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Free access

Nima Sharifi, Robert J Lechleider and William L Farrar

Abstract

The transforming growth factor-β (TGF-β) pathway plays dual roles in cancer, inhibiting epithelial cell growth under normal physiologic conditions, but promoting invasion and metastasis once growth inhibitory responses are lost. Two recent papers show that TGF-β receptor III is the most common TGF-β pathway component downregulated in prostate cancer. Here, we discuss the implications of these findings and what it may mean about the biology of this disease.

Free access

Bettina Sederquist, Paola Fernandez-Vojvodich, Farasat Zaman and Lars Sävendahl

Children with inflammatory diseases usually display abnormal growth patterns as well as delayed puberty. This is a result of several factors related to the disease itself, such as malnutrition, hypercortisolism, and elevated levels of pro-inflammatory cytokines. These factors in combination with glucocorticoid treatment contribute to growth retardation during chronic inflammation by systemically affecting the major regulator of growth, the GH/IGF1 axis. However, recent studies have also shown evidence of a direct effect of these factors at the growth plate level. In conditions of chronic inflammation, pro-inflammatory cytokines are upregulated and released into the circulation. The most abundant of these, tumor necrosis factor α, interleukin 1β (IL1β), and IL6, are all known to directly act on growth plate cartilage to induce apoptosis and thereby suppress bone growth. Both clinical and experimental studies have shown that growth retardation can partly be rescued when these cytokines are blocked. Therefore, therapy modulating the local actions of these cytokines may be effective for preventing growth failure in patients with chronic inflammatory disorders. In this review, we report the current knowledge of inflammatory cytokines and their role in regulating bone growth.

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A G Aprikian, K Han, S Chevalier, M Bazinet and J Viallet

ABSTRACT

Bombesin and gastrin-releasing peptide (GRP) are potent neuropeptides expressed by prostate cancer neuroendocrine cells and are related to the progression of this malignancy. This study characterizes bombesin receptors in human prostate cancer cell lines (PC-3, DU-145, LNCaP) and assesses the in vitro effect of bombesin on signal transduction and cell proliferation. [125I]Tyr4-bombesin binding assays (37 °C) and Scatchard analyses revealed the presence of a single class of high-affinity receptors with similar K d values (1·5, 1·1 and 3·6 × 10−10 m in PC-3, DU-145 and LNCaP cells respectively) but with significant differences in the number of binding sites per cell (47·6, 1·5 and 0·1 × 103 in PC-3, DU-145 and LNCaP cells respectively). Molecular characterization of the binding sites performed in PC-3 cells by cross-linking experiments and SDS/PAGE revealed a single radioactive band of 85 kDa. To determine which of the three known bombesin receptor subtypes (GRP receptor (GRP-R), neuromedin B receptor, bombesin receptor subtype-3) were expressed in the cell lines, reverse transcription/PCR analysis of cellular RNA followed by hybridization with receptor-specific cDNA was performed. This revealed the presence of GRP-R transcript in all cell lines, while neither of the other two receptor transcripts were expressed. When intracellular calcium mobilization was measured by Fura-2/AM cell labeling and spectrofluorometric monitoring, bombesin (100 nm) induced rapid calcium mobilization in both PC-3 (>200% of baseline) and DU-145 (>100% of baseline) cells, but not in LNCaP cells. However, as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and [3H]thymidine incorporation, no growth modulation was observed with bombesin or bombesin receptor antagonist at various concentrations (0-500 nm). Our data indicate that bombesin is a potent inducer of signal transduction via GRP-R receptors in androgen-insensitive PC-3 and DU-145 prostate cancer cells. This suggests that the bombesin/GRP family of neuropeptides may play a regulatory role in the biology of androgen-independent prostate cancer.

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U. Michel, J. W. McMaster and J. K. Findlay

ABSTRACT

The regulation of steady-state follistatin mRNA levels by different pituitary hormones and peptide factors was examined in granulosa cell cultures derived from diethylstilboestrol-treated immature rats. Cytosolic RNA from cell cultures was prepared by lysis and equal amounts of RNA from all samples were analysed with a solution—hybridization assay using a 32P-labelled antisense probe corresponding to a part of exon 5 together with a part of the 5′ end of exon 6 of the rat follistatin gene. In addition, a specific 35S-labelled probe for cyclophilin was used as an internal standard.

The results show that 5 μg FSH/1 for 24 to 72 h stimulated steady-state follistatin mRNA levels, reaching levels 18·5-fold higher than controls. LH (0·2-100 μg/l) had only minor effects on follistatin mRNA levels in FSH-primed granulosa cells and prolactin, GH and IGF-I did not show any significant effects. Activin raised basal as well as FSH-stimulated steady-state follistatin mRNA levels up to ten- and twofold above controls respectively, whereas epidermal growth factor was found to inhibit FSH-stimulated follistatin mRNA levels in a dose-dependent manner.

