Publications (9)54.26 Total impact
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Article: Pleiotrophin produced by multiple myeloma induces transdifferentiation of monocytes into vascular endothelial cells: a novel mechanism of tumor-induced vasculogenesis.
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ABSTRACT: Enhanced angiogenesis is a hallmark of cancer. Pleiotrophin (PTN) is an angiogenic factor that is produced by many different human cancers and stimulates tumor blood vessel formation when it is expressed in malignant cancer cells. Recent studies show that monocytes may give rise to vascular endothelium. In these studies, we show that PTN combined with macrophage colony-stimulating factor (M-CSF) induces expression of vascular endothelial cell (VEC) genes and proteins in human monocyte cell lines and monocytes from human peripheral blood (PB). Monocytes induce VEC gene expression and develop tube-like structures when they are exposed to serum or cultured with bone marrow (BM) from patients with multiple myeloma (MM) that express PTN, effects specifically blocked with antiPTN antibodies. When coinjected with human MM cells into severe combined immunodeficient (SCID) mice, green fluorescent protein (GFP)-marked human monocytes were found incorporated into tumor blood vessels and expressed human VEC protein markers and genes that were blocked by anti-PTN antibody. Our results suggest that vasculogenesis in human MM may develop from tumoral production of PTN, which orchestrates the transdifferentiation of monocytes into VECs.Blood 01/2009; 113(9):1992-2002. · 9.90 Impact Factor -
Article: Pleiotrophin, a multifunctional tumor promoter through induction of tumor angiogenesis, remodeling of the tumor microenvironment, and activation of stromal fibroblasts.
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ABSTRACT: Pleiotrophin (PTN, Ptn) is a widely expressed, developmentally regulated 136 amino acid secreted heparin-binding cytokine. It signals through a unique signaling pathway; the PTN receptor is the transmembrane receptor protein tyrosine phosphatase (RPTP)beta/zeta. RPTPbeta/zeta is inactivated by PTN, which leads to increased tyrosine phosphorylation of the downstream targets of the PTN/RPTPbeta/zeta signaling pathway. Pleiotrophin gene expression is found in cells in early differentiation during different developmental periods. It is upregulated in cells with an early differentiation phenotype in wound repair. The Ptn gene also is a proto-oncogene; PTN is expressed in human tumor cells, and, in cell lines derived from human tumors that express Ptn, Ptn expression is constitutive and thus "inappropriate". Importantly, properties of different cells induced by PTN in PTN-stimulated cells are strikingly similar to properties of highly malignant cells. Furthermore, transformed cells into which Ptn is introduced undergo "switches" to malignant cells of higher malignancy with properties that are strikingly similar to properties of PTN-stimulated cells. These unique features of PTN support the conclusion that constitutive PTN signaling in malignant cells that inappropriately express Ptn functions as a potent tumor promoter. Recently, in confirmation, Ptn targeted by the mouse mammary tumor virus (MMTV) promoter in a transgenic mouse model was found to promote breast cancers to a more aggressive breast cancer cell phenotype that morphologically closely resembles scirrhous carcinoma in human; in addition, it promoted a striking increase in tumor angiogenesis and a remarkable degree of remodeling of the micro-environment. Pleiotrophin thus regulates both different normal and pathological functions; collectively, the different studies have uncovered the unique ability of a single cytokine PTN, which signals through the unique PTN/RPTPbeta/zeta signaling pathway, to induce the many properties associated with tumor promotion in the malignant cells that constitutively express Ptn and in their microenvironment.Cell cycle (Georgetown, Tex.) 10/2007; 6(23):2877-83. · 5.36 Impact Factor -
Article: Anaplastic lymphoma kinase is activated through the pleiotrophin/receptor protein-tyrosine phosphatase beta/zeta signaling pathway: an alternative mechanism of receptor tyrosine kinase activation.
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ABSTRACT: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) first discovered as the constitutively active nucleophosmin-ALK oncoprotein in anaplastic large cell lymphomas (ALCL). Full-length ALK has a critical role in normal development and differentiation. Activated full-length ALK also is found in different malignant cancers. Nevertheless, the ligand to activate ALK remained unknown until recently, when ALK was proposed to be the physiological receptor of the cytokine pleiotrophin (PTN, Ptn). However, earlier studies had demonstrated that receptor protein tyrosine phosphatase (RPTP) beta/zeta is a physiological PTN receptor. We now demonstrate that phosphorylation of ALK in PTN-stimulated cells is mediated through the PTN/RPTPbeta/zeta signaling pathway. ALK is phosphorylated independently of a direct interaction of PTN with ALK. The data thus support a unique model of ALK activation. In cells not stimulated by PTN, RPTPbeta/zeta dephosphorylates ALK at the site(s) in ALK that is undergoing autophosphorylation through autoactivation. In contrast, when RPTPbeta/zeta is inactivated in PTN-stimulated cells, the sites that are autophosphorylated in ALK no longer can be dephosphorylated by RPTPbeta/zeta; thus, autoactivation and tyrosine phosphorylation of ALK rapidly increase. The data indicate that the PTN/RPTPbeta/zeta signaling pathway is a critical regulator of the steady state levels of tyrosine phosphorylation and activation of ALK; the data support the conclusion that ALK phosphorylation and activation in PTN-stimulated cells are increased through a unique "alternative mechanism of RTK activation."Journal of Biological Chemistry 10/2007; 282(39):28683-90. · 4.77 Impact Factor -
Article: Pleiotrophin is highly expressed by myeloma cells and promotes myeloma tumor growth.
