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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The negative control of B cell generation is only partially resolved. We assessed the role of activin A in regulation of B lymphopoiesis in view of its specific inhibitory effects on tumor B lineage cells. Activin A is constitutively expressed in mouse hemopoietic organs and in cultured mesenchymal cell lines. We observed an inverse relationship between activin A titer and B lineage cell production. In the spleen, the red pulp exhibited a relatively higher abundance of the protein as compared with the lymphoid follicles, wherein B cell accumulation occurs. Furthermore, a specific shut off in activin A expression was observed in bone marrow and spleen following in vivo induction of B lymphocyte polyclonal activation. We further substantiated these in vivo observations by in vitro studies of primary bone marrow cultures, in which the expression of functional activin A was found to be diminished prior to the onset of B lymphopoiesis. The reduction in functional activin A is shown to concomitantly occur with spontaneous induction of the expression of activin A specific inhibitors. We therefore propose that the mesenchymal organ stroma expresses activin A that negatively controls B cell lymphopoiesis.
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PMID:The mesenchymal stroma negatively regulates B cell lymphopoiesis through the expression of activin A. 1279 3

Activin and transforming growth factor (TGF)-beta, members of the TGF-beta superfamily of growth factors, have been implicated in both mammary gland development and breast carcinogenesis. TGF-beta is thought to be involved in the maintenance of mammary gland ductal architecture and postlactational involution. TGF-beta acts as both a tumor suppressor and has oncogenic capacities in breast cancer tissue. Activin is associated with growth modulation in glandular organs, and its receptors and signaling proteins are present and regulated during postnatal mammary gland development, primarily during the lactational phase. The presence of the major components of the activin signal transduction pathway in different pathologic grades of breast cancer tissue has not been described thoroughly, despite evidence from in vitro studies suggesting that activin can inhibit proliferation in breast cancer-derived cells. On the basis of the growth regulatory capacity of activin, we hypothesized that the components of this signal transduction system would be deregulated as breast cancer becomes more aggressive. To test this hypothesis, breast cancer samples were substratified by pathologic grade, a known prognostic marker for breast cancer, and then examined for the presence and cellular localization of activin ligand subunits (beta A- and beta B-), receptors (Act RIIA, Act RIIB, and Act RIB), and signaling proteins, Smads 2, 3, and 4, by immunohistochemistry and immunofluorescent analysis. Breast tissue from healthy patients undergoing reduction mammoplasty was also studied. The activin beta A-subunit was present in all of the tissues examined, whereas the beta B-subunit, activin type II receptors, and Smads were less evident in high-grade cancers. Significant correlations were made in breast cancer specimens between a decrease in nuclear Smad 3 abundance and high tumor grade, high architectural grade, larger tumor size, and hormone receptor negativity. Thus, activin signal transduction components are present in normal tissue and grade 1 cancer but down-regulated in high-grade cancer. The deregulation of this signal transduction system may be relevant to advancing oncogenic progression.
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PMID:Down-regulation of activin, activin receptors, and Smads in high-grade breast cancer. 1283 74

Cripto, a cell surface-associated protein belonging to the EGF-CFC family of growth factor-like molecules, is overexpressed in many human solid tumors, including 70-80% of breast and colon tumors, yet how it promotes cell transformation is unclear. During embryogenesis, Cripto complexes with Alk4 via its unique cysteine-rich CFC domain to facilitate signaling by the TGF-beta ligand Nodal. We report, for the first time to our knowledge, that Cripto can directly bind to another TGF-beta ligand, Activin B, and that Cripto overexpression blocks Activin B growth inhibition of breast cancer cells. This result suggests a novel mechanism for antagonizing Activin signaling that could promote tumorigenesis by deregulating growth homeostasis. We show that an anti-CFC domain antibody, A8.G3.5, both disrupts Cripto-Nodal signaling and reverses Cripto blockade of Activin B-induced growth suppression by blocking Cripto's association with either Alk4 or Activin B. In two xenograft models, testicular and colon cancer, A8.G3.5 inhibited tumor cell growth by up to 70%. Both Nodal and Activin B expression was found in the xenograft tumor, suggesting that either ligand could be promoting tumorigenesis. These data validate that functional blockade of Cripto inhibits tumor growth and highlight antibodies that block Cripto signaling mediated through its CFC domain as an important class of antibodies for further therapeutic development.
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PMID:Antibody blockade of the Cripto CFC domain suppresses tumor cell growth in vivo. 1292 90