It is concluded that follistatin mRNA levels in granulosa cells are regulated by FSH rather than LH, and that the stimulation by FSH can be inhibited by epidermal growth factor but enhanced by activin. Activin alone was also capable of stimulating follistatin mRNA.

Free access

Michiyo Ishida, Midori Maehara, Tsukasa Watanabe, Yu Yanagisawa, Yukiko Takata, Ryojun Nakajima, Mika Suzuki and Toshio Harigaya

Vasoinhibins are a family of peptides that act on endothelial cells to suppress angiogenesis and promote apoptosis-mediated vascular regression. Vasoinhibins include the N-terminal fragments from prolactin (PRL), GH, and placental lactogen. One of the vasoinhibins, the N-terminal PRL fragment of 16 kDa, is generated by the lysosomal representative protease cathepsin D (Cath D). Because the normal growth and involution of the mammary gland (MG) are profoundly affected by the expansion and regression of blood vessels and also because PRL stimulates the growth and differentiation of MG, we proposed that intact PRL produced during lactation contributes to MG angiogenesis and increased blood flow, whereas during involution, the N-terminal PRL fragment would have proapoptotic effects on mammary epithelial cells (MECs). Therefore, we investigated the production of the N-terminal PRL fragment and its direct effect on the MG. Mouse PRL (mPRL) was proteolytically cleaved by Cath D between amino acids 148 and 149. N-terminal PRL fragment and Cath D expression increased during MG involution. Furthermore, incubation of MG fragments and MCF7 with recombinant 16 kDa mPRL revealed a proapoptotic effect in MECs. Ectopic mPRL in MECs was cleaved to 16 kDa PRL by Cath D in the MG lysosomal fraction. The majority of PRL derived from pituitary gland was cleaved to 16 kDa PRL in culture medium. Therefore, N-terminal PRL fragment increases during the involution period, has a proapoptotic effect on MECs, and is mainly generated by secreted Cath D in the extracellular space of MG.

Free access

Angela Delaney, Vasantha Padmanabhan, Geoffrey Rezvani, Weiping Chen, Patricia Forcinito, Crystal S F Cheung, Jeffrey Baron and Julian C K Lui

Body size varies enormously among mammalian species. In small mammals, body growth is typically suppressed rapidly, within weeks, whereas in large mammals, growth is suppressed slowly, over years, allowing for a greater adult size. We recently reported evidence that body growth suppression in rodents is caused in part by a juvenile genetic program that occurs in multiple tissues simultaneously and involves the downregulation of a large set of growth-promoting genes. We hypothesized that this genetic program is conserved in large mammals but that its time course is evolutionarily modulated such that it plays out more slowly, allowing for more prolonged growth. Consistent with this hypothesis, using expression microarray analysis, we identified a set of genes that are downregulated with age in both juvenile sheep kidney and lung. This overlapping gene set was enriched for genes involved in cell proliferation and growth and showed striking similarity to a set of genes downregulated with age in multiple organs of the juvenile mouse and rat, indicating that the multiorgan juvenile genetic program previously described in rodents has been conserved in the 80 million years since sheep and rodents diverged in evolution. Using microarray and real-time PCR, we found that the pace of this program was most rapid in mice, more gradual in rats, and most gradual in sheep. These findings support the hypothesis that a growth-regulating genetic program is conserved among mammalian species but that its pace is modulated to allow more prolonged growth and therefore greater adult body size in larger mammals.

Free access

MP Rounseville and TP Davis

A hallmark of small cell lung carcinoma (SCLC) is the expression of autocrine growth factors such as neurotensin and gastrin-releasing peptide, which bind to cellular receptors and stimulate cell division. The biological activity of autocrine growth factors requires the concurrent expression of prohormone convertases that cleave the growth factors to their active form, suggesting the expression of these genes is linked in SCLCs. RNase protection assays were used to detect the expression of autocrine growth factor and prohormone convertase mRNAs in a panel of lung cancer cell lines. These mRNAs are coexpressed in SCLC and lung carcinoid cell lines, but not in normal lung epithelium or in non-small cell lung cancers. These findings, together with earlier results from our laboratory, suggest the expression of prohormone convertases has an important role in the development and maintenance of the SCLC phenotype and that autocrine growth factor and prohormone convertase genes respond to a common transcriptional activator in SCLC.

Free access

VS Densmore and HF Urbanski

The hypothalamus of rhesus macaques expresses two molecular forms of gonadotropin-releasing hormone (GnRH-I and GnRH-II). However, it is unclear whether these two neuropeptides play similar roles in the control of reproductive neuroendocrine function, especially in the context of positive and negative estrogen feedback. To address this issue, in situ hybridization histochemistry was used to compare the effect of 17beta-estradiol (E) on the expression of GnRH-I and GnRH-II mRNA in the medial basal hypothalamus (MBH) of adult female macaques. GnRH-I mRNA expression was found to be significantly (P<0.01) more abundant in ovariectomized (ovx) animals compared with ovariectomized E-treated (ovx+E) animals. In marked contrast, GnRH-II mRNA expression was found to be significantly (P<0.05) more abundant in ovx+E animals than in the ovx animals. To help elucidate how E exerts this stimulatory action on GnRH-II gene expression, hypothalamic sections were subsequently double labeled using a combination of immunohistochemisty for estrogen receptor (ER) -alpha or -beta and in situ hybridization histochemistry for GnRH-II. Approximately 50% of the GnRH-II positive cells in the MBH were found to express ERbeta, but none expressed ERalpha. Taken together, these data give credence to a novel pathway by which E may control the primate neuroendocrine reproductive axis, one that involves stimulation of GnRH-II release via an ERbeta-mediated mechanism.

Free access

Laura E Ellestad, Stefanie A Malkiewicz, H David Guthrie, Glenn R Welch and Tom E Porter

The expression profile of glucocorticoid-induced leucine zipper (GILZ) in the anterior pituitary during the second half of embryonic development in the chick is consistent with in vivo regulation by circulating corticosteroids. However, nothing else has been reported about the presence of GILZ in the neuroendocrine system. We sought to characterize expression and regulation of GILZ in the chicken embryonic pituitary gland and determine the effect of GILZ overexpression on anterior pituitary hormone levels. Pituitary GILZ mRNA levels increased during embryogenesis to a maximum on the day of hatch, and decreased through the first week after hatch. GILZ expression was rapidly upregulated by corticosterone in embryonic pituitary cells. To determine whether GILZ regulates hormone gene expression in the developing anterior pituitary, we overexpressed GILZ in embryonic pituitary cells and measured mRNA for the major pituitary hormones. Exogenous GILZ increased prolactin mRNA above basal levels, but not as high as that in corticosterone-treated cells, indicating that GILZ may play a small role in lactotroph differentiation. The largest effect we observed was a twofold increase in FSH β subunit in cells transfected with GILZ but not treated with corticosterone, suggesting that GILZ may positively regulate gonadotroph development in a manner not involving glucocorticoids. In conclusion, this is the first report to characterize avian GILZ and examine its regulation in the developing neuroendocrine system. We have shown that GILZ is upregulated by glucocorticoids in the embryonic pituitary gland and may regulate expression of several pituitary hormones.

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D. J. Woods, J. Soden, S. Tomlinson and S. P. Bidey

ABSTRACT

Using the fluorescent pH indicator 2′7′-bis(2-carboxyethyl)-5′-(6′)-carboxyfluorescein to monitor intracellular pH (pHi), we have investigated whether transmembrane Na+/H+ exchange, as measured by experimental changes in pHi under bicarbonate-free incubation conditions, may be involved in the early growth-promoting actions of insulin-like growth factor-I (IGF-I) on the rat thyroid cell stain FRTL-5. In initial studies to characterize Na+/H+ exchange in FRTL-5 cell suspensions, the recovery of a resting pHi in acid-loaded cells was shown to be dependent upon the presence of extracellular Na+, was enhanced by the presence of the sodium ionophore monensin and was abolished by amiloride, an antagonist of Na+/H+ antiport activity.

Unlike TSH, which was without effect on the pHi of FRTL-5 cells for up to 15 min after addition, IGF-I (1000 μg/1) caused a rapid and sustained increase within 3 min, which was abolished in medium in which Na+ had been replaced with an iso-osmotic level of choline chloride. The change in pHi in response to IGF-I was mimicked by phorbol 12-myristate 13-acetate (PMA; 100 nmol/1), an activator of thyroid cell proliferation. In the presence of TSH, exposure of cells to IGF-I or PMA had no additional effect on the cytoplasmic alkalinization induced by either of these two agonists alone. However, blockade of transmembrane Na+/H+ exchange with amiloride inhibited both the individual actions of IGF-I and PMA on [methyl-3H]thymidine incorporation, and the synergistic interaction between TSH and IGF-I. These findings are consistent with a differential mode of action of TSH and IGF-I on the early events associated with FRTL-5 cell proliferation, and suggest involvement of an amiloride-sensitive transmembrane Na+/H+ exchange in mediating the early cellular response to the latter. Furthermore, the later actions of PMA, which are also dependent upon early transmembrane Na+/H+ exchange, differ from those of IGF-I with respect to interaction with the growth-promoting actions of TSH.