Role of the epithelial-stromal interaction during the development and expression of ovary-independent vaginal hyperplasia

Cunha, Gerald R.; Lung, Ben; Kato, Kaori

doi:10.1016/0012-1606(77)90154-3

Cited by 41 publications

(15 citation statements)

References 28 publications

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“…In our study, epithelial cells in neoDES vagina seem to exhibit direct mitogenic and differentiation responses in epithelial cells, and they lose their normal stromal association. Actually, tissue recombinant experiments showed that the reciprocal recombination of neonatally estrogenized vaginal epithelium and untreated vaginal stroma exhibited ovary-independent hyperplasia (Cunha et al, 1977). This is the first report that ligand-independent ER action induces a precancerous status in estrogen-target organ in vivo.…”

Section: Discussionmentioning

confidence: 85%

Estrogen-independent activation of erbBs signaling and estrogen receptor α in the mouse vagina exposed neonatally to diethylstilbestrol

et al. 2004

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Growth factors and estrogen receptor (ER) signaling cooperate to play essential roles in cell proliferation, differentiation and tumor progression in mouse reproductive organs. Treatment of neonatal mice with diethylstilbestrol (DES) induces an estrogen-independent persistent proliferation and cornification of the vaginal epithelium, which results in cancerous lesions later in life. However, the mechanisms of the estrogen-dependent andindependent pathways essentially remain unknown. We characterized the expression of epidermal growth factor (EGF)-like growth factors (EGF, transforming growth factor a (TGF-a), heparin-binding EGF-like growth factor (HB-EGF), betacellulin (BTC), amphiregulin (APR), epiregulin (EPR) and neuregulin (NRG) 1) and erbB receptors (EGF receptor (EGFR), erbB2/neu, erbB3 and erbB4) in the vaginae of mice treated either neonatally (0-4 day) or as adults (55-59 day) with estrogens. EGFR and erbB2 were activated in the vaginal epithelium of mice by estrogen treatment. This activation was also encountered in vaginae from neonatally DES-exposed mice, along with the expression of EGF, TGF-a, HB-EGF, BTC, APR, EPR and NRG1. Immunohistochemical analysis indicated that erbB2 was primarily expressed in vaginal epithelium. Finally, we found that serine 118 and 167 located in the AF-1 domain of ERa were phosphorylated in these vaginae. AG825, AG1478 or ICI 182,780 administration blocked proliferation of vaginal epithelium induced by neonatal DES exposure. Thus, signal transduction via EGFR and erbB2 could be related to the estrogen-induced vaginal changes and persistent erbBs phosphorylation and sustained expression of EGF-like growth factors, leading to ERa activation that may result in cancerous lesions in vaginae from neonatally DES-exposed mice later in life.

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Section: Discussionmentioning

confidence: 85%

Estrogen-independent activation of erbBs signaling and estrogen receptor α in the mouse vagina exposed neonatally to diethylstilbestrol

et al. 2004

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“…Positive tumor responses (in bold) were defined by a significantly smaller tumor area of the treated xenografts (≤50% of control; P < 0.05). The tumor response rates to regimens A, B, and C were 28% (9 of 32), 42% (8 of 19), and 44% (7 of 16), respectively.…”

Section: Resultsmentioning

confidence: 99%

“…The high engraftment rate (90%) obtained by subrenal capsule grafting allowed the survival of the various types of NSCLC examined. The high take rate contrasts with the much lower rates (20-40%) reported for subcutaneous graft models (13)(14)(15)(16)(17) and is likely a result of superior nutrient supply and enhancement of graft microvascularity provided by the subrenal capsule site (18)(19)(20)(21)(22)(23)(24). The high engraftment rate was further ensured by rigorous selection of viable tumor tissue through fluorescence illumination and by identifying such tissue in cryostat sections from randomly selected pregraft fragments.…”

Section: Discussionmentioning

confidence: 97%

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Patient-Derived First Generation Xenografts of Non–Small Cell Lung Cancers: Promising Tools for Predicting Drug Responses for Personalized Chemotherapy