Activins and inhibins are structurally related glycoprotein hormones modulating pituitary FSH secretion and gonadal steroidogenesis. Activins and inhibins are also produced in the adrenal cortex where their physiological role is poorly known. Hormonally active human adrenocortical tumors express and secrete inhibins, while in mice adrenal inhibins may function as tumor suppressors. To clarify the significance of adrenal activins and inhibins we investigated the localization of activin/inhibin signaling components in the adrenal gland, and the effects of activins and inhibins on adrenocortical steroidogenesis and apoptosis. Activin receptor type II/IIB and IB, activin signal transduction proteins Smad2/3, and inhibin receptor betaglycan were expressed throughout the adrenal cortex, whereas Smad4 expression was seen mainly in the zona reticularis and the innermost zona fasciculata as evaluated by immunohistochemistry. Treatment of cultured adrenocortical carcinoma NCI-H295R cells with activin A inhibited steroidogenic acute regulatory protein and 17alpha-hydroxylase/17,20-lyase mRNA accumulation as evaluated by the Northern blot technique, and decreased cortisol, androstenedione, dehydroepiandrosterone and dehydroepiandrosterone sulfate secretion as determined by specific enzyme immunoassays. Activin A increased apoptosis as measured by a terminal deoxynucleotidyl transferase in situ apoptosis detection method. Inhibins had no effect on steroidogenesis or apoptosis. In summary, activin/inhibin signaling components are coexpressed in the zona reticularis and the innermost zona fasciculata indicating full signaling potential for adrenal activins and inhibins in these layers. Activin inhibits steroidogenic enzyme gene expression and steroid secretion, and increases apoptosis in human adrenocortical cells. Thus, the activin-inhibin system may have a significant role in the regulation of glucocorticoid and androgen production and apoptotic cell death in the human adrenal cortex.
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PMID:Expression of activin/inhibin signaling components in the human adrenal gland and the effects of activins and inhibins on adrenocortical steroidogenesis and apoptosis. 1296 39

Activins are multifunctional growth and differentiation factors and stimulate FSH-beta gene expression and FSH secretion by the pituitary gonadotropes. Follistatins bind activin, resulting in the neutralization of activin bioactivity. The activin/follistatin system is present in the prostate tissue. Prostate-specific antigen (PSA) plays an important role in male reproductive physiology as well as being very important as a tumor marker for prostate cancer. Thus the regulation of PSA has important clinical implications. Previous studies showed that PSA is primarily regulated by androgens. In the present study, we evaluated the direct effects of activin A on the proliferation and PSA production of prostate cancer LNCaP cells, which express functional activin receptors and androgen receptor and PSA. LNCaP cells were treated with activin A and 5alpha-dihydrotestosterone (DHT) with or without their antagonists (follistatin or the nonsteroidal anti-androgen bicalutamide). Activin A decreased cell growth of LNCaP cells in a dose-dependent manner, whereas DHT increased it in a biphasic manner. In contrast to their opposing actions on cell growth, both activin A and DHT upregulated PSA gene expression and increased PSA secretion by LNCaP cells. The effects of activin A and DHT to increase PSA production were synergistic or additive. Follistatin or bicalutamide was without effect on cell growth or PSA production. The effects of activin A on LNCaP cells were blocked by follistatin, not by bicalutamide, whereas effects of DHT were prevented by bicalutamide, not by follistatin. Activin A upregulates PSA production, and the effect is through an androgen receptor-independent pathway. The activin/follistatin system can be a physiological modulator of PSA gene transcription and secretion in the prostate tissue, and activins may cooperate with androgen to upregulate PSA in vivo.
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PMID:Regulation of prostate-specific antigen by activin A in prostate cancer LNCaP cells. 1476 77

