PDGF autocrine stimulation dedifferentiates cultured = astrocytes and induces oligodendrogliomas and oligoastrocytomas from = neural progenitors and astrocytes in vivo

We present evidence = that some=20 low-grade oligodendrogliomas may be comprised of proliferating = glial=20 progenitor cells that are blocked in their ability to = differentiate,=20 whereas malignant gliomas have additionally acquired other = mutations such=20 as disruption of cell cycle arrest pathways by loss of = Ink4a=E2=80=93Arf.=20 We have modeled these effects in cell culture and in mice by = generating=20 autocrine stimulation of glia through the platelet-derived growth = factor=20 receptor (PDGFR). In cell culture, PDGF signaling induces = proliferation of=20 glial precursors and blocks their differentiation into = oligodendrocytes=20 and astrocytes. In addition, coexpression of PDGF and PDGF = receptors has=20 been demonstrated in human gliomas, implying that autocrine = stimulation=20 may be involved in glioma formation. In this study, using somatic = cell=20 type-specific gene transfer we investigated the functions of PDGF=20 autocrine signaling in gliomagenesis by transferring the = overexpression of=20 PDGF-B into either nestin-expressing neural progenitors or glial=20 fibrillary acidic protein (GFAP)-expressing astrocytes both in = cell=20 culture and in vivo. In cultured astrocytes, overexpression of = PDGF-B=20 caused significant increase in proliferation rate of both = astrocytes and=20 neural progenitors. Furthermore, PDGF gene transfer converted = cultured=20 astrocytes into cells with morphologic and gene expression = characteristics=20 of glial precursors. In vivo, gene transfer of PDGF to neural = progenitors=20 induced the formation of oligodendrogliomas in about 60% of mice = by 12 wk=20 of age; PDGF transfer to astrocytes induced the formation of = either=20 oligodendrogliomas or mixed oligoastrocytomas in about 40% of mice = in the=20 same time period. Loss of Ink4a=E2=80=93Arf, a mutation = frequently found=20 in high-grade human gliomas, resulted in shortened latency and = enhanced=20 malignancy of gliomas. The highest percentage of PDGF-induced = malignant=20 gliomas arose from of Ink4a=E2=80=93Arf null progenitor = cells. These data=20 suggest that chronic autocrine PDGF signaling can promote a = proliferating=20 population of glial precursors and is potentially sufficient to = induce=20 gliomagenesis. Loss of Ink4a=E2=80=93Arf is not required = for PDGF-induced=20 glioma formation but promotes tumor progression toward a more = malignant=20 phenotype.

Keywords: PDGF, oligodendroglioma, INK4a=E2=80=93ARF, glial = differentiation

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Abstract

Results

Discussion

Materials=20 and methods

References

Neuroglial tumors = (gliomas), including=20 astrocytomas, oligodendrogliomas, oligoastrocytomas, and = glioblastoma,=20 comprise over half of all primary brain tumors. Gliomas are = classified=20 into four clinical grades, and the most malignant is referred to = as=20 glioblastoma (GBM). A number of common mutations have been = identified in=20 human gliomas that disrupt the cell cycle arrest pathways leading = to p53=20 and pRb (Louis and Cavenee 1997), the most common of these = mutations=20 in high-grade gliomas is the loss of Ink4a=E2=80=93Arf = (Ichimura et al. 1996). In addition, gliomas = frequently have=20 other mutations and gene expression alterations that lead to = constitutive=20 activation of receptor tyrosine kinase signaling pathways, such as = epidermal growth factor receptor (EGFR; Wong et al. 1987, 1992), platelet-derived growth factor receptor = (PDGFR; Nister et al. 1988; Hermanson et al. 1992, 1996), fibroblast growth factor receptor (FGFR; Yamaguchi et al. 1994), and insulin-like growth = factor=20 receptor (IGFR; Sara et al. 1986; Trojan et al. 1992). How alterations in these two = processes=20 function in human gliomagenesis remains unclear. However, animal = modeling=20 of these alterations in mice is beginning to identify causal = relationships=20 between these genetic alterations and the formation of gliomas (Holland 2001).

The PDGF receptor has two isoforms = (=CE=B1 and =CE=B2) and=20 belongs to the receptor tyrosine kinase family (Claesson-Welsh et al. 1989). Upon binding PDGF, = these=20 receptors activate a number of downstream signal transduction = pathways,=20 including PI3 kinase/AKT, RAS/MAP kinases, and PLC/PKC pathways = (de Vries-Smits et al. 1992; Franke et al. 1995; Moriya et al. 1996). Accumulated evidence has = suggested that=20 PDGF signaling may play an important role in both normal = development and=20 tumorigenesis of the central nervous system (CNS). In cell = culture, PDGF=20 functions to block differentiation and promote proliferation of = the O2A=20 glial progenitor that gives rise to either oligodendrocytes or = type-2=20 astrocytes (Raff et al. 1983; Noble et al. 1988; Richardson et al. 1988). Although it is known that = PDGFR,=20 especially the =CE=B1 isoform, is expressed at high levels in = glial=20 progenitors, mature astrocytes also express low levels of PDGFR = (Hutchkins 1995; Fruttinger et al. 1996). PDGF and PDGF receptors = are=20 frequently coexpressed in human glioma cell lines as well as = gliomas=20 including oligodendrogliomas (Nister et al. 1988; Di Rocco et al. 1998; Robinson et al. 2001), and amplification of = PDGFR=CE=B1 is found=20 in some high-grade oligodendrogliomas (Shoshan et al. 1999; Smith et al. 2000), suggesting the possible = existence of an=20 autocrine loop comprising of PDGF and its receptors (Guha et al. 1995). Recently, PDGF-B chain, encoded = in a=20 replication competent retroviral vector system, was shown to = induce=20 primary brain tumors in mice with multiple histopathological = appearances=20 (Uhrbom et al. 1998). These data indicate that = abnormal PDGF=20 signaling can contribute to the etiology of brain tumors, but = whether=20 additional mutations are required for gliomagenesis in this system = is not=20 known. The variable histology seen in the above experiment may be = due to=20 the variety of cell types infected by this vector system. = Dissecting the=20 correlation between the histology of PDGF-induced tumors and their = cell of=20 origin requires cell type-specific gene transfer.

We have achieved cell type-specific = gene transfer=20 of PDGF using the replication competent ALV splice acceptor = (RCAS)/tv-a=20 system (Holland and Varmus 1998; Holland et al. 1998a,b). This system consists of the avian leukosis = virus=20 (ALV)-based RCAS viral vectors and transgenic mice that express = the RCAS=20 receptor TVA from cell type-specific promoters. One mouse line = (Gtv-a)=20 expresses the TVA receptor from the astrocyte-specific glial = fibrillary=20 acidic protein (GFAP) promoter; a second mouse line (Ntv-a) = expresses the=20 TVA from the nestin promoter, as nestin is expressed in the CNS = progenitor=20 cells. Comparing the effects of gene transfer to Gtv-a and Ntv-a = mice=20 enables us to determine the influence of differentiation status on = the=20 ability of a cell to respond to a genetic stimulus. For example, = the=20 combined gene transfer of active forms of K-RAS and AKT induces = GBM=20 formation from Ntv-a mice but not Gtv-a mice (Holland et al. 2000a), implying that neural = progenitors are=20 more sensitive to the oncogenic effects of these particular = signaling=20 pathways than differentiated astrocytes.

In this study, we used an = RCAS vector=20 that encodes PDGF-B chain to infect Gtv-a and Ntv-a cells both in = cell=20 culture and in vivo. In culture, infection with this RCAS vector = caused a=20 significant increase in the proliferation rate of both = GFAP-expressing=20 astrocytes and nestin-expressing neural progenitors. Additionally, = the=20 dramatic changes in morphology and in the expression pattern of = cellular=20 differentiation markers are reversibly induced by overexpressing = PDGF.=20 These data indicate that signaling from this receptor appears to = induce a=20 conversion from differentiated astrocytes to glial precursor-like = cells.=20 In vivo, gene transfer of PDGF-B alone induced oligodendroglioma = and=20 oligoastrocytoma formation from nestin-expressing neural = progenitors and=20 GFAP-expressing astrocytes, respectively. Experimental loss of=20 Ink4a=E2=80=93Arf was not required for PDGF-induced = glioma formation;=20 however, this additional mutation did result in shortened tumor = latency=20 and enhanced tumor malignancy. The highest percentage of malignant = gliomas=20 arose from the combination of neural progenitor origin and loss of = Ink4a=E2=80=93Arf.

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Abstract

Discussion

Materials=20 and methods

References

Results

Construction of RCAS 3D"

vectors

An RCAS vector = containing a=20 bicistronic recombinant construct was generated by connecting the=20 PDGF-B/c-sis and eGFP (green fluorescence protein) coding = sequences=20 together with an internal ribosome entry site (IRES), which = results in=20 expression of both gene products and allows detection of infection = of=20 cells. This vector is referred to as RCAS=E2=80=93PBIG=20 (RCAS=E2=80=93PDGF-B=E2=80=93IRES=E2=80=93EGFP). A second RCAS = vector was also constructed that=20 contains only the PDGF-B sequence and is referred to as = RCAS=E2=80=93PB=20 (RCAS=E2=80=93PDGF-B). The vectors, along with an RCAS vector = carrying the gene=20 encoding =CE=B2-galactosidase (lacZ) (gift of Yi Li, = Memorial=20 Sloan-Kettering Cancer Center, New York, NY) and another RCAS = vector=20 carrying polyoma virus middle T antigen (MTA) (Holland et al. 2000b), were propagated in the = chicken=20 fibroblast cell line DF-1.

