Increased expression of galectin-1 in carcinoma-associated stroma predicts poor outcome in prostate carcinoma patients.

Galectin-1, a member of the beta-galactoside-binding galectin family, is a pleiotropic dimeric protein participating in a variety of normal and pathological processes, including cancer progression. Modulation of the interactions with the basement membrane glycoprotein laminin and induction of apoptosis in activated T lymphocytes are well-known functions of this galectin. In this study, the expression of galectin-1 was examined in 148 human primary prostate carcinoma samples. Immunohistochemical staining of paraffin sections of prostate tissues revealed that galectin-1 was not detected in normal, PIN (prostatic intraepithelial neoplasia) or carcinoma cells, but accumulated in the stroma and associated fibroblasts. Galectin-1 expression was significantly increased in the tumour-associated stroma compared with the non-neoplastic gland-associated stroma in 21.3% of the cases (Mantel-Haenszel test, p=0.001; Wilcoxon signed rank test, p<0.0001). Increased galectin-1 expression in the cancer-associated stroma compared to the normal gland-associated stroma (p=0.03) was identified by multivariate analysis as a strong independent predictor of prostate-specific antigen (PSA) recurrence, just after the pathological stage (p<0.0001). The association between accumulation of galectin-1 in the stroma of the malignant tissue and aggressiveness of the tumour adds weight to the body of evidence that identifies a role for galectin-1 in the acquisition of the invasive phenotype. In addition to modulating cancer cell interactions with laminin, galectin-1 accumulated around the cancer cells may act as an immunological shield by inducing activated T-cell apoptosis. This exciting hypothesis warrants further investigation.

Alteration of the cytoplasmic/nuclear expression pattern of galectin-3 correlates with prostate carcinoma progression.

Galectin-3, a member of the beta-galactoside-binding lectin family, is involved in a variety of biological events including interactions with galactose-containing glycoconjugates, cell proliferation, differentiation and apoptosis. Galectin-3 appears to intervene during tumor progression and altered expression patterns have been reported in a variety of malignancies. In our study, we have examined the expression of galectin-3 in a population of 145 prostate carcinoma samples using immunohistochemistry. We found that most of the non-tumoral prostatic glands exhibited moderate immunostaining for galectin-3 localized in both nucleus and cytoplasm. In prostatic cancer cells, galectin-3 was usually not expressed or decreased compared with the normal glands. Interestingly, when galectin-3 was detected in the cancer cells, it was consistently excluded from the nucleus and only present in the cytoplasmic compartment. The latter observation was also made for prostatic intraepithelial neoplasia (PIN) cells. Furthermore, we found that the levels of galectin-3 expression in the cancer cells were significantly associated with prostate-specific antigen (PSA) relapse in univariate analysis (p = 0.044). Cytoplasmic expression of galectin-3 in the carcinoma cells was an independent predictor of disease progression in multivariate analysis, after the pathological stage and the Gleason score. Our data demonstrate that galectin-3 is generally down-regulated in human prostate carcinoma cells, and consistently excluded from the nucleus. Interestingly, specific cytoplasmic expression of galectin-3 in a subset of lesions is associated with disease progression. These results suggest that galectin-3 might play anti-tumor activities when present in the nucleus, whereas it could favor tumor progression when expressed in the cytoplasm. Further studies should determine the exact role and mechanisms by which galectin-3 differentially affects cell behavior in the different locations where it is expressed.

Combined interferon-gamma and tumor necrosis factor-alpha treatment differentially affects adhesion and migration of keratinocyte-derived cells to laminin-1.