Activin, a member of the TGFbeta superfamily, is a negative regulator of cell growth and prolactin (PRL) production in pituitary lactotrope cells. However, the mechanisms by which this growth factor exerts its growth-inhibitory and -repressive effect on PRL remain unclear. In this study, we show that activin negatively regulates PRL expression at the transcriptional level through the Smad pathway and the multiple endocrine neoplasia type 1 gene product, menin. Our results also demonstrate that the tumor suppressor menin is required for activin-induced growth arrest of somatolactotrope cells. Moreover, we show that activin represses transcription and expression of Pit-1, a pituitary transcription factor that is essential for maintenance and development of lactotrope cells. We defined two Pit-1 DNA-binding sites in the proximal region of the PRL promoter as critical for the activin-mediated inhibition. Together, our results highlight the Smad pathway and the tumor suppressor menin as key regulators of activin effects on PRL and Pit-1 expression, as well as on cell growth inhibition, and emphasize the critical role of activin in the regulation of pituitary function.
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PMID:Activin inhibits pituitary prolactin expression and cell growth through Smads, Pit-1 and menin. 1503 21

Activins and inhibins are growth factors involved in cell differentiation and proliferation. Human breast tissues such as normal mammary tissue, fibroadenoma, and breast cancer express inhibin and activin mRNA and proteins. Activin A and its binding protein, follistatin, are also present in human milk during the first week of lactation. Using immunohistochemistry, we have observed that the inhibin/activin alpha, betaA, and betaB subunits are present in normal breast tissue regardless of menstrual cycle phase or menopause, as well as in fibrocystic disease, and breast tumors. The mRNAs encoding all three activin/inhibin subunits are expressed in breast carcinoma, fibroadenoma, and normal mammary tissue. The betaA subunit gene expression is higher in either local or metastatic breast carcinoma than in normal tissue. In addition, dimeric activin A is detectable in homogenates of breast cancer tissue at concentrations twice as high as in non-neoplastic adjoining tissue. Recent evidence suggests that some of the activin A produced by breast carcinoma is released into systemic circulation. In women with breast cancer, serum activin A levels are often elevated, and a significant decrease is observed in the first and second days following tumor excision. The role of activin and inhibin as endocrine and/or paracrine factors in the breast is still uncertain. Activin has complex effects on cell growth during branching morphogenesis, but it is generally considered as an inhibitor of cell proliferation as in vitro studies have shown that activin A treatment of breast cancer cells arrests cell growth. Inhibin is generally considered as a tumor suppressor, but its possible role in the breast is less understood.
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PMID:Activin, inhibin and the human breast. 1545 71

Malignant ovarian epithelial tumors have been shown to have decreased inhibin production relative to activin production compared with normal ovarian surface epithelial (OSE) cells and nonmalignant ovarian tumors. Activin stimulates proliferation of many ovarian cancer cell lines. Inhibin antagonizes the action of activin, and inhibin-deficient mice develop gonadal tumors, suggesting that inhibin may be a tumor suppressor. However, its effects on OSE and ovarian cancer cells are unknown. We hypothesize that activin and inhibin are important regulators of biological activity in ovarian cancers. We found that inhibin A decreased murine OSE proliferation, whereas activin A had no effect. Activin A increased the proliferation of four of eight ovarian cancer cell lines (SKOV3, OCC1, OVCAR3, and A2780-s). Inhibin A decreased the proliferation of SKOV3, A2780-s, and OVCAR3 but had no effect on OCC1, ES-2, HEY, A2780-cp, and OVCA429 cells. When injected into nude mice, the inhibin-resistant cancer cell lines resulted in shorter survival time compared with the inhibin-responsive cells. Further investigations on SKOV3 and OCC1 cells showed that activin A increased invasion through Matrigel. Inhibin A decreased both basal and activin-induced proliferation and invasion of SKOV3 but had no effect on OCC1 cells. Reverse transcription-PCR analyses showed that the SKOV3 and OCC1 cells produced activin, but only SKOV3 produced inhibin. Analysis of the activin/inhibin signaling pathways indicated that Smad anchor for receptor activation was elevated in SKOV3 and OCC1 cells and that an up-regulation of the activin receptor expression may explain the inhibin resistance of OCC1 cells. Our results suggest that activin responsiveness may be gained during transformation of OSE cells and that inhibin resistance may contribute to the aggressive behavior of ovarian cancer cells.
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PMID:Inhibin resistance is associated with aggressive tumorigenicity of ovarian cancer cells. 1567 Dec 49

