The epithelial ovarian carcinomas, which make up more than 85% of human ovarian cancer, arise in the ovarian surface epithelium (OSE). The etiology and early events in the progression of these carcinomas are among the least understood of all major human malignancies because there are no appropriate animal models, and because methods to culture OSE have become available only recently. The objective of this article is to review the cellular and molecular mechanisms that underlie the control of normal and neoplastic OSE cell growth, differentiation, and expression of indicators of neoplastic progression. We begin with a brief discussion of the development of OSE, from embryonic to the adult. The pathological and genetic changes of OSE during neoplastic progression are next summarized. The histological characteristics of OSE cells in culture are also described. Finally, the potential involvement of hormones, growth factors, and cytokines is discussed in terms of their contribution to our understanding of the physiology of normal OSE and ovarian cancer development.

/pdf/ovarian-surface-epithelium-biology-endocrinology-and-1ln38b94gz.pdf

Ovarian surface epithelium: biology, endocrinology, and pathology.

Relaxin has vital physiological roles in pregnant rats, mice, and pigs. Relaxin promotes growth and softening of the cervix, thus facilitating rapid delivery of live young. Relaxin also promotes development of the mammary apparatus, thus enabling normal lactational performance. The actions of relaxin on the mammary apparatus vary among species. Whereas relaxin is required for development of the mammary nipples in rats and mice, it is essential for prepartum development of glandular parenchyma in pregnant pigs. During pregnancy relaxin also inhibits uterine contractility and promotes the osmoregulatory changes of pregnancy in rats. Recent studies with male and nonpregnant female rodents revealed diverse therapeutic actions of relaxin on nonreproductive tissues that have clinical implications. Relaxin has been reported to reduce fibrosis in the kidney, heart, lung, and liver and to promote wound healing. Also, probably through its vasodilatory actions, relaxin protects the heart from ischemia-induced injury. Finally, relaxin counteracts allergic reactions. Knowledge of the diverse physiological and therapeutic actions of relaxin, coupled with the recent identification of relaxin receptors, opens numerous avenues of investigation that will likely sustain a high level of research interest in relaxin for the foreseeable future.

Relaxin's physiological roles and other diverse actions.

BACKGROUND—Following liver injury, hepatic stellate cells (HSC) transform into myofibroblast-like cells (activation) and are the major source of type I collagen and the potent collagenase inhibitors tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1 and TIMP-2) in the fibrotic liver. The reproductive hormone relaxin has been reported to reduce collagen and TIMP-1 expression by dermal and lung fibroblasts and thus has potential antifibrotic activity in liver fibrosis.
AIMS—To determine the effects of relaxin on activated HSC.
METHODS—Following isolation, HSC were activated by culture on plastic and exposed to relaxin (1-100 ng/ml). Collagen deposition was determined by Sirius red dye binding and radiolabelled proline incorporation. Matrix metalloproteinase (MMP) and TIMP expression were assessed by zymography and northern analysis. Transforming growth factor β1 (TGF-β1) mRNA and protein levels were quantified by northern analysis and ELISA, respectively.
RESULTS—Exposure of activated HSC to relaxin resulted in a concentration dependent decrease in both collagen synthesis and deposition. There was a parallel decrease in TIMP-1 and TIMP-2 secretion into the HSC conditioned media but no change in gelatinase expression was observed. Northern analysis demonstrated that primary HSC, continuously exposed to relaxin, had decreased TIMP-1 mRNA expression but unaltered type I collagen, collagenase (MMP-13), alpha smooth muscle actin, and TGF-β1 mRNA expression.
CONCLUSION—These data demonstrate that relaxin modulates effective collagen deposition by HSC, at least in part, due to changes in the pattern of matrix degradation.


Keywords: relaxin; hepatic stellate cell; hepatic fibrosis; type I collagen

https://gut.bmj.com/content/gutjnl/49/4/577.full.pdf

Relaxin inhibits effective collagen deposition by cultured hepatic stellate cells and decreases rat liver fibrosis in vivo

Although substantial advances have been achieved in recent decades in the clinical management of heart diseases, new therapies that provide better or additional efficacy with minimal adverse effects are urgently required. Evidence that has accumulated since the 1990s indicates that the peptide hormone relaxin has multiple beneficial actions in the cardiovascular system under pathological conditions and, therefore, holds promise as a novel therapeutic intervention. Clinical trials for heart failure therapy using relaxin revealed several beneficial actions. Here we review findings from mechanistic and applied research in this field, comment on the outcomes of recent phase I/II clinical trails on patients with heart failure, and highlight settings of cardiovascular diseases where relaxin might be effective.

