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UV-induction of keratinocyte endothelin-1 downregulates E-cadherin in melanocytes and melanoma cells
Sumayah Jamal, Robert J. Schneider
Sumayah Jamal, Robert J. Schneider
Published August 15, 2002
Citation Information: J Clin Invest. 2002;110(4):443-452. https://doi.org/10.1172/JCI13729.
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UV-induction of keratinocyte endothelin-1 downregulates E-cadherin in melanocytes and melanoma cells

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Abstract

Research Article

Authors

Sumayah Jamal, Robert J. Schneider

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Improving chemotherapeutic drug penetration in tumors by vascular targeting and barrier alteration
Flavio Curnis, … , Angelina Sacchi, Angelo Corti
Flavio Curnis, … , Angelina Sacchi, Angelo Corti
Published August 15, 2002
Citation Information: J Clin Invest. 2002;110(4):475-482. https://doi.org/10.1172/JCI15223.
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Improving chemotherapeutic drug penetration in tumors by vascular targeting and barrier alteration

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Abstract

Research Article

Authors

Flavio Curnis, Angelina Sacchi, Angelo Corti

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Huntingtin-interacting protein 1 is overexpressed in prostate and colon cancer and is critical for cellular survival
Dinesh S. Rao, … , Martin G. Sanda, Theodora S. Ross
Dinesh S. Rao, … , Martin G. Sanda, Theodora S. Ross
Published August 1, 2002
Citation Information: J Clin Invest. 2002;110(3):351-360. https://doi.org/10.1172/JCI15529.
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Huntingtin-interacting protein 1 is overexpressed in prostate and colon cancer and is critical for cellular survival

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Abstract

Research Article

Authors

Dinesh S. Rao, Teresa S. Hyun, Priti D. Kumar, Ikuko F. Mizukami, Mark A. Rubin, Peter C. Lucas, Martin G. Sanda, Theodora S. Ross

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G1 and G2 cell-cycle arrest following microtubule depolymerization in human breast cancer cells
April L. Blajeski, … , Timothy J. Kottke, Scott H. Kaufmann
April L. Blajeski, … , Timothy J. Kottke, Scott H. Kaufmann
Published July 1, 2002
Citation Information: J Clin Invest. 2002;110(1):91-99. https://doi.org/10.1172/JCI13275.
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G1 and G2 cell-cycle arrest following microtubule depolymerization in human breast cancer cells

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Abstract

Research Article

Authors

April L. Blajeski, Vy A. Phan, Timothy J. Kottke, Scott H. Kaufmann

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Blockade of TGF-β inhibits mammary tumor cell viability, migration, and metastases
Rebecca S. Muraoka, … , Victor Koteliansky, Carlos L. Arteaga
Rebecca S. Muraoka, … , Victor Koteliansky, Carlos L. Arteaga
Published June 15, 2002
Citation Information: J Clin Invest. 2002;109(12):1551-1559. https://doi.org/10.1172/JCI15234.
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Blockade of TGF-β inhibits mammary tumor cell viability, migration, and metastases

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Abstract

TGF-βs are potent inhibitors of epithelial cell proliferation. However, in established carcinomas, autocrine/paracrine TGF-β interactions can enhance tumor cell viability and progression. Thus, we studied the effect of a soluble Fc:TGF-β type II receptor fusion protein (Fc:TβRII) on transgenic and transplantable models of breast cancer metastases. Systemic administration of Fc:TβRII did not alter primary mammary tumor latency in MMTV-Polyomavirus middle T antigen transgenic mice. However, Fc:TβRII increased apoptosis in primary tumors, while reducing tumor cell motility, intravasation, and lung metastases. These effects correlated with inhibition of Akt activity and FKHRL1 phosphorylation. Fc:TβRII also inhibited metastases from transplanted 4T1 and EMT-6 mammary tumors in syngeneic BALB/c mice. Tumor microvessel density in a mouse dorsal skin window chamber was unaffected by Fc:TβRII. Therefore, blockade of TGF-β signaling may reduce tumor cell viability and migratory potential and represents a testable therapeutic approach against metastatic carcinomas.

Authors

Rebecca S. Muraoka, Nancy Dumont, Christoph A. Ritter, Teresa C. Dugger, Dana M. Brantley, Jin Chen, Evangeline Easterly, L. Renee Roebuck, Sarah Ryan, Philip J. Gotwals, Victor Koteliansky, Carlos L. Arteaga

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Myeloerythroid-restricted progenitors are sufficient to confer radioprotection and provide the majority of day 8 CFU-S
Thanyaphong Na Nakorn, … , Irving L. Weissman, Koichi Akashi
Thanyaphong Na Nakorn, … , Irving L. Weissman, Koichi Akashi
Published June 15, 2002
Citation Information: J Clin Invest. 2002;109(12):1579-1585. https://doi.org/10.1172/JCI15272.
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Myeloerythroid-restricted progenitors are sufficient to confer radioprotection and provide the majority of day 8 CFU-S

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Abstract

Whole-body irradiation at the minimal lethal dose causes bone marrow failure and death within 12–18 days. To identify the principal components of the hematopoietic system that are radioprotective, we transplanted lethally irradiated mice with purified progenitors: common myeloid progenitors (CMPs), megakaryocyte/erythrocyte-restricted progenitors (MEPs), or granulocyte/monocyte-restricted progenitors (GMPs). Transplanted CMPs gave rise to cells both of the granulocyte/monocyte (GM) series and the megakaryocyte/erythrocyte series, whereas GMPs or MEPs showed reconstitution of only GM or ME cells, respectively. CMPs and MEPs but not GMPs protected mice in a dose-dependent manner, suggesting that erythrocytes, platelets, or both are the critical effectors of radioprotection. Accordingly, CMPs and MEPs formed robust colonies in recipient bone marrow and spleen, whereas GMPs formed small colonies that rapidly disappeared. Direct comparisons of spleen CFU (CFU-S) potentials among each progenitor subset showed that MEPs contain the vast majority of day 8 CFU-S activity, suggesting that day 8 CFU-S are the precursors of radioprotective cell subsets. All animals radioprotected for 30 days subsequently survived for at least 6 months post-transplant, and showed only host-derived hematopoiesis after 30 days. These findings suggest that rare hematopoietic stem cells survive myeloablation that can eventually repopulate irradiated hosts if myeloerythroid-restricted progenitors transiently rescue ablated animals through the critical window of bone marrow failure.

Authors

Thanyaphong Na Nakorn, David Traver, Irving L. Weissman, Koichi Akashi

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Lifetime exposure to a soluble TGF-β antagonist protects mice against metastasis without adverse side effects
Yu-an Yang, … , Glenn Merlino, Lalage M. Wakefield
Yu-an Yang, … , Glenn Merlino, Lalage M. Wakefield
Published June 15, 2002
Citation Information: J Clin Invest. 2002;109(12):1607-1615. https://doi.org/10.1172/JCI15333.
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Lifetime exposure to a soluble TGF-β antagonist protects mice against metastasis without adverse side effects

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Abstract

TGF-βs play diverse and complex roles in many biological processes. In tumorigenesis, they can function either as tumor suppressors or as pro-oncogenic factors, depending on the stage of the disease. We have developed transgenic mice expressing a TGF-β antagonist of the soluble type II TGF-β receptor:Fc fusion protein class, under the regulation of the mammary-selective MMTV-LTR promoter/enhancer. Biologically significant levels of antagonist were detectable in the serum and most tissues of this mouse line. The mice were resistant to the development of metastases at multiple organ sites when compared with wild-type controls, both in a tail vein metastasis assay using isogenic melanoma cells and in crosses with the MMTV-neu transgenic mouse model of metastatic breast cancer. Importantly, metastasis from endogenous mammary tumors was suppressed without any enhancement of primary tumorigenesis. Furthermore, aged transgenic mice did not exhibit the severe pathology characteristic of TGF-β null mice, despite lifetime exposure to the antagonist. The data suggest that in vivo the antagonist may selectively neutralize the undesirable TGF-β associated with metastasis, while sparing the regulatory roles of TGF-βs in normal tissues. Thus this soluble TGF-β antagonist has potential for long-term clinical use in the prevention of metastasis.

Authors

Yu-an Yang, Oksana Dukhanina, Binwu Tang, Mizuko Mamura, John J. Letterio, Jennifer MacGregor, Sejal C. Patel, Shahram Khozin, Zi-yao Liu, Jeffrey Green, Miriam R. Anver, Glenn Merlino, Lalage M. Wakefield

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Matrix metalloproteinase-7 is expressed by pancreatic cancer precursors and regulates acinar-to-ductal metaplasia in exocrine pancreas
Howard C. Crawford, … , Lynn M. Matrisian, Steven D. Leach
Howard C. Crawford, … , Lynn M. Matrisian, Steven D. Leach
Published June 1, 2002
Citation Information: J Clin Invest. 2002;109(11):1437-1444. https://doi.org/10.1172/JCI15051.
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Matrix metalloproteinase-7 is expressed by pancreatic cancer precursors and regulates acinar-to-ductal metaplasia in exocrine pancreas

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Abstract

In gastrointestinal epithelium, metaplastic conversion between predominant cell types is associated with an increased risk of neoplasia. However, the mechanisms regulating metaplastic transitions in adult epithelia are largely undefined. Here we show that matrix metalloproteinase-7 (MMP-7) is expressed not only in the majority of human pancreatic ductal adenocarcinoma specimens, but also in human pancreatic intraepithelial neoplasia and metaplastic duct lesions in human and mouse. In a mouse model of pancreatic acinar-to-ductal metaplasia, MMP-7 progressively accumulates during the metaplastic transition, resulting in a concomitant increase in solubilization of Fas ligand (FasL). Under identical conditions, mice either deficient in MMP-7 or carrying an inactive FasL gene are severely inhibited in development of progressive metaplasia and acinar cell apoptosis. Thus, MMP-7 and FasL influence the initiation and maintenance of metaplastic events in pancreatic epithelium, explaining the observed link between metaplasia and apoptosis in pancreas and other gastrointestinal tissues.