PDGF-B overexpression promotes=20 proliferation of both GFAP-expressing astrocytes and = nestin-expressing CNS=20 progenitors in cell 3D"

culture

To test the mitogenic = functions of=20 PDGF-B in specific cell types, we infected primary brain cell = cultures=20 from both Gtv-a (astrocytes) and Ntv-a (glial progenitors) = transgenic mice=20 with RCAS=E2=80=93PB, RCAS=E2=80=93PBIG, and = RCAS=E2=80=93lacZ vectors=20 respectively. After infection, these cells were passaged in = culture for 40=20 d and their proliferative capacity was measured by growth curves = (Holland et al. 1998b). Infection of either Gtv-a = (Fig. 1A)=20 or Ntv-a cell cultures (data not shown) with PDGF-encoding viruses = resulted in a substantial increase in the growth rate of these = cells=20 relative to infection with the control LacZ-encoding vector. A = similar=20 growth rate was seen for both RCAS=E2=80=93PBIG and = RCAS=E2=80=93PB=20 indicating that the expression of GFP did not affect the growth = potential=20 of these cells. Cells infected with RCAS=E2=80=93PBIG = were visualized by=20 green fluorescence secondary to the expression of eGFP (Fig. 1B).=20

Figure=20 1

Dedifferentiation=20 of cultured astrocytes to glial progenitors caused by = overexpression=20 of PDGF-B chain. (A) The proliferation rate of = primary=20 astrocytes (from Gtv-a mouse) was significantly increased by = overexpression of PDGF-B. The details of generating=20 (more ...)

PDGF/PDGFR autocrine loop = stimulation=20 dedifferentiates GFAP-expressing astrocytes to glial = precursor-like cells=20 in 3D"

culture

In addition to the enhanced = proliferative capacity induced by PDGF signaling, PDGF also = induced=20 morphological and gene expression characteristics of = undifferentiated=20 cells. These changes were most striking in the astrocytes from = Gtv-a mice.=20 After 40 d in culture, the control = RCAS=E2=80=93lacZ-infected Gtv-a cells=20 showed a large, flat morphology expected for cultured astrocytes. = In=20 contrast, both RCAS=E2=80=93PB and = RCAS=E2=80=93PBIG infected Gtv-a=20 cells showed a small, elongated, bipolar or simple multipolar = morphology,=20 characteristics of glial progenitor cells (Fig. 1B).

Western blot and = immunocytochemical=20 analyses showed gene expression patterns similar to that of glial=20 precursors (Fig. 1C).=20 Expression of myelin proteolipid protein (PLP) (Asakura et al. 1998; Spassky et al. 1998), PDGFR=CE=B1 (Hart et al. 1989; Hall et al. 1996) and =CE=B2, A2B5 (Williams et al. 1985; Dubois-Dalcq 1987; data not shown), all known as = markers for=20 glial progenitors, were up-regulated in cells infected with = PDGF-encoding=20 vectors. Moreover, these cells also showed elevated expression of = Id4, an=20 HLH gene whose expression is shown to correlate inversely with=20 differentiation status of oligodendrocyte precursors (Andres-Barquin et al. 1999; Kondo and Raff 2000; Nogueira et al. 2000). By contrast, these cells = did not=20 express O4 antigen, which is expressed in premature and mature=20 oligodendrocytes (Sommer and Schachner 1981), implying that they are = not=20 differentiating to oligodendrocytes. Of note, NG2, which is = expressed in=20 bipotential O2A progenitors (Stallcup and Beasley 1987), was not expressed in = these=20 cells, nor was the expression of neuronal markers such as = neurofilament=20 (NF) or synaptophysin (data not shown). Therefore, the expression = pattern=20 of cellular markers, along with the morphology and the = proliferation=20 capacity, suggest an early glial precursor stage for these cells, = similar=20 but not identical to the well-known O-2A progenitors (Raff et al. 1983). The potential for autocrine = loop=20 stimulation of PDGF and PDGFR is demonstrated by the elevated = expression=20 of both PDGFR=CE=B1 and =CE=B2 compared with the = RCAS=E2=80=93lacZ-infected=20 cells.

Blocking PDGF autocrine = signaling=20 reverses the PDGF-induced phenotype in 3D"

vitro

The PDGF-induced = alterations=20 described above could either be direct effects of elevated PDGF = signaling=20 or a result of selection for growth advantage in culture. To = address this=20 issue, we treated long-term cultured PDGF-transformed astrocytes = (from=20 Gtv-a mice) with a tyrosine kinase inhibitor (PTK787/ZK222584) (Wood et al. 2000) that blocks the activation of = PDGF=20 receptors. At 1 3D"

=CE=BCM drug concentration, the proliferation rate of = the=20 PDGF-expressing cells was dramatically inhibited (Fig. 2A,B)=20 and the progenitor-like morphology reverted back to a large, flat, = astrocyte-like morphology (Fig. 2C).=20 Western blot analyses of RCAS=E2=80=93PBIG-infected = astrocytes showed=20 that the expression levels of PLP and Id4 were down-regulated by = treatment=20 with PTK787 implying a direct effect of PDGF signaling in control = of these=20 genes. In contrast, the elevated PDGFR=CE=B1 and PDGFR=CE=B2 = levels seen in the PDGF=20 overexpressing astrocytes were not reduced by PTK787, suggesting = that the=20 elevated expression of PDGFRs may be due to selection during = extended=20 culture for cells with high level of PDGFR expression that can = maximally=20 respond to overexpression of PDGF. The expression level of eGFP = pre- and=20 post-drug treatment was similar, indicating that the effects of = PTK787=20 were not due to decreased expression of virally encoded PDGF-B = (Fig. 2D).=20 We demonstrated that this effect of PTK787 was not a general = property of=20 this drug by its effect on astrocytes infected with an RCAS vector = carrying the coding sequence for polyoma middle T antigen=20 (RCAS=E2=80=93MTA). MTA expression can activate similar = signal=20 transduction pathways as PDGF and infection with = RCAS=E2=80=93MTA causes=20 increased proliferation rate of astrocytes in cell culture and = induces=20 oligoastrocytomas from astrocytes in vivo (Holland et al. 2000b). At the same concentration = of PTK787=20 that reversed the phenotype of RCAS=E2=80=93PBIG-infected = cells, there=20 was no effect on the proliferation capacity or morphology of=20 RCAS=E2=80=93MTA-infected cells, implying specificity of = the PTK787=20 effect for signaling through PDGFR in these glial cells.

Figure=20 2

Reversion = of=20 PDGF-induced phenotypic effects by blocking PDGF receptor = kinase.=20 Astrocytes (1 3D"

=C3=97

10⁵) were plated and grown in culture = either=20 with or without 1 =CE=BCM PTK787 that inhibits the PDGF = receptor kinase.=20 The cells were=20 (more ...)

Gene transfer of PDGF-B into=20 nestin-expressing neural progenitors induces oligodendroglioma = formation=20 in 3D"

mice

To investigate the effect = of PDGF=20 autocrine loop stimulation on these same cell types in vivo, we = infected=20 Ntv-a and Gtv-a transgenic mice with RCAS=E2=80=93PBIG by = a single=20 intracranial injection of about 10⁴ DF-1 cells = producing this=20 vector. All the mice were sacrificed at the end of week 12, or = earlier if=20 they showed signs or symptoms of intracranial disease such as = macrocephaly=20 or lethargy. The brains were fixed and sections were analyzed by = standard=20 hemotoxylin and eosin (H&E) staining. Previous experiments = have=20 demonstrated that gene transfer of the marker gene alkaline = phosphatase,=20 activated Ras, or activated Akt alone to either of these mouse = lines by=20 this procedure does not induce tumors or histologic abnormalities = (Holland and Varmus 1998; Holland et al. 2000a).

Initially, we directly infected a = total of 34=20 newborn Ntv-a transgenic mice. Over 60% of this population of mice = harbored gliomas. Histologically, these tumors were diffusely = infiltrating=20 neoplasms composed of small tumor cells with monotonous, regular = round=20 nuclei surrounded by cleared cytoplasm (=E2=80=9Cperinuclear = halos=E2=80=9D) (Fig. 3B).=20 These morphologic features are identical to those seen in human=20 oligodendrogliomas. The tumors did not express neuronal = differentiation=20 markers, such as NeuN and synaptophysin, as demonstrated by=20 immunohistochemistry (data not shown). Further, also similar to = human=20 oligodendrogliomas, except for scattered entrapped reactive = astrocytes the=20 majority of tumor cells were immunonegative for GFAP, suggesting = the=20 absence of astrocytic differentiation (Fig. 3C).=20 In addition to the morphologic and immunohistochemical similarity = of the=20 individual tumor cells to human oligodendrogliomas, the = infiltrative=20 behavior and interactions with normal host cellular constituents = also=20 closely resembled that seen in human gliomas. The murine gliomas = displayed=20 all of the classical morphologic formations seen in infiltrating = human=20 oligodendrogliomas referred to as secondary structures of Scherer (1938); including intrