Heparin-binding proteins HB-GAM (pleiotrophin) and amphoterin in the regulation of cell motility

Rauvala, Heikki; Huttunen, Henri J.; Fages, Carole; Kaksonen, Marko; Kinnunen, Tarja; Imai, Shunsuke; Raulo, Erkki; Kilpeläinen, Ilkka

doi:10.1016/s0945-053x(00)00084-6

Cited by 135 publications

(121 citation statements)

References 49 publications

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“…We have shown that PTN is chemotactic and mitogenic for microglial cells in vitro. Apart from promoting neurite outgrowth, the chemotactic effects of PTN and MK have been demonstrated in particular for osteoblasts/osteoblast precursor cells (Qi et al 2001;Rauvala et al 2000). Now we have shown that PTN is also chemotactic and weakly proliferative for microglial cells.…”

Section: Discussionsupporting

confidence: 57%

“…Mature PTN is a non-glycosylated, lysine-rich peptide that migrates anomalously as an 18-kDa band in sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) (therefore also termed p18; Corbley 1997) and is derived from a 168-residue precursor with a 32 amino acid signal sequence. PTN is mitogenic for various cell types, it promotes angiogenesis, stimulates neurite outgrowth from cultured neurones, and induces cell migration (Li et al 1990;Fang et al 1992;Delbe et al 1995;Souttou et al 1997Souttou et al , 2001Rauvala et al 2000). Together with midkine (MK) it forms a family of heparin-binding proteins that are normally expressed during embryogenesis, but rarely in healthy adult tissues (Iwasaki et al 1997).…”

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confidence: 99%

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Pleiotrophin, an angiogenic and mitogenic growth factor, is expressed in human gliomas

Mentlein

Held‐Feindt

2002

Journal of Neurochemistry

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Pleiotrophin (PTN) is a mitogenic/angiogenic, 15.3 kDa heparin-binding peptide that is found in embryonic or early postnatal, but rarely in adult, tissues. Since developmentally regulated factors often re-appear in malignant cells, we examined PTN expression in human glioma cell lines, cell cultures derived from solid gliomas and glioma sections. PTN mRNA or protein was detected by reverse transcriptasepolymerase chain reaction, immunohistochemistry, western blot or enzyme-linked immunoassay in all WHO III and IV grade gliomas and cells analyzed in vitro or in situ. One WHO II grade glioma investigated was PTN negative. In vitro, PTN was synthesized in perinuclear regions of glioma cells, secreted into the cultivation medium, but its production varied considerably between glioma cells cultivated from different solid gliomas or glioma cell lines. In situ, PTN expression was restricted to distinct parts/cells of the tumour. PTN did not influence the proliferation of glioma cells themselves, but stimulated [ 3 H]thymidine incorporation into DNA of microglial cells. Furthermore, in Boyden chamber assays, PTN showed a strong chemotactic effect on murine BV-2 microglial cells. PTN is supposed to be a paracrine growth/angiogenic factor that is produced by gliomas and contributes to their malignancy by targeting endothelial and microglial cells.

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Section: Discussionsupporting

confidence: 57%

mentioning

confidence: 99%

Pleiotrophin, an angiogenic and mitogenic growth factor, is expressed in human gliomas

Mentlein

Held‐Feindt

2002

Journal of Neurochemistry

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“…In metastatic cancer cells, migration-stimulating signaling by HA and secreted proteoglycans is supposed to occur in an autocrine, cell autonomous fashion (Kosaki et al, 1999;Rauvala et al, 2000). To study whether the effect of Has2 on lamellipodia formation in lateral cells during zebrafish gastrulation is cell autonomous or non-cell autonomous, has2 morphant cells labeled with membrane-localized GFP were transplanted into the lateral margin of wild-type recipients.…”

