Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously we reported the purification of the heparin-binding growth factor pleiotrophin (PTN) from supernatants of the human breast cancer cell line MDA-MB-231. To investigate further the biological activities of PTN and its potential role in cancer, we cloned a PTN cDNA and expressed the gene in a human kidney and in a human adrenal carcinoma cell line (SW-13). The supernatants harvested from cells transfected with PTN contained a heparin-binding specific protein of an apparent molecular mass of 18 kDa. These supernatants stimulated the proliferation of endothelial cells as well as the anchorage-independent growth of SW-13 cells and of normal rat kidney fibroblasts. Furthermore, SW-13 cells transfected with PTN acquired autonomous growth in soft agar and were tumorigenic in athymic nude mice. In contrast to these results with PTN from human cells, PTN obtained from insect cells (Sf9) using recombinant baculovirus as a vector was biologically inactive. We detected high levels of PTN mRNA in 16 of 27 primary human breast cancer samples (62%) as well as in 8 of 8 carcinogen-induced rat mammary tumors. Furthermore, 9 of 34 human tumor cell lines of different origin showed detectable PTN mRNA. We conclude that PTN may function as a tumor growth and angiogenesis factor in addition to its role during embryonic development.
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PMID:Pleiotrophin stimulates fibroblasts and endothelial and epithelial cells and is expressed in human cancer. 146 2

We report purification of an 18-kDa heparin-binding growth factor secreted from human cancer cells which is homologous to a developmentally regulated, neurotrophic factor, heparin-binding growth-associated molecule/pleiotrophin (HB-GAM/PTN; Merenmies, J., and Rauvala, H. (1990) J. Biol. Chem. 265, 16721-16724; Li, Y. S., Milner, P. G., Chauhan, A. K., Watson, M. A., Hoffman, R. M., Kodner, C. M., Milbrandt, J., and Deuel, T. F. (1990) Science 250, 1690-1694). We have purified the protein from tissue culture supernatants of human breast cancer cells (MDA-MB 231) and have used soft agar cloning of an epithelial cell line (SW-13) to detect its growth stimulating activity. A 32,000-fold purification was achieved by isoelectric focusing, heparin affinity chromatography, and reversed phase high pressure liquid chromatography. The molecular mass of the protein was confirmed by gel filtration chromatography in the presence of detergent and bioassay of the fractions. The N-terminal sequence was homologous to HB-GAM/PTN, and polymerase chain reaction amplification and DNA sequencing confirmed that the respective transcript was present in the cancer cells. We conclude that HB-GAM/PTN can function as a tumor growth factor in addition to its role during neuronal development.
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PMID:A heparin-binding growth factor secreted from breast cancer cells homologous to a developmentally regulated cytokine. 173 56

We propose that the secreted protein pleiotrophin (PTN) is a major factor in the malignant progression of breast cancer. This hypothesis is based on the growth-stimulatory effects of PTN on cells in vitro and in vivo and on its high levels of expression in 60% of tumor samples from breast cancer patients. The stimulation of proliferation and tube formation of endothelial cells by PTN suggests that it can serve as an angiogenesis factor during tumor growth. We hypothesize that PTN has the potential to support growth of breast cancer at its primary site and to enhance the ability of tumor cells to metastasize. Furthermore, we suggest that specific endocrine signals interact to regulate the expression of PTN in vitro and in vivo. Finally, we propose that understanding the functions of PTN and its hormonal regulation can lead to the development of novel therapeutic strategies for breast cancer.
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PMID:The potential role of the heparin-binding growth factor pleiotrophin in breast cancer. 753 62

The growth and metastasis of solid tumors rely on the activities of polypeptide growth factors. However, numerous growth factors are expressed in tumors, and it is difficult to decipher which are essential for tumor progression. We found the secreted growth factor pleiotrophin (PTN) expressed at high levels in a number of human tumor cell lines as well as in tumor samples. To assess the role of PTN in tumor growth, we inactivated the PTN gene with PTN-targeted hammerhead ribozyme constructs. Cotransfection of PTN and of the ribozymes inhibited PTN-induced colony formation of PTN-responsive cells whereas a point mutant, catalytically inactive ribozyme was ineffective. Colony formation induced by transfections with a closely related growth factor (midkine) was not affected by the ribozymes. In human melanoma cells that express high levels of PTN mRNA, stable transfection with PTN-targeted ribozymes quenched production of PTN, inhibited colony formation of the cells, and prevented their tumor growth in mice. This demonstrates that expression of a growth factor can be a rate-limiting step for malignant progression and suggests that ribozymes could be used therapeutically to target tumor growth factors.
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PMID:Ribozyme-targeting elucidates a direct role of pleiotrophin in tumor growth. 806 62

Polypeptide growth factors contribute to the development and maintenance of normal tissues and are essential for the growth and metastasis of solid tumors. During tumor progression these factors function as autocrine stimulators of tumor cells and/or serve to recruit stromal tissue and blood supply to the expanding tumor. In particular, tumor-induced angiogenesis appears to be significant not only for local tumor growth but also for metastasis to distant organ sites. We purified several years ago the heparin-binding growth factor pleiotrophin (PTN) from the supernatants of human breast cancer cells and demonstrated that PTN can serve as an angiogenesis factor. We found the gene expressed in a number of human tumor cell lines as well as in human tumor tissues. Here we present different approaches to inhibit production and function of this growth factor. Finally we discuss how the experience from this growth factor can be applied to improve our understanding of the role of other factors thought to contribute to tumor angiogenesis.
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PMID:Molecular and pharmacologic targeting of angiogenesis factors--the example of pleiotrophin. 853 64