Interactions with the extracellular matrix constitute basic steps in cervix carcinoma cell invasion. In this study, we examined the adhesion and migration profiles of two human papillomavirus (HPV) DNA-transfected keratinocyte-derived cell lines, EIL8 and 18-11S3, and of the cervix adenocarcinoma SiHa cell line, towards laminin-1, and the selective effect of a 24-72 h treatment of 1000 U/ml interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha), a treatment that significantly decreases cervix carcinoma cell proliferation and progression in nude mice, on these parameters. Compared to normal cervix keratinocytes (CK) and two HPV DNA-transfected keratinocyte cell lines, in basal conditions, the SiHa cell line was characterized by increased attachment (SiHa, 48.74 +/- 4.02 vs. normal keratinocytes, 4.32 +/- 0.40, EIL8, 17.80 +/- 3.03 and 18-11S3, 17.82 +/- 1.48% of attached cells after 30 min) and marked directed chemotactic migration towards laminin-1. Interestingly, treatment of the cells with the cytokines (1000 U/ml IFN-gamma and TNF-alpha) did not modulate the adhesion properties of the cells, but chemotactic migration of SiHa cells to laminin-1 was significantly decreased, while migration towards type I collagen was increased. Similar results were obtained with the Ca Ski cervix carcinoma cell line. Our results emphasize the altered pattern of interactions of cervix carcinoma cells with extracellular matrix components such as laminin-1, compared to normal and pre-neoplastic cells, and contributes to the understanding of the effects of cytokine treatment on cervix carcinoma cells.

[Comparison of contrast hysterosonography and transvaginal ultrasonography for uterus imaging]. / Comparaison de l'hystérosonographie de contraste et de l'échographie vaginale en imagerie utérine.

AIM OF THE STUDY: To evaluate the efficacy of transvaginal sonography and saline infusion hysterosonography, as imaging tools, for the diagnosis of uterine abnormalities. METHODS: Two hundred seventy five patients were examined using transvaginal sonography (TVS) and saline infusion sonography (SIS), and the results were compared. RESULTS: Saline infusion sonography was performed in 88.4% of the cases. The most frequent cause of SIS failure was the presence of a stenotic cervix. In case of normal TVS, SIS allowed to visualize a polypoid lesion that was not demonstrated by TVS in 20.4% of the cases (n = 29/142). Saline infusion sonography confirmed the diagnosis of focal lesion suspected after TVS in all cases (n = 36). Finally, the localization of intramyometrial or submucous myomas was improved by SIS: myomas diagnosed by TVS as intramyometrial were demonstrated by SIS to be submucous in 41% of the cases (n = 23/56). CONCLUSIONS: Our results confirm that saline infusion sonography is a useful complementary tool for transvaginal sonography in the diagnosis of focal endometrial lesions and for the localization of fibromyomas.

Decreased expression of galectin-3 in basal cell carcinoma of the skin.

Galectins are beta-galactoside-binding lectins that play multiple roles during tumor progression. Previous work conducted in our laboratory has demonstrated decreased galectin-3 expression in carcinomas from colon, breast, ovary and endometrium, compared to the corresponding normal tissues. In this study, we examined the pattern of galectin-3 expression by immunohistochemistry in a group of 10 basal cell carcinomas of the skin. In the surrounding normal skin, galectin-3 immunostaining was found predominantly in the middle epidermis (spine layer) and eccrine sweat glands. Compared to the normal epidermal cells, basal carcinoma cells observed in all 10 samples examined presented with significantly decreased galectin-3 immunostaining. These data further demonstrates that galectin-3 is down-regulated in a variety of human cancers, including basal cell carcinoma.

[Raloxifene: a selective modulator of estrogen receptors]. / Le raloxifène: un modulateur sélectif du récepteur aux oestrogènes.

It has been demonstrated that postmenopausal hypoestrogenia induces numerous complications including osteoporosis and increased risk of cardiovascular disease. Oral or transdermal administration of estrogens can reduce these risks, but induces adverse effects. Recently, raloxifene, a new molecule from the benzothiophene family, has been demonstrated to prevent postmenopausal bone loss. It does not induce endometrial stimulation, and recent studies show that it could reduce breast cancer incidence. Its mode of action, consisting of mixed agonist and antagonistic estrogenic actions on different organs and systems, allows to classify it into the selective estrogen receptor modulator (SERM) family. In this review article, we will describe the characteristics of the molecule, its mode of action and the potential indications of its clinical use.

Transglutaminase-mediated oligomerization of galectin-3 modulates human melanoma cell interactions with laminin.