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ABSTRACT: Pleiotrophin (PTN) is an important developmental cytokine that is highly expressed during embryogenesis but shows very limited expression in adult tissues, where it is largely restricted to the brain. High PTN serum levels are associated with a variety of solid tumors. We recently showed that patients with multiple myeloma (MM) also have elevated serum levels of this protein and the amount of PTN correlated with the patients' disease status and response to treatment. In this study, we demonstrate that MM cell lines and the malignant cells from MM patients' bone marrow produced PTN and secreted PTN protein into the supernatants during short-term culture. Moreover, Ptn gene expression correlated with the patients' disease status. Inhibition of PTN with a polyclonal anti-PTN antibody reduced growth and enhanced apoptosis of MM cell lines and freshly isolated bone marrow tumor cells from MM patients in vitro. Importantly, this antibody also markedly suppressed the growth of MM in vivo using a severe combined immunodeficiency (SCID)-hu murine model. This represents the first study showing the importance of PTN in the growth of any hematological disorder. Because the expression of this protein is very limited in normal adult tissues, PTN may represent a new target for the treatment of MM.Blood 08/2007; 110(1):287-95. · 9.90 Impact Factor -
Article: Secretion of pleiotrophin stimulates breast cancer progression through remodeling of the tumor microenvironment.
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ABSTRACT: Pleiotrophin (PTN, Ptn) is an 18-kDa secretory cytokine expressed in many breast cancers; however, the significance of Ptn expression in breast cancer has not been established. We have now tested three models to determine the role of inappropriate expression of Ptn in breast cancer. Mouse mammary tumor virus (MMTV) promoter-driven Ptn expressed in MMTV-polyoma virus middle T antigen (PyMT)-Ptn mouse breast cancers was first shown to induce rapid growth of morphologically identified foci of "scirrhous" carcinoma and to extensively remodel the microenvironment, including increased tumor angiogenesis and striking increases in mouse protocollagens Ialpha2, IValpha5, and XIalpha1, and elastin. Ectopic Ptn expression in MCF-7 (human breast cancer)-Ptn cell xenografts also was shown to markedly increase MCF-7-Ptn cell xenograft growth in nude mice; furthermore, it induced extensive remodeling of the microenvironment and tumor angiogenesis. In a coculture model of equal numbers of NIH 3T3 stromal fibroblasts and MCF-7-Ptn cells, PTN secreted from MCF-7-Ptn cells was then shown to induce a more malignant MCF-7-Ptn breast cancer cell phenotype and extensive remodeling of the MCF-7-Ptn/NIH 3T3 cell microenvironment; it up-regulated expression of markers of aggressive breast cancers, including PKCdelta and matrix metalloproteinase-9 in both MCF-7-Ptn and NIH 3T3 cells. The morphological phenotypes of MCF-7-Ptn cell xenografts and MCF-7-Ptn cell/NIH 3T3 cell cocultures closely resembled breast cancers in MMTV-PyMT-Ptn mice. Inappropriate expression of Ptn thus promotes breast cancer progression in mice; the data suggest that secretion of PTN through stimulation of the stromal cell microenvironment alone may be sufficient to account for significant features of breast cancer progression.Proceedings of the National Academy of Sciences 07/2007; 104(26):10888-93. · 9.68 Impact Factor -
Article: Dominant negative pleiotrophin induces tetraploidy and aneuploidy in U87MG human glioblastoma cells.
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ABSTRACT: Pleiotrophin (PTN, Ptn) is an 18kDa secretory cytokine that is expressed in many human cancers, including glioblastoma. In previous experiments, interruption of the constitutive PTN signaling in human U87MG glioblastoma cells that inappropriately express endogenous Ptn reversed their rapid growth in vitro and their malignant phenotype in vivo. To seek a mechanism for the effect of the dominant-negative PTN, flow cytometry was used to compare the profiles of U87MG cells and four clones of U87MG cells that express the dominant-negative PTN (U87MG/PTN1-40 cells); here, we report that the dominant-negative PTN in U87MG cells induces tetraploidy and aneuploidy and arrests the tetraploid and aneuploid cells in the G1 phase of the cell cycle. The data suggest that PTN signaling may have a critical role in chromosomal segregation and cell cycle progression; the data suggest induction of tetraploidy and aneuploidy in U87MG glioblastoma cells may be an important mechanism that contributes to the loss of the malignant phenotype of U87MG cells.Biochemical and Biophysical Research Communications 01/2007; 351(2):336-9. · 2.48 Impact Factor -
Article: A variant of estrogen receptor-{alpha}, hER-{alpha}36: transduction of estrogen- and antiestrogen-dependent membrane-initiated mitogenic signaling.