Upregulation of HER2/ErbB2/Neu occurs in 15-30% of human breast cancers and correlates with poor prognosis. Identification of ErbB2/Neu transcriptional targets should facilitate development of novel therapeutic approaches. Development of breast cancer is a multistep process; thus, to identify the transcriptomes associated with different stages of progression of tumorigenesis, we compared expression profiles of mammary tumors and preneoplastic mammary tissue from MMTV-Neu transgenic mice to expression profiles of wild-type mammary glands using Affymetrix microarrays. We identified 324 candidate genes that were unique to ErbB2/Neu-induced tumors relative to normal mammary gland tissue from wild-type controls. Expression of a subset of these genes (82) was also changed in the preneoplastic mammary glands compared to wild-type controls, indicating that they may play a pivotal role during early events of ErbB2/Neu-initiated mammary tumorigenesis. Further analysis of the microarray data revealed that expression of several known transforming growth factor (TGF)-beta target genes was altered, suggesting that the TGF-beta signaling cascade is downregulated in ErbB2/Neu-induced tumors. Western blot analysis for TGF-beta-Receptor-I/ALK5 and immunohistochemistry for TGF-beta-Receptor-I/ALK5 and phosphorylated/activated Smad2 confirmed that the Smad-dependent TGF-beta signaling cascade was inactive in these tumors. Although absent in most of the tumor, phosphorylated Smad2 was present in the periphery of tumors. Interestingly, presence of phosphorylated/activated Smad2 correlated with expression of Activin-Receptor-IB/ALK4, suggesting that although Smad-dependent TGF-beta signaling is absent in ErbB2/Neu-induced tumors, Activin signaling may be active at the leading edge of these tumors. Cumulatively, these data indicate that the TGF-beta pathway is intrinsically suppressed in ErbB2/Neu tumors via a mechanism involving loss of TGF-beta-Receptor-I/ALK5.
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PMID:Gene expression profiling of cancer progression reveals intrinsic regulation of transforming growth factor-beta signaling in ErbB2/Neu-induced tumors from transgenic mice. 1589 83

The transforming growth factor-beta superfamily member activin and its antagonist, follistatin, act as a pleiotropic growth factor system that controls cell proliferation, differentiation, and apoptosis. Activin inhibits fibroblast growth factor 2-induced sprouting angiogenesis in vitro (spheroidal angiogenesis assay) and in vivo (Matrigel assay). To further study the role of the activin/follistatin system during angiogenesis and tumor progression, activin- and follistatin-expressing R30C mammary carcinoma cells were studied in mouse tumor experiments. Surprisingly, activin-expressing tumors grew much faster than follistatin-expressing tumors although they failed to induce increased angiogenesis (as evidenced by low microvessel density counts). Conversely, follistatin-expressing tumors were much smaller but had a dense network of small-diameter capillaries. Qualitative angioarchitectural analyses (mural cell recruitment, perfusion) revealed no major functional differences of the tumor neovasculature. Analysis of activin- and follistatin-expressing R30C cells identified a cell autonomous role of this system in controlling tumor cell growth. Whereas proliferation of R30C cells was not altered, follistatin-expressing R30C cells had an enhanced susceptibility to undergo apoptosis. These findings in experimental tumors are complemented by an intriguing case report of a human renal cell carcinoma that similarly shows a dissociation of angiogenesis and tumorigenesis during tumor progression. Collectively, the data shed further light into the dichotomous stimulating and inhibiting roles that the activin/follistatin system can exert during angiogenesis and tumor progression. Furthermore, the experiments provide a critical proof-of-principle example for the dissociation of angiogenesis and tumorigenesis, supporting the concept that tumor growth may not be dependent on increased angiogenesis as long as a minimal intratumoral microvessel density is maintained.
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PMID:Dissociation of angiogenesis and tumorigenesis in follistatin- and activin-expressing tumors. 1674 Jul 6


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