Tumor cell adhesion and migration to laminin are important events during invasion and metastatic spread. Galectin-3, a multifunctional member of the galectin family, binds specifically the poly-N-acetyllactosamine residues of laminin and has been implicated in tumor invasion and metastasis. Galectin-3 is multimerized by transglutaminase, an enzyme that catalyzes cross-linking between glutamine and other aminoacid residues. In this study, we examined the consequences of transglutaminase-mediated galectin-3 oligomerization on the interactions between cancer cells and laminin. We first demonstrated that human galectin-3 is cross-linked by guinea pig liver transglutaminase, forms oligomers, and incorporates the marker 5-(biotinamido) pentylamine. Expression of transglutaminase activity in the A375 and A2058 human melanoma cell extracts was revealed by its ability to induce galectin-3 oligomerization and 5-(biotinamido) pentylamine incorporation. Transglutaminase-treated galectin-3 did not affect adhesion or migration of the melanoma cells to laminin but consistently induced a significant increase of the percentage of cell spreading compared to the control (23.5 +/- 2.3%, vs. 10.6 +/- 1.9% at 180 min, p < 0.05), or to untreated galectin-3 or transglutaminase alone. Our study is the first demonstration that human galectin-3 is oligomerized by transglutaminase with, as a consequence, a specific effect of melanoma cell spreading on laminin. This phenomenon could be of significance in the modulation of cancer cell interactions with laminin during tumor invasion and metastasis.

[Contrast hysterosonography: an efficient means of investigation in gynecology. Review of the literature]. / L'hystérosonographie de contraste: un moyen d'investigation contributif en gynécologie. Revue de la littérature.

Contrast-enhanced vaginosonography constitutes a new way of imaging the uterine cavity. Real time transcervical injection of sterile saline in the uterine cavity (saline infusion sonography, SIS) allows to precisely visualize numerous intrauterine pathologies such as endometrial polyps, myomas, intrauterine adhesions and various anatomical malformations. We introduced the technique of saline infusion sonography in October 1996 for the evaluation of endouterine pathologies. In this review article, we will describe the technique of contrast sonography, its indications, contraindications and semiology, the practical problems to be solved and its performances.

[Contrast hysterosonography: indications and technic]. / L'hystérosonographie de contraste: indications et technique.

Contrast-enhanced sonography constitutes a new way of visualizing the uterine cavity. Indeed, real-time transcervical instillation of sterile saline inside the uterine cavity during transvaginal sonography (saline infusion sonography, SIS) allows a precise diagnosis of various intrauterine pathologies such as endometrial polyps, submucous myomas, intrauterine adhesions and various anatomical malformations. The aim of this article is to detail the technique of saline infusion sonography, its indications, contra-indications and semiology.

Differential expression of galectin-1 and galectin-3 during first trimester human embryogenesis.

Development of complex organisms requires specific temporospatial differentiation and expression of the correct phenotype through activation of a variety of genes. Galectins are mammalian lectins able to interact with various extracellular matrix glycoconjugates and have been implicated in several biological events including cell attachment, differentiation, apoptosis, embryogenesis, and cancer invasion and metastasis. In this study, we have examined the expression of galectin-1 and galectin-3 during human first trimester embryogenesis using immunohistochemistry and Western blotting. Variable amounts of galectin-1 and galectin-3 were detected in all tissue protein extracts. Galectin-1 expression was demonstrated in the connective tissue and derived tissues such as smooth and striated muscle cells, and in some epithelia, such as in the basal layers of the skin after 14 weeks and in the epithelial cells of the gonads. Galectin-3 was detected mainly in epithelia, such as the skin, epithelial lining of the digestive and respiratory tract, and urothelium and excretory tubes of the kidney, but also in the myocardial cells, in the peripheral and preossifying hypertrophic chondrocytes, and in the notochord and in the liver. Our study constitutes the first demonstration of galectin-1 and galectin-3 during human embryogenesis. The differential expression of these two lectins suggests that they could participate in the complex processes of tissue differentiation.

Changes in the distribution pattern of galectin-1 and galectin-3 in human placenta correlates with the differentiation pathways of trophoblasts.

Human placentation is a complex biological phenomenon that results from precisely regulated interactions between cells and the extracellular matrix. Galectin- 1 and galectin-3 belong to a newly defined family of galactose-binding lectins that can bind several glycoconjugates such as the basement membrane glycoprotein laminin, and are involved in many biological events including cell adhesion. In this study, the expression of these two galectins in first and third trimester normal human placenta was examined using single and double immunohistochemical staining and specific antibodies for galectins and cytokeratins. Galectin-3 was detected in all trophoblastic lineages including villous cytotrophoblasts and extravillous trophoblasts (trophoblastic cell columns, infiltrating trophoblasts, endovascular trophoblasts and placental bed giant cells). On the contrary, galectin-1 distribution was restricted to endometrium. A reduction of galectin-3 expression was observed from the villous trophoblasts to the trophoblastic cell columns. This pattern correlated with the switch from a proliferative to a migratory phenotype. Galectin-1 and galectin-3 were both detected in maternal decidual cells. Our data demonstrate a specific pattern of galectin-1 and galectin-3 expression in trophoblastic tissue, and suggest these lectins could contribute to cell-cell and cell matrix interactions of trophoblast during placentation.