/pdf/cardiovascular-effects-of-relaxin-from-basic-science-to-4ywvdrm1dq.pdf

Cardiovascular effects of relaxin: from basic science to clinical therapy

Objective: To investigate cardiac phenotypes in mice deficient in the peptide hormone relaxin by gene targeting. Methods: Echocardiography and cardiac catheterization were performed on male and female relaxin deficient (Rlx−/−) mice as well as heterozygous (Rlx+/−) and wildtype (Rlx+/+) littermates aged between 8 and 24 months. Collagen expression and content in the heart were analysed by real-time PCR, hydroxyproline assay and histology. Results: Heart rate, blood pressures, left ventricular (LV) dimensions, fractional shortening and maximal and minimal d P /d t did not differ significantly between the three genotypes of either gender at any age. However, 8–10-month-old Rlx−/− males exhibited a greater transmitral flow velocity (A-wave) at the late LV diastolic phase. Male Rlx−/− mice aged between 12 and 24 months had significantly higher LV end-diastolic pressures, a 30% increase in atrial weight and 10–30% increases in lung and liver weights. Male mice also showed an age-dependent increase ( P <0.01) in LV collagen content that was more pronounced in Rlx−/− than control littermates ( P <0.01). Procollagen type-1 expression was also significantly higher in the LV of Rlx−/− males compared with either Rlx+/− or Rlx+/+ males at 6, 9 and 12 months of age. Age-matched female Rlx−/− mice did not display any of these cardiac phenotypes seen in Rlx−/− males. Conclusions: Male Rlx−/− mice had impeded LV diastolic filling and increased atrial weights, most likely due to an increase in ventricular collagen content and chamber stiffness. These phenotypes in the Rlx−/− males were not observed in Rlx−/− females, indicating the importance of other gender-related factors in cardiovascular function.

/pdf/increased-myocardial-collagen-and-ventricular-diastolic-27mzbz8mg4.pdf

Increased myocardial collagen and ventricular diastolic dysfunction in relaxin deficient mice: a gender-specific phenotype.

Matrix metalloproteinases are proteolytic enzymes that degrade the extracellular matrix and are essential for tissue remodeling. Uterine and cervical growth require remodeling of structural barriers to cell invasion and matrix metalloproteinase-2 and -9 degrade type IV collagen, the major component of basement membranes. Relaxin stimulates uterine and cervical growth and remodeling, which includes remodeling of support elements such as basement membranes. The objective of this study was to determine whether relaxin alters the production and/or activity of matrix metalloproteinase-2 and -9 in the uterus or cervix of the pig. The growth-promoting effects of relaxin were elicited by administering relaxin to prepubertal gilts every 6 h for 54 h. The expression of matrix metalloproteinase-2 and matrix metalloproteinase-9 was characterized by gel zymography, and proteins were quantified by immunoblotting. Total enzyme activity was measured using matrix metalloproteinase-specific fluorescent substrate assays. In both uterine and cervical tissues, immunoreactive matrix metalloproteinase-2 and matrix metalloproteinase-9 protein expression was similar in relaxin-treated and control animals. However, tissue-associated gelatinase activity was attenuated by relaxin (P < 0.05). In contrast, relaxin significantly increased the secretion of active matrix metalloproteinase-2 and -9 protein into uterine fluid (P < 0.05). Given the importance of matrix metalloproteinases in extracellular matrix degradation, the observation that relaxin promotes uterine secretion of matrix metalloproteinase-2 and -9 supports the concept that relaxin facilitates the growth and remodeling of reproductive tissues by increasing extracellular proteolysis in the pig reproductive tract.

/pdf/relaxin-increases-secretion-of-matrix-metalloproteinase-2-3ouba2d2gv.pdf

Relaxin increases secretion of matrix metalloproteinase-2 and matrix metalloproteinase-9 during uterine and cervical growth and remodeling in the pig.

Epithelial cadherin (E-cadherin) is one member of a family of intracellular calcium (Ca(2+))-dependent adhesion molecules that mediates selective cell-cell adhesion in a variety of species. Since changes in adhesive function accompany ovarian tissue development and remodeling, we were interested in studying the expression of E-cadherin during ovarian maturation in the pig. The objectives of this study were 1) to investigate the pattern of E-cadherin mRNA and protein expression during ovarian ontogeny in the pig, 2) to identify specific cells expressing E-cadherin in the mature porcine ovary, and 3) to compare E-cadherin expression in cells of morphologically healthy and atretic follicles. The results showed the presence of a 120-kDa protein, corresponding to E-cadherin, which was highest in fetal and neonatal ovaries and declined markedly (3- to 8-fold, p < 0.05) with maturity (16 wk to adult). In the adult ovary, E-cadherin was highest in ovarian surface epithelium (OSE) whereas in healthy follicles, granulosa cells had the highest levels. A significant decline (p < 0.05) in E-cadherin expression was evident in granulosa and theca cells from atretic follicles when compared with E-cadherin expression in cells of healthy follicles. A 4.2-kb E-cadherin transcript was detected in ovaries from 15-day-old pigs, and expression was markedly reduced (p < 0.05) by 16 wk of age. In the ovary of pregnancy, there was a faint E-cadherin mRNA signal, whereas in follicles the signal was stronger and uniform across follicle size. This is the first report that E-cadherin is expressed by the porcine ovary during ontogeny and that follicular and OSE cells of the adult ovary express the protein. Although the role of E-cadherin in the porcine ovary is unknown, the decline in E-cadherin expression in atretic follicular cells suggests that E-cadherin has a role in maintaining the structural integrity of the ovarian follicle during growth and development.