Authors

Howard C. Crawford, Charles R. Scoggins, M. Kay Washington, Lynn M. Matrisian, Steven D. Leach

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A role for p53 in terminal epithelial cell differentiation
Zubaida Saifudeen, … , Susana Dipp, Samir S. El-Dahr
Zubaida Saifudeen, … , Susana Dipp, Samir S. El-Dahr
Published April 15, 2002
Citation Information: J Clin Invest. 2002;109(8):1021-1030. https://doi.org/10.1172/JCI13972.
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A role for p53 in terminal epithelial cell differentiation

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Abstract

Terminal epithelial cell differentiation is a crucial step in development. In the kidney, failure of terminal differentiation causes dysplasia, cystogenesis, and cancer. The present study provides multiple lines of evidence implicating the tumor suppressor protein p53 in terminal differentiation of the renal epithelium. In the developing kidney, p53 is highly enriched in epithelial cells expressing renal function genes (RFGs), such as receptors for vasoactive hormones, the sodium pump, and epithelial sodium and water channels. In comparison, proliferating renal progenitors express little if any p53 or RFGs. p53 binds to and transactivates the promoters of RFGs. In contrast, expression of a dominant negative mutant form of p53 inhibits endogenous RFG expression. Moreover, binding of endogenous p53 to the promoters of RFGs coincides with the differentiation process and is attenuated once renal epithelial cells are fully differentiated. Finally, p53-null pups exhibit a previously unrecognized aberrant renal phenotype and spatial disorganization of RFGs. Interestingly, the p53-related protein p73 is unable to functionally compensate for the loss of p53 and fails to efficiently activate RFG transcription. We conclude that p53 promotes the biochemical and morphological differentiation of the renal epithelium. Aberrations in p53-mediated terminal differentiation may therefore play a role in the pathogenesis of nephron dysgenesis and dysfunction.

Authors

Zubaida Saifudeen, Susana Dipp, Samir S. El-Dahr

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Regulation of herpes simplex virus γ134.5 expression and oncolysis of diffuse liver metastases by Myb34.5
Hideo Nakamura, … , Richard Y. Chung, Kenneth K. Tanabe
Hideo Nakamura, … , Richard Y. Chung, Kenneth K. Tanabe
Published April 1, 2002
Citation Information: J Clin Invest. 2002;109(7):871-882. https://doi.org/10.1172/JCI10623.
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Regulation of herpes simplex virus γ134.5 expression and oncolysis of diffuse liver metastases by Myb34.5

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Abstract

Myb34.5 is a herpes simplex virus 1 (HSV-1) mutant deleted in the gene for ribonucleotide reductase (ICP6). It also carries a version of γ134.5 (a viral gene product that promotes the dephosphorylation of eIF-2α) that is under control of the E2F-responsive cellular B-myb promoter, rather than of its endogenous promoter. Myb34.5 replication in tumor cells results in their destruction (oncolysis). γ134.5 expression by HSV-1 subverts an important cell defense mechanism against viral replication by preventing shutoff of protein synthesis after viral infection. Infection of colon carcinoma cells with Myb34.5 results in greater eIF-2α dephosphorylation and viral replication compared with infection with HSV-1 mutants completely defective in γ134.5 expression. In contrast, infection of normal hepatocytes with Myb34.5 results in low levels of eIF-2α dephosphorylation and viral replication that are similar to those observed with HSV-1 mutants completely defective in γ134.5 and ICP6. When administered intravascularly into mice with diffuse liver metastases, Myb34.5 has greater antineoplastic activity than HSV-1 mutants with completely defective γ134.5 expression and more restricted biodistribution compared with HSV-1 mutants with wild-type γ134.5 expression. Myb34.5 displays reduced virulence and toxicity compared to HSV-1 mutants with wild-type γ134.5 expression. Portal venous administration of Myb34.5 significantly reduces liver tumor burden in and prolongs the life of mice with diffuse liver metastases. Preexisting Ab’s to HSV-1 do not reduce the antitumor efficacy of Myb34.5 in vivo.

Authors

Hideo Nakamura, Hideki Kasuya, John T. Mullen, Sam S. Yoon, Timothy M. Pawlik, Soundararajalu Chandrasekhar, James M. Donahue, E. Antonio Chiocca, Richard Y. Chung, Kenneth K. Tanabe

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