Expression of the 67 KD laminin receptor in human cervical preneoplastic and neoplastic squamous epithelial lesions: an immunohistochemical study.

Interactions of cancer cells with laminin play a critical role during the progression of solid malignant tumours. Increased expression of the 67 kD laminin receptor (67LR), one of the several laminin binding proteins, is associated with the invasive and metastatic capacity of various types of cancer, including breast, colon, ovary, lung, and endometrial carcinoma. In this study, 67LR expression was analysed in a series of cervical biopsy specimens including 16 normal cervical tissues, 36 low-grade squamous intraepithelial lesions (SILs), 24 high-grade SILs, and 11 invasive carcinomas. Detection of the 67LR was performed using immunoperoxidase staining and the monoclonal antibody MLuC5 which specifically recognizes the 67LR. Immunostaining of the 67LR was correlated with human papillomavirus (HPV) type detected by in situ hybridization and with proliferative activity of the lesion determined by immunohistochemistry with the MIB-1 monoclonal antibody, specific for the Ki67 antigen. Increased expression of the 67LR was correlated with the histological severity of the lesions, with the strongest immunoreactivity being found in invasive carcinomas. Significant differences in 67LR expression were found between normal cervical epithelium and high-grade SILs (P < 0.05, non-parametric Mann-Whitney test) or invasive carcinomas (P < 0.001), as well as between low- or high-grade SILs and invasive carcinoma (P < 0.01 and P < 0.05, respectively). Ki67 antigen expression also increased with the severity of the lesions. There was a positive correlation for each type of lesion between expression of the 67LR and of the Ki67 antigen. No specific relationship was found between 67LR or Ki67 antigen immunostaining and HPV type detected in SILs, segregated into low-grade and high-grade lesions. These data add weight to the evidence that increased expression of the 67LR is a consistent, but not sufficient feature of the invasive and metastatic phenotype and suggest that high expression of the 67LR might be associated with both more proliferative and more aggressive cervical (pre)neoplastic lesions.

Expression of the 67-kD laminin receptor, galectin-1, and galectin-3 in advanced human uterine adenocarcinoma.

Alterations of tumor cell interactions with laminin, a basement membrane glycoprotein, are consistent features of the invasive and metastatic phenotype. Qualitative and quantitative changes in the expression of cell surface laminin-binding proteins have been correlated with the ability of cancer cells to cross basement membranes during the metastatic cascade. Such phenotypic modifications are usually associated with poor prognosis. In this study, the authors examined the possibility that expression of three laminin-binding proteins, the 67-kD laminin receptor (67LR), galectin-1, and galectin-3, is altered in human endometrial cancer in a fashion similar to that reported in other carcinomas, such as breast, colon, and ovarian cancer. Twenty advanced uterine adenocarcinomas were analyzed for expression of these three molecules using immunoperoxidase staining and specific antibodies. The authors found a significant increase in the expression of the 67LR and galectin-1 in cancer cells compared with normal adjacent endometrium (P = .0004 and .0022, respectively). As observed in other carcinomas, a significant down-regulation of galectin-3 expression was found in endometrial cancer cells compared with normal mucosa (P = .02). In the galectin-3 positive tumors, galectin-3 was detected in the cytoplasm and/or nucleus of cancer cells. Interestingly, tumors in which galectin-3 was detected only in the cytoplasm were characterized by deeper invasion of the myometrium than lesions where galectin-3 was found both in nucleus and cytoplasm (P = .02). This study shows an alteration of nonintegrin laminin-binding protein expression in advanced human endometrial cancer. Further studies on larger populations should determine the prognostic value of the detection of these laminin-binding proteins in endometrial carcinoma. Inverse modulation of the 67LR and galectin-3 appears to be a phenotypical feature of invasive carcinoma.

