Estrogen Enhances whereas Tamoxifen Retards Development of Tsc Mouse Liver Hemangioma: A Tumor Related to Renal Angiomyolipoma and Pulmonary Lymphangioleiomyomatosis

El-Hashemite, Nisreen; Walker, Victoria; Kwiatkowski, David J.

doi:10.1158/0008-5472.can-04-3840

Cited by 47 publications

(43 citation statements)

References 35 publications

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“…Others have shown that oestrogen can stimulate proliferation of angiomyolipoma derived cells (Yu et al 2004) and angiomyolipoma related tumours (El-Hashemite et al 2005). Similarly, we have shown that oestrogen can stimulate AML cell growth to a similar degree to PDGF; although it is not clear whether this is a direct or indirect effect of oestrogen.…”

Section: Discussionsupporting

confidence: 53%

“…Although the most accurate model of TSC-related hamartoma developed, these lesions also develop in most female animals over 7 months (El-Hashemite et al 2005). Like these other model systems, the AML xenograft has phosphorylated S6K1 but also has the advantage of a relatively short natural history allowing experiments to be performed more quickly, possibly making it a useful tool for screening new therapies.…”

Section: Discussionmentioning

confidence: 99%

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Analysis of the oestrogen response in an angiomyolipoma derived xenograft model

Clements¹,

Asprey²,

McCulloch³

et al. 2009

Endocrine-Related Cancer

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Angiomyolipomas are benign mesenchymal tumours of smooth muscle, blood vessels and fat which occur sporadically or associated with tuberous sclerosis and lymphangioleiomyomatosis (LAM), a rare cystic lung disease. Angiomyolipoma and LAM are caused by loss of function of either the tuberous sclerosis-1 or -2 genes resulting in activation of p70S6kinase (S6K1) and uncontrolled cellular proliferation. LAM and angiomyolipoma can be exacerbated by oestrogens but how this occurs is not understood. To address this question, we created a xenograft tumour system in nude mice using immortalised angiomyolipoma cells. Angiomyolipoma xenografts had active S6K1, p38, p42/44 MAPK and Akt; they grew more rapidly and had greater Akt phosphorylation after oestrogen treatment of tumour-bearing mice. Transcriptional profiling showed oestrogen induced 300 genes including extracellular matrix proteins, proteases, cell cycle regulatory proteins and growth factors including platelet derived growth factor-C (PDGF-C). Biologically active PDGF-C was produced by primary angiomyolipoma cells in culture and PDGF-C protein was present in the neoplastic smooth muscle cells of 5/5 human angiomyolipoma and 4/5 LAM tissues examined by immunohistochemistry. These findings suggest that the response to oestrogen in this model is mediated by activation of Akt and transcriptional events. This model may prove useful for studying the biology and effect of drugs on angiomyolipoma and diseases related to TSC.

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Analysis of the oestrogen response in an angiomyolipoma derived xenograft model

Clements¹,

Asprey²,

McCulloch³

et al. 2009

Endocrine-Related Cancer

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“…Estrogen receptor alpha is expressed in LAM cells and in angiomyolipoma cells from LAM patients (17), and estrogen has been shown to activate p42/44 MAPK and stimulate the proliferation of Tsc2-null ELT3 cells and TSC2-null angiomyolipoma cells (11). Estrogen has also been shown to enhance liver hemangioma development in Tsc2Ϯ mice (30). Despite these findings, the role of estrogen in LAM pathogenesis is not well defined.…”

Section: Discussionmentioning

confidence: 99%

Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells

Robb

Morrison

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

155

198

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Lymphangioleiomyomatosis (LAM) is an often fatal disease primarily affecting young women in which tuberin (TSC2)-null cells metastasize to the lungs. The mechanisms underlying the striking female predominance of LAM are unknown. We report here that 17-␤-estradiol (E2) causes a 3-to 5-fold increase in pulmonary metastases in male and female mice, respectively, and a striking increase in circulating tumor cells in mice bearing tuberin-null xenograft tumors. E 2-induced metastasis is associated with activation of p42/44 MAPK and is completely inhibited by treatment with the MEK1/2 inhibitor, CI-1040. In vitro, E 2 inhibits anoikis of tuberin-null cells. Finally, using a bioluminescence approach, we found that E 2 enhances the survival and lung colonization of intravenously injected tuberin-null cells by 3-fold, which is blocked by treatment with CI-1040. Taken together these results reveal a new model for LAM pathogenesis in which activation of MEKdependent pathways by E 2 leads to pulmonary metastasis via enhanced survival of detached tuberin-null cells.L AM, the pulmonary manifestation of tuberous sclerosis complex (TSC), affects women almost exclusively (1). LAM affects 30Ϫ40% of women with TSC (2, 3). In a Mayo Clinic series, LAM was the third most frequent cause of TSC-related death, after renal disease and brain tumors (4). LAM can also occur in women who do not have germline mutations in TSC1 or TSC2 (sporadic LAM). LAM cells from both TSC-LAM and sporadic LAM carry inactivating mutations in both alleles of the TSC1 or TSC2 genes (5). The protein products of TSC1 and TSC2, hamartin and tuberin, respectively, form heterodimers (6, 7) that inhibit the small GTPase Ras homologue enriched in brain (Rheb), via tuberin's highly conserved GTPase activating domain. In its active form, Rheb activates the mammalian target of rapamycin (mTOR) complex 1 (TORC1), which is a key regulator of protein translation, cell size, and cell proliferation (8). Evidence of TORC1 activation, including hyperphosphorylation of ribosomal protein S6, has been observed in tumor specimens from TSC patients and LAM patients (9-11). Independent of its activation of mTOR, Rheb inhibits the activity of B-Raf and C-Raf/Raf-1 kinase, resulting in reduced phosphorylation of p42/44 MAPK (12-14), but the impact of the Raf/MEK/ MAPK pathway on disease pathogenesis is undefined.LAM is characterized pathologically by widespread proliferation of abnormal smooth muscle cells and by cystic changes within the lung parenchyma (1). About 60% of women with the sporadic form of LAM also have renal angiomyolipomas. The presence of TSC2 mutations in LAM cells and renal angiomyolipoma cells from women with sporadic LAM, but not in normal tissues, has led to the hypothesis that LAM cells spread to the lungs via a metastatic mechanism, despite the fact that LAM cells have a histologically benign appearance (15,16). Genetic and fluorescent in situ hybridization analyses of recurrent LAM after lung transplantation support this benign metastatic model (16).The female...

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“…14 In animal studies, tumors that are closely related to human angiomyolipomas have also been reported to grow with estrogen therapy and regress on tamoxifen. 15 In Hamster animal models, renal epithelial tumors have been shown to be inducible with estrogen. 16,17 Figure 1 Non-tumorous stromal proliferation, (a) subjacent to calyceal urothelial lining and between dilated collecting ducts in a benign kidney with hydronephrosis, (b) underlying the urothelium (MLS), adjacent to a clear cell renal cell carcinoma extending close to the pelvicalyceal system, and (c) surrounding a benign cyst in a case of acquired cystic disease of the kidney.…”

Section: Discussionmentioning

confidence: 99%

Estrogen and progesterone-receptor-positive stroma as a non-tumorous proliferation in kidneys: a possible metaplastic response to obstruction

Tickoo

Gopalan

et al. 2008

Modern Pathology

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The presence of estrogen and progesterone-receptor-positive stroma is well known in renal mixed epithelial and stromal tumor, cystic nephroma, and angiomyolipoma with epithelial cysts. It has been suggested that the hormone receptor positivity in mixed epithelial and stromal tumor may be etiologically related to exogenous hormone intake-a phenomenon that has become more frequent in recent years. In the past few years, we have observed such stroma in some non-neoplastic kidneys, as well as in tumor-bearing kidneys away from the tumor. Herein we present our experience with 10 such cases. In a prospective manner, whenever we noted stroma resembling that in ovaries or mü llerian organs (endometrial or cervical-like) in kidneys removed for any cause, immunohistochemical stains for estrogen and progesterone receptors were performed. There were eight males and two females among the group, with ages ranging from 11 months to 71 years. In six cases, the nephrectomies were performed for a non-functional kidney, and in three for tumors (one each of chromophobe, clear cell, and acquired cystic disease-associated renal cell carcinoma). One case was a partial nephrectomy for vesico-ureteric reflux, with upper pole hydronephrosis. Such stroma was present in nine cases as a non-mass forming proliferation around dilated, frequently inflamed pelvicalyceal system and collecting ducts. In one it was present at the periphery of an acquired cystic disease-associated renal cell carcinoma, as well as around non-tumorous cysts. The only common finding in all cases was a generalized or segmental hydronephrosis, or tumor compression-related focal obstruction. The stroma was positive for estrogen receptors in all 10 cases, and for progesterone receptors in seven. Thus, estrogen-and progesterone receptor-positive stroma can be present in the kidney, not only as a component of certain tumors, but also in association with non-neoplastic conditions. Its association with obstructive changes suggests that it may represent a metaplastic change in the renal interstitial cells surrounding these obstructed epithelial structures.

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Estrogen Enhances whereas Tamoxifen Retards Development of Tsc Mouse Liver Hemangioma: A Tumor Related to Renal Angiomyolipoma and Pulmonary Lymphangioleiomyomatosis

Cited by 47 publications

References 35 publications

Analysis of the oestrogen response in an angiomyolipoma derived xenograft model

Analysis of the oestrogen response in an angiomyolipoma derived xenograft model

Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells

Estrogen and progesterone-receptor-positive stroma as a non-tumorous proliferation in kidneys: a possible metaplastic response to obstruction

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