Clinical and experimental evidence suggests that spreading of malignant cells from a localized tumor (metastasis) is directly related to the number of microvessels in the primary tumor. This tumor angiogenesis is thought to be mediated by tumor-cell-derived growth factors. However, most tumor cells express a multitude of candidate angiogenesis factors and it is difficult to decipher which of these are rate-limiting factors in vivo. Herein we use ribozyme targeting of pleiotrophin (PTN) in metastatic human melanoma cells to assess the significance of this secreted growth factor for angiogenesis and metastasis. As a model we used human melanoma cells (1205LU) that express high levels of PTN and metastasize from subcutaneous tumors to the lungs of experimental animals. In these melanoma cells, we reduced PTN mRNA and growth factor activity by transfection with PTN-targeted ribozymes and generated cell lines expressing different levels of PTN. We found that the reduction of PTN does not affect growth of the melanoma cells in vitro. In nude mice, however, tumor growth and angiogenesis were decreased in parallel with the reduced PTN levels and apoptosis in the tumors was increased. Concomitantly, the metastatic spread of the tumors from the subcutaneous site to the lungs was prevented. These studies support a direct link between tumor angiogenesis and metastasis through a secreted growth factor and identify PTN as a candidate factor that may be rate-limiting for human melanoma metastasis.
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PMID:Melanoma angiogenesis and metastasis modulated by ribozyme targeting of the secreted growth factor pleiotrophin. 896 27

Recent analysis of bladder tumors has correlated expression of the neurokine midkine (MK) with poor patient survival. To examine a role for MK and the related pleiotrophin (PTN) in tumorigenesis, they were overexpressed in MCF-7 breast carcinoma cells. Expression had no effect on in vitro growth but conferred a growth advantage in vivo. Enhanced tumor growth correlated with increased vascular density and endothelial proliferation, implicating an angiogenic role for MK and PTN. Angiogenic activity of MK and PTN was confirmed in the rabbit corneal assay. Our data therefore identify two novel targets for antiangiogenic drug development.
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PMID:An angiogenic role for the neurokines midkine and pleiotrophin in tumorigenesis. 913 27

Pleiotrophin (PTN) is a developmentally regulated protein which exhibits neurite-outgrowth, mitogenic, and angiogenic properties. It has also been shown to be involved in tumor growth and metastasis. Here we used primary BEL (bovine epithelial lens) cells to investigate the signal transduction pathways involved in the mitogenic activity of recombinant PTN. PTN was purified from conditioned media of SW-13 cells transfected with the human PTN cDNA. We show that inhibitors of tyrosine kinase, mitogen-activated protein kinase, or phosphoinositide (PI) 3-kinase inhibit DNA synthesis stimulated by PTN. Analysis of tyrosine-phosphorylated proteins following PTN stimulation showed phosphorylation of two novel 190- and 215-kDa proteins in addition to SHC, ERK1, and ERK2. A mobility shift of phosphorylated ERK1 and ERK2 was detected with a panERK antibody confirming the phosphorylation of the two ERKs. Furthermore, in vitro immunocomplex kinase assay with Akt1, a natural substrate of PI 3-kinase, showed an activation of the kinase following PTN stimulation and a reversal by the PI 3-kinase inhibitor wortmannin. We conclude that the mitogenic activity of PTN is dependent on tyrosine kinase activation and utilizes the mitogen-activated protein kinase and the PI 3-kinase pathways to transduce a mitogenic signal.
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PMID:Signal transduction pathways involved in the mitogenic activity of pleiotrophin. Implication of mitogen-activated protein kinase and phosphoinositide 3-kinase pathways. 923 65

The heparin-binding polypeptide homologs pleiotrophin and midkine are the only known members of a family of secreted growth/differentiation cytokines. Pleiotrophin and midkine are both developmentally regulated and highly conserved among species. They signal a number of physiological functions involved with angiogenesis, neuorogenesis, cell migration, and mesoderm-epithelial interactions. Constitutive expression of pleiotrophin and midkine in responsive cells support their role as "tumor growth factors" and positive regulators of tumor angiogenesis. Widespread deregulation of pleiotrophin and midkine is found in many known human cancers or their derived cell lines, and the molecular targeting of pleiotrophin to block its signaling in tumor cells has limited tumor growth and metastasis in animal models. Elucidating the molecular mechanisms of pleiotrophin and midkine action in tumorgenesis and tumor angiogenesis may lead to the identification of novel targets for tumor therapy.
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PMID:Pleiotrophin and midkine, a family of mitogenic and angiogenic heparin-binding growth and differentiation factors. 991 53

Using HER-2- and pleiotrophin-targeting ribozymes we demonstrated that ribozymes can be used to identify molecules which are highly relevant for tumor growth. Furthermore, ribozymes may be a useful new tool for a highly specific and efficient adjuvant therapy.
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PMID:[Ribozyme targeting as gene therapy method for treatment of malignant tumors]. 993 16


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