Expression of the 67 kD laminin receptor in human ovarian carcinomas as defined by a monoclonal antibody, MLuC5.

Previous immunohistochemical data from our laboratory have demonstrated that expression of the 67 kD laminin receptor (67LR), a cancer-associated, high-affinity laminin-binding protein, is upregulated in ovarian carcinoma cells compared with normal serosal cells, and that this increased expression in cancer cells could be related to patient outcome. The aim of this study was to validate MLuC5, a monoclonal antibody that recognises the 67LR, as a tool to perform future immunohistochemical studies on larger populations of ovarian carcinoma patients. Expression of the 67LR was determined in 51 primary human ovarian carcinoma samples using immunohistochemistry and MLuC5. The 67LR was detected in ovarian carcinoma cell clusters of variable extent. Analysis of the data determined that 67LR expression was significantly increased in the samples from patients with disease progression, compared with those with no evidence of disease after completion of primary therapy, and in pooled grade 2 and 3 tumours compared to borderline and grade 1 tumours (P < 0.05, chi-squared test). No other significant correlation between 67LR expression and other clinicopathological parameters could be established. These data suggest that the 67LR is correlated to ovarian tumour progression. Detection of the 67LR using this monoclonal antibody could constitute an interesting parameter in prognosis determination of ovarian cancer.

Decreased expression of galectin-3 is associated with progression of human breast cancer.

Galectin-3, a member of the beta-galactoside-binding lectin family, is involved in several biological events including binding to the basement membrane glycoprotein laminin. Although the exact role of galectin-3 during the interactions between cells and laminin is not yet known, it has recently been observed that its expression is down-regulated at both the protein and the mRNA level in colon cancer tissues in correlation with progression of the disease. This study investigated the possibility that breast cancer cells might also exhibit decreased galectin-3 expression in association with their aggressiveness. The expression of galectin-3 was examined by immunoperoxidase staining, using a polyclonal antibody raised against recombinant galectin-3, in a collection of 98 human breast lesions including 12 fibroadenomas, 15 fibrocystic disease lesions, 22 in situ carcinomas, and 49 infiltrating ductal carcinomas, 19 of which had positive axillary lymph nodes. Normal breast tissue adjacent to the lesions was present in 59 biopsies. Normal breast tissue expressed high levels (3+) of galectin-3. High expression (2+ to 3+) was also found in most benign lesions examined. The expression of galectin-3 was significantly decreased in in situ carcinoma and this down-regulation was more pronounced in invasive ductal carcinoma, particularly when associated with infiltration of axillary lymph nodes. These data constitute the first observation that galectin-3 is down-regulated in breast cancer and suggest the decreased expression of this galactoside-binding lectin is associated with the acquisition of the invasive and metastatic phenotype.

Absence of antisteroid antibodies in oral contraceptive users presenting with vascular events.

Previous reports speculated that vascular events could be related to the development of antibodies against synthetic steroids contained in oral contraceptives or other hormonal treatments. This study describes original immunoassays designed to detect antisynthetic steroid antibodies. In a first step, the assays were characterized and validated using animal-raised antisteroid antibodies. In a second step, a population of 88 oral contraceptive users, 47 of them having developed a vascular thrombosis during synthetic steroid use and 41 serving as healthy control users, were tested. Detection of antibodies against ethinylestradiol, levonorgestrel, norethisterone, cyproterone acetate, and gestodene showed that the values obtained in normal oral contraceptive users as well as thrombosis patients are very low, and show no statistically significant difference between the two groups tested. Taken together, these data indicate that the "immunological hypothesis" related to antisteroid antibodies is unlikely to explain the pathogenesis of vascular events in oral contraceptive users.

Postmenopausal changes of lipid and glucose metabolism: a review of their main aspects.

In postmenopausal women, partly in relation to advancing age and partly due to oestrogen deficiency, there is a frequent increase in body weight, and more specifically, in android fat distribution. In addition, loss of ovarian function is associated with the development of a more atherogenic profile with increased triglycerides, LDL-cholesterol and its smaller dense subfractions, decreased HDL- and HDL2-cholesterol and, potentially, an irregular increase in Lp(a). Not only does oestrogen therapy counteract all these changes towards a definitely less atherogenic profile but oestrogens seem also implicated in reducing LDL oxidative products, in favouring a higher ratio of prostacyclin to thromboxane and, potentially, of endothelium derived relaxing factor to endothelin, and also in acting as a calcium antagonist in the vessel wall. All of these favourable vascular effects are not solely attributable to lipid-related oestrogen effects. Excess weight and central obesity, diet changes and lack of exercise, more frequent with advancing age, all concur to alter glucose tolerance and increase insulin resistance during the postmenopause. Impaired glucose tolerance and diabetes mellitus may be found in nearly 20% of women aged 55 to 65 years. In addition, oestrogen deficiency may be further responsible for decreased pancreatic insulin secretion and alteration of its metabolic clearance rate-changes that can be reversed toward improved insulin secretion and sensitivity by oestrogen treatment in small dosages. By contrast, synthetic androgenic progestins can counteract these effects of oestrogens more than progesterone derivatives do, and they may partly help to promote insulin resistance and hyperinsulinism.(ABSTRACT TRUNCATED AT 250 WORDS)

Galectin-1 modulates human melanoma cell adhesion to laminin.

Galectins constitute a gene family of beta-galactoside-specific lectins that show high homology in their carbohydrate-binding site. They have been postulated to be involved in many biological events, but their specific functions are not yet well defined. Galectin-1 is a laminin binding protein that recognizes poly-N-acetyllactosamine chains on this major basement membrane glycoprotein. In this study, we analyzed the possibility that galectin-1 could modulate interactions between human melanoma cells and laminin. We demonstrated that A375 and A2058 cell lines express galectin-1 both intracellularly and on the cell surface. In an in vitro assay, recombinant galectin-1 increased melanoma cell attachment to laminin in a dose-dependent manner. This effect was abolished by lactose. Anti-galectin-1 inhibited adhesion of melanoma cells to laminin in a dose-dependent fashion. However, neither galectin-1 nor anti-galectin-1 antibody affected melanoma cell spreading on laminin in vitro. These data indicate that galectin-1 might participate in melanoma cell adhesion to laminin and therefore could be a modulator of invasion and metastasis.

Galectin-3, a laminin binding protein, fails to modulate adhesion of human melanoma cells to laminin.

Galectin-3 is a laminin binding protein which expression is altered in a variety of human carcinomas including colon, breast and endometrium. In these tumors, we consistently observed a down regulation of galectin-3 expression related to increased aggressiveness. Galectin-3 belongs to a family of galactose-binding lectins and binds laminin through its numerous poly-N-acetyllactosamine chains. To date, the exact role of galectin-3 in the complex interactions between cancer cells and laminin has not been clearly defined. Adhesion of melanoma cells to laminin is a critical event during tumor invasion and metastasis. In this study, we explore the possibility that galectin-3 could modulate attachment of two human melanoma cell lines to laminin. A2058 and A375 melanoma cell expressed galectin-3 on their surface as demonstrated by immunofluorescence, and attached to laminin in an in vitro assay. We demonstrate that neither recombinant galectin-3 nor an affinity purified antigalectin-3 antiserum altered adhesion of A2058 or A375 melanoma cells to laminin. Our data strongly suggest that galectin-3 is not a key element in adhesion of the melanoma cells to laminin. These results are not surprising in light of the observation that galectin-3 expression is down regulated in cancer and that increased adhesion to laminin is a constant feature of invasive cancer cells.

[Epithelial cancers of the ovary. Recent trends]. / Cancers épithéliaux de l'ovaire. Acquisitions récentes.

Ovarian carcinomas constitute the major cause of the mortality and morbidity in gynaecology. Most ovary carcinomas are epithelial tumours. Our understanding of ovarian cancerogenesis has been hampered by the lack of a well defined precursor lesion, the lack of knowledge about tumour progression, and by the relative inaccessibility of the ovaries in the abdominal cavity. Recent studies using experimental models allow us to better define the fundamental mechanisms of carcinogenesis from the serous ovarian cells and of invasion of the abdominopelvic cavity by proximity. This review article tries to update on epidemiology, genetic syndromes, biology, screening, and therapy of these epithelial tumours, and about the new directions taken by basic and clinical research. We will present data concerning oncogenes and tumour suppressor genes involved in epithelial ovarian tumours, regulation of tumour cells by growth factors, genes involved in tumour invasion, and mechanisms used by the cancer cell to resist to therapies. Non-epithelial ovarian tumours will not be examined in this manuscript.