Dong

Guan

English

et al. 2010

Clinical Cancer Research

166

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Purpose: Current chemotherapeutic regimens have only modest benefit for non-small cell lung cancer (NSCLC) patients. Cumulative toxicities/drug resistance limit chemotherapy given after the first-line regimen. For personalized chemotherapy, clinically relevant NSCLC models are needed for quickly predicting the most effective regimens for therapy with curative intent. In this study, first generation subrenal capsule xenografts of primary NSCLCs were examined for (a) determining responses to conventional chemotherapeutic regimens and (b) selecting regimens most effective for individual patients.Experimental Design: Pieces (1×3×3 mm 3 ) of 32 nontreated, completely resected patients' NSCLCs were grafted under renal capsules of nonobese diabetic/severe combined immunodeficient mice and treated with (A) cisplatin+vinorelbine, (B) cisplatin+docetaxel, (C) cisplatin+gemcitabine, and positive responses (treated tumor area ≤50% of control, P < 0.05) were determined. Clinical outcomes of treated patients were acquired.Results: Xenografts from all NSCLCs were established (engraftment rate, 90%) with the retention of major biological characteristics of the original cancers. The entire process of drug assessment took 8 weeks. Response rates to regimens A, B, and C were 28% (9 of 32), 42% (8 of 19), and 44% (7 of 16), respectively. Certain cancers that were resistant to a particular regimen were sensitive to others. The majority of responsive tumors contained foci of nonresponding cancer cells, indicative of tumor heterogeneity and potential drug resistance. Xenografts from six of seven patients who developed recurrence/metastasis were nonresponsive.Conclusions: Models based on first generation NSCLC subrenal capsule xenografts have been developed, which are suitable for quick assessment (6-8 weeks) of the chemosensitivity of patients' cancers and selection of the most effective regimens. They hold promise for application in personalized chemotherapy of NSCLC patients. Clin Cancer Res; 16(5); 1442-51. ©2010 AACR.Lung cancer is the leading cause of cancer-related mortality worldwide (1). Non-small cell lung cancer (NSCLC) represents over 80% of lung cancer deaths (2, 3). Chemotherapy has been shown to improve the survival of patients with advanced, inoperable NSCLCs or, as adjuvant therapy, to reduce the rate of relapse of patients following resection of early-stage cancers (2, 3). Generally, two-drug combinations of cytotoxic drugs such as gemcitabine, vinorelbine, and docetaxel with cisplatin or carboplatin are used. A recent meta-analysis study showed that platinum-based, adjuvant chemotherapy of patients with resected NSCLCs was associated with a 5% greater 5-year survival rate, revealing marginal effectiveness of current chemotherapeutic regimens (4). Moreover, only a portion of patients who receive first-line treatment can receive further chemotherapy because of rapid disease progression and intolerance to side effects. Additional chemotherapy is particularly limited for patients who have experienced severe toxic...

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“…The vaginal epithelium of female mice given injec tions of estrogenic or androgenic steroids during a criti cal neonatal period showed estrogen-independent per sistent proliferation and cornification [Takasugi, 1963;Kohrman and Greenberg, 1968;Cunha et al, 1977; for a review, see Takasugi, 1976). Histological and histochemical studies have revealed no difference in the final structure of the vagi nal epithelium between neonatally estrogen-and androgen-treated mice.…”

Section: Introductionmentioning

confidence: 99%

Electron-microscopic study on the development of permanently proliferated and cornified vaginal epithelium in mice treated neonatally with androgen

Iguchi¹,

Ohta²

1980

Cells Tissues Organs

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In the vaginal epithelium of mice given 5 daily injections of 100 µg 5α-dihydrotestosterone from the day of birth, highly electron-dense cells with numerous cytoplasmic processes appeared in the basal layer within 35 days after the last injection. These cells were similar to the B cells reported in earlier works in neonatally estrogen-treated mice undergoing ovary-independent, permanent proliferation and cornification. The present electron-microscopic study suggests that the permanently proliferating, highly electron-dense cells are derived from electronlucent cells (clear cells) appearing in the basal layer of the vaginal epithelium 15–20 days after neonatal androgen treatment.

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Role of the epithelial-stromal interaction during the development and expression of ovary-independent vaginal hyperplasia

Cited by 41 publications

References 28 publications

Estrogen-independent activation of erbBs signaling and estrogen receptor α in the mouse vagina exposed neonatally to diethylstilbestrol

Estrogen-independent activation of erbBs signaling and estrogen receptor α in the mouse vagina exposed neonatally to diethylstilbestrol

Patient-Derived First Generation Xenografts of Non–Small Cell Lung Cancers: Promising Tools for Predicting Drug Responses for Personalized Chemotherapy

Electron-microscopic study on the development of permanently proliferated and cornified vaginal epithelium in mice treated neonatally with androgen

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