Section: Has2 and Rac1 Act In A Cell Autonomous Fashionmentioning

confidence: 99%

Has2 is required upstream of Rac1 to govern dorsal migration of lateral cells during zebrafish gastrulation

et al. 2004

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The large extracellular polysaccharide Hyaluronan (HA) and its synthesizing enzymes (Has) have been implicated in regulating the migratory potential of metastatic cancer cells. Here, we analyze the roles of zebrafish Has2 in normal development. Antisense morpholino oligonucleotide (MO)-mediated knockdown of zebrafish Has2 leads to the loss of HA, and severe migratory defects during gastrulation, somite morphogenesis and primordial germ cell migration. During gastrulation, ventrolateral cells of has2 morphant embryos fail to develop lamellipodia and to migrate dorsally, resulting in a blockage of dorsal convergence, whereas extension of the dorsal axis is normal. The effect is cell autonomous, suggesting that HA acts as an autocrine signal to stimulate the migration of HA-generating cells. Upon ectopic expression in axial cells, has2 causes the formation of supernumerary lamellipodia and a blockage of axis extension. Epistasis analyses with constitutively active and dominant-negative versions of the small GTPase Rac1 suggest that HA acts by Rac1 activation, rather than as an essential structural component of the extracellular matrix. Together, our data provide evidence that convergence and extension are separate morphogenetic movements of gastrulation. In addition, they suggest that the same HA pathways are active to auto-stimulate cell migration during tumor invasion and vertebrate embryogenesis.

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“…The MK family consists of only two members, namely MK and pleiotrophin (PTN; also called HB-GAM), and is distinct from other heparin-binding growth factor families (Kurtz et al, 1995;Rauvala et al, 2000;Deuel et al, 2002;Muramatsu, 2002). Regarding the biological roles of MK, at least three important issues should be pointed out.…”

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confidence: 99%

Correlation of elevated level of blood midkine with poor prognostic factors of human neuroblastomas

et al. 2003

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The heparin-binding growth factor midkine (MK) is the product of a retinoic acid-responsive gene, and is implicated in neuronal survival and differentiation, and carcinogenesis. We previously reported that MK mRNA expression is elevated in neuroblastoma specimens at all stages, whereas pleiotrophin, the other member of the MK family, is expressed at high levels in favourable neuroblastomas. As MK is a secretory protein, it can be detected in the blood. Here, we show a significant correlation of the plasma MK level with prognostic factors of neuroblastomas. The plasma MK level was determined in 220 patients with neuroblastomas, and compared with that in children without malignant tumors (n ¼ 17, o500 pg ml À1 ). The plasma MK level became significantly elevated with advancing stages (stage 1: 445 pg ml À1 (median), n ¼ 73; stage 2: 589, n ¼ 39; stage 3: 864, n ¼ 40; stage 4: 1445, n ¼ 56; and stage 4S: 2439, n ¼ 12). More importantly, a higher MK level was strongly correlated with poor prognostic factors: over 1 year of age (P ¼ 0.0299), MYCN amplification (Po0.0001), low TrkA expression (P ¼ 0.0005), nonmass screening, sporadic neuroblastomas (Po0.0001), and diploidy/tetraploidy (P ¼ 0.0007). Thus, these results demonstrate that the plasma MK level is a good marker for evaluating the progression of neuroblastomas. Moreover, considering the ability of antisense MK oligodeoxyribonucleotide to suppress tumour growth of colorectal carcinoma cells in nude mice, as recently reported, the present study suggests that MK is a possible candidate molecular target for therapy for neuroblastomas.

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Heparin-binding proteins HB-GAM (pleiotrophin) and amphoterin in the regulation of cell motility

Cited by 135 publications

References 49 publications

Pleiotrophin, an angiogenic and mitogenic growth factor, is expressed in human gliomas

Pleiotrophin, an angiogenic and mitogenic growth factor, is expressed in human gliomas

Has2 is required upstream of Rac1 to govern dorsal migration of lateral cells during zebrafish gastrulation

Correlation of elevated level of blood midkine with poor prognostic factors of human neuroblastomas

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