 0 to 5.3 mitoses/mm2 (0 to 13 mitoses per 10 high power fields (hpf); 1 hpf=0.246 mm2), with a mean of 2.4/mm2 (6/10 hpf) and a median of 0.8/mm2 (2/10 hpf). No atypical mitoses were identified. The proliferative fraction (MIB-1 index) correlated with the mitotic index (correlation coefficient 0.94; P<0.0001) and varied from 1% to 10.5% (mean 3.9%, median 3.0%). There were no recurrences or metastases over a mean period of 8 years. Consequently, we have shown that the mitotic index in these lesions can be variable and often high, but it does not predict a more aggressive outcome.

Molecular genetic evidence that endometriosis is a precursor of ovarian cancer.

Histopathology and epidemiology studies have consistently demonstrated a strong link between endometriosis and endometriosis-associated ovarian cancers (EAOCs)--in particular, the endometrioid and clear cell subtypes. However, it is still unclear whether endometriosis is a precursor to EAOCs, or whether there is an indirect link because similar factors predispose to both diseases. In order to search for evidence of clonal progression, we analyzed 10 EAOCs (endometrioid=4; clear cell=6) with coexisting endometriosis for common molecular genetic alterations in both the carcinoma and corresponding endometriosis. We used 82 microsatellite markers spanning the genome to examine loss of heterozygosity (LOH) in the coexisting carcinoma and endometriosis samples. A total of 63 LOH events were detected in the carcinoma samples; twenty two of these were also detected in the corresponding endometriosis samples. In each case, the same allele was lost in the endometriosis and cancer samples. Interestingly, no marker showed LOH in the endometriosis alone. These data provide evidence that endometriosis is a precursor to EAOCs.

Allelic loss studies do not provide evidence for the "endometriosis-as-tumor" theory.

OBJECTIVE: To identify consistent genetic changes in endometriosis samples to determine whether endometriosis lesions are true neoplasms. DESIGN: We analyzed ovarian endometriosis lesions for loss of heterozygosity (LOH) at 12 loci of potential importance (D9S1870, D9S265, D9S270, D9S161, D11S29, D1S199, D8S261, APOA2, PTCH, TP53, D10S541, and D10S1765), including some at which genetic changes were previously reported in endometriosis. SETTING: Molecular biology laboratory in a university hospital department. PATIENT(S): Seventeen women with ovarian endometriosis. INTERVENTION(S): Laser capture microdissection to separate the endometriotic epithelium, the adjacent endometriotic stroma, and surrounding normal ovarian stromal tissue, followed by DNA extraction and polymerase chain reaction amplification of polymorphic microsatellite markers. MAIN OUTCOME MEASURE(S): Fluorescence-based quantitation for the LOH analysis. RESULT(S): We identified LOH in only one lesion at one locus (D8S261). CONCLUSION(S): Our data do not support the hypothesis that ovarian endometriosis is a true neoplasm.

Clinical features of multiple cutaneous and uterine leiomyomatosis: an underdiagnosed tumor syndrome.

OBJECTIVE: To investigate the clinical features of the multiple cutaneous and uterine leiomyomatosis (MCUL) syndrome, including the hereditary leiomyomatosis and renal cell cancer syndrome. DESIGN: A case series of patients with multiple skin leiomyomas solicited via a circular letter to dermatologists. SETTING: Research institute. PATIENTS: A total of 108 affected individuals, including 46 probands and 62 affected relatives. MAIN OUTCOME MEASURES: The proportion of probands with underlying fumarate hydratase (FH) mutations, the penetrance of FH mutations, and clinicopathologic features of MCUL. RESULTS: Forty-one (89%) of 46 probands with multiple skin leiomyomas had evidence of germline FH mutations, which were highly penetrant. All 26 male mutation carriers had skin leiomyomas. Of 67 women with FH mutations, 46 (69%) had both skin and uterine leiomyomas; 10 (15%) had only skin leiomyomas; 5 (7%) had only uterine leiomyomas; and 6 (9%) were clinically unaffected. Patients presented with skin leiomyomas at a mean age of 24 years and had a mean of 25 lesions. Forty-one individuals (89%) reported painful lesions, particularly in response to cold or trauma. Fibroids were histologically unremarkable, highly symptomatic, and associated with a high risk of early hysterectomy. One individual had a very aggressive collecting duct renal cancer. The G354R FH mutation predisposed patients to uterine fibroids without skin leiomyomas (P = .03). Many patients with skin leiomyomas had not previously presented for medical attention. Fibroids were rarely recognized as cases of MCUL. CONCLUSIONS: Highly penetrant FH mutations underlie MCUL. Increased clinical awareness is important because of the associated risk of severe uterine fibroids and, in some cases, aggressive renal cancer.

Evidence of increased microvessel density and activation of the hypoxia pathway in tumours from the hereditary leiomyomatosis and renal cell cancer syndrome.

The Mendelian tumour syndromes hereditary leiomyomatosis and renal cell cancer (HLRCC) and hereditary paragangliomatosis with phaeochromocytomas (HPGL) result from mutations in nuclear genes (FH and SDHB/C/D, respectively) that encode Krebs cycle enzymes. HPGL tumours are highly vascular and there is evidence that inactivation of SDH leads to activation of the hypoxia/angiogenesis pathway. In contrast, uterine leiomyomas are not generally regarded as particularly vascular lesions. In order to test the possibility that activation of the hypoxia/angiogenesis pathway contributes to tumourigenesis in HLRCC, increased vascularity and hypoxia pathway activation were searched for in HLRCC tumours. Microvessel density was markedly higher in uterine leiomyomas from HLRCC than in the surrounding myometrium; it was notable that sporadic uterine leiomyomas were actually less vascular than normal myometrium. In HLRCC tumours, there was increased expression of transcripts from the hypoxia-responsive genes vascular endothelial growth factor (VEGF) and BNIP3; sporadic uterine leiomyomas did not show these changes. All uterine leiomyomas showed decreased expression of thrombospondin 1. Although sporadic and HLRCC uterine leiomyomas appear to have identical morphology, their pathways of tumourigenesis may be fundamentally different. As is the case in HPGL, it is probable that failure of the Krebs cycle in HLRCC tumours causes inappropriate signalling that the cell is in a hypoxic state, leading to angiogenesis and perhaps directly to clonal expansion and tumour growth through some uncharacterized, cell-autonomous effect.

Heparin-binding epidermal growth factor and its receptors mediate decidualization and potentiate survival of human endometrial stromal cells.

Heparin-binding epidermal growth factor (HB-EGF) has pleiotropic biological functions in many tissues, including those of the female reproductive tract. It facilitates embryo development and mediates implantation and is thought to have a function in endometrial receptivity and maturation. The mature HB-EGF molecule manifests its activity as either a soluble factor (sol-HB-EGF) or a transmembrane precursor (tm-HB-EGF) and can bind two receptors, EGFR and ErbB4/HER4. In this study, we identify factors that modulate expression of HB-EGF, EGFR, and ErbB4 in endometrial stromal cells in vitro. We demonstrate that levels of sol- and tm-HB-EGF, EGFR, and ErbB4 are increased by cAMP, a potent inducer of decidualization of the endometrial stroma. We also show that production of sol- and tm-HB-EGF is differentially modulated by TNF alpha and TGF beta. Our data suggest that HB-EGF has a function in endometrial maturation in mediating decidualization and attenuating TNF alpha- and TGF beta-induced apoptosis of endometrial stromal cells.