Expression of epithelial cadherin in the developing and adult pig ovary.

Remodeling of reproductive organs during pregnancy requires degradation and resynthesis of structural barriers to cell invasion. Matrix metalloproteinases (MMPs) are enzymes that break down components of the extracellular matrix (ECM) and are essential for tissue remodeling processes. Tissue inhibitors of metalloproteinases (TIMPs) are important regulators of MMP activity. In the pig, relaxin stimulates growth and remodeling of the uterus and cervix during pregnancy, effects that include the ability to alter elements of the ECM. Therefore, the objective of this study was to determine whether relaxin alters the production and/or activity of TIMP-1 and TIMP-2 in the porcine uterus or cervix. The growth-promoting effects of relaxin were elicited by administering relaxin to prepubertal gilts every 6 h for 54 h. Expression of TIMP-1 and TIMP-2 was characterized by immunoblotting. Total enzyme activity was measured using an MMP-specific fluorescent substrate assay. TIMP-1 and TIMP-2 proteins were present in the uterus and cervix of control and relaxin-treated pigs, and both proteins were increased by relaxin in the uterine flushes and tissues (P < 0.05). Inhibitor activity in uterine tissue extracts and uterine flushes from relaxin-treated animals was greater than that in controls; however, this activity was restricted to inhibition of MMP-2. In the uterine cervix, relaxin enhanced expression of TIMP-1 and TIMP-2 (P < 0.05), whereas expression of both TIMP proteins was similar in the vaginal cervix of control and relaxintreated animals. Likewise, inhibitor activity against MMP-2 in the uterine cervix was enhanced in response to relaxin (P < 0.05). In contrast, inhibitor activity was attenuated in extracts from the vaginal cervix (P < 0.05). This study highlights the complex nature of MMP/TIMP regulation during reproductive tissue growth and suggests that TIMP-1 and TIMP-2 may be involved in other aspects of the growth process. These data support a role for relaxin in regulating the activity of TIMPs during growth and remodeling of reproductive connective tissue. (Endocrinology 143: 91–98, 2002)

/pdf/relaxin-increases-secretion-of-tissue-inhibitor-of-matrix-1w1dp6zejv.pdf

Relaxin Increases Secretion of Tissue Inhibitor of Matrix Metalloproteinase-1 and -2 during Uterine and Cervical Growth and Remodeling in the Pig

Data presented here support the hypothesis that serum relaxin is a reliable indicator of placental insufficiency in mares. Relaxin, as a biological marker of placental function and fetal well-being, may provide veterinarians with a useful diagnostic tool to help reduce the incidence of late-term abortions and stillbirths in horses. Authors’ addresses: Dept. of Molecular Biology, Princeton University, Princeton, NJ 08544 (Ryan); Mid-Atlantic Veterinary Clinic, P.O. Box 188, Ringoes, NJ 08551 (Vaala); and Dept. of Animal Sciences, Rutgers University, New Brunswick, NJ 08903 (Bagnell). r 1998 AAEP.

Evidence that Equine Relaxin Is a Good Indicator of Placental Insufficiency in the Mare

Epithelial cadherin (E-cadherin), a member of the cadherin family of calcium-dependent adhesion molecules, is present in reproductive tissues. Relaxin, a hormone important for uterine and cervical growth in pigs, increases the expression of E-cadherin in the MCF-7 mammary epithelial cell line. The objective of this study was to characterize the expression of E-cadherin during relaxin-induced growth of the uterus and cervix in an immature pig model, independent of high circulating steroids. After administration of relaxin to prepubertal gilts, the uterus and cervix were collected. E-cadherin mRNA and protein were measured by northern and western blot analysis, respectively. A 120 kDa protein band, corresponding to E-cadherin, was detected in all tissues examined. Relaxin significantly (P < 0.05) increased the amount of E-cadherin protein in the uterus (P < 0.05), whereas no significant changes were observed in E-cadherin protein in the cervix. A 4.2 kb E-cadherin transcript was detected in all tissues and E-cadherin mRNA was significantly higher (P < 0.05) in uteri from relaxin-treated gilts compared with control gilts. E-cadherin was localized by immunocytochemistry to the epithelial cells of the uterine and cervical lumen, and the uterine glandular epithelium. Quantitative analysis revealed that administration of relaxin significantly increased (P < 0.05) the height of the uterine luminal epithelium compared with that of the controls. This is the first report of the expression of E-cadherin in the uterus and cervix of pigs. The findings from this study indicate that relaxin increases the expression of uterine E-cadherin in the reproductive tract of pigs. Administration of relaxin to prepubertal gilts in vivo increased uterine epithelial cell growth independent of circulating steroids, with a concomitant increase in E-cadherin expression.

/pdf/expression-of-uterine-and-cervical-epithelial-cadherin-38jlt792zh.pdf

Expression of uterine and cervical epithelial cadherin during relaxin-induced growth in pigs

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