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ABSTRACT: The status of the 66-kDa human estrogen receptor-alpha (hER-alpha66) is a critical determinant in the assessment of the prognosis and in the design of treatment strategies of human breast cancer. Recently, we cloned the cDNA of an alternatively spliced variant of hER-alpha66, termed hER-alpha36; the predicted protein lacks both transcriptional activation domains of hER-alpha66 but retains its DNA-binding domain, partial dimerization, and ligand-binding domains and three potential myristoylation sites located near the N terminus. These findings thus predict that hER-alpha36 functions very differently from hER-alpha66 in response to estrogen signaling. We now demonstrate that hER-alpha36 inhibits the estrogen-dependent and estrogen-independent transactivation activities of hER-alpha66 and hER-beta. We further demonstrate that hER-alpha36 is predominantly associated with the plasma membrane where it transduces both estrogen- and antiestrogen-dependent activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway and stimulates cell growth. We conclude that hER-alpha36 is a predominantly membrane-based, unique alternatively spliced variant of hER-alpha66 that acts as a dominant-negative effector of both estrogen-dependent and estrogen-independent transactivation functions signaled through hER-alpha66 and ER-beta; it also transduces membrane-initiated estrogen-dependent activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase mitogenic signaling pathway. The estrogen and antiestrogen signaling pathways mediated by hER-alpha36 provide an alternative explanation for why some human breast cancers are resistant to and others are worsened by antiestrogen therapy; the data suggest that hER-alpha36 also may be an important marker to direct therapy in human breast cancers, and perhaps hER-alpha36 also may transduce estrogen-dependent signaling in other estrogen target tissues.Proceedings of the National Academy of Sciences 07/2006; 103(24):9063-8. · 9.68 Impact Factor -
Article: Identification, cloning, and expression of human estrogen receptor-alpha36, a novel variant of human estrogen receptor-alpha66.
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ABSTRACT: The identification and subsequent cloning of the 66-kDa human estrogen receptor (here termed hER-alpha66), its 46-kDa splice variant hER-alpha46, and the closely related hER-beta have had a profound impact on the generation of new understanding of estrogen-mediated functions and led to progress in diagnosis and treatment of human breast cancer. However, a persistent problem has been that not all findings previously reported in estrogen-stimulated cell proliferation can be explained through the known properties of the different estrogen receptors described. As the consequence of a search for alternative mechanisms to account for these different findings, we have now identified, cloned, and expressed in HEK 293 cells a previously unrecognized 36-kDa variant of hER-alpha66, termed hER-alpha36. hER-alpha36 differs from hER-alpha66 since it lacks both transcriptional activation domains (AF-1 and AF-2) but it retains the DNA-binding domain, and partial dimerization and ligand-binding domains of hER-alpha66. It also contains three myristoylation sites postulated to direct ER-alpha36 to the plasma membrane. It is concluded that ER-alpha36 is a unique variant of ER-alpha66; ER-alpha36 is predicted to function as a dominant-negative effector of hER-alpha66-mediated estrogen-responsive gene pathways and has the potential to trigger membrane-initiated mitogenic estrogen signaling.Biochemical and Biophysical Research Communications 12/2005; 336(4):1023-7. · 2.48 Impact Factor -
Article: Identification, cloning, and expression of human estrogen receptor-α36, a novel variant of human estrogen receptor-α66
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ABSTRACT: The identification and subsequent cloning of the 66-kDa human estrogen receptor (here termed hER-α66), its 46-kDa splice variant hER-α46, and the closely related hER-β have had a profound impact on the generation of new understanding of estrogen-mediated functions and led to progress in diagnosis and treatment of human breast cancer. However, a persistent problem has been that not all findings previously reported in estrogen-stimulated cell proliferation can be explained through the known properties of the different estrogen receptors described. As the consequence of a search for alternative mechanisms to account for these different findings, we have now identified, cloned, and expressed in HEK 293 cells a previously unrecognized 36-kDa variant of hER-α66, termed hER-α36. hER-α36 differs from hER-α66 since it lacks both transcriptional activation domains (AF-1 and AF-2) but it retains the DNA-binding domain, and partial dimerization and ligand-binding domains of hER-α66. It also contains three myristoylation sites postulated to direct ER-α36 to the plasma membrane. It is concluded that ER-α36 is a unique variant of ER-α66; ER-α36 is predicted to function as a dominant-negative effector of hER-α66-mediated estrogen-responsive gene pathways and has the potential to trigger membrane-initiated mitogenic estrogen signaling.Biochemical and Biophysical Research Communications.
Top co-authors
Top Journals
Institutions
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2006–2007
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The Scripps Research Institute
- Department of Molecular and Experimental Medicine
La Jolla, CA, USA
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2005–2006
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Creighton University
- Cancer Center
Omaha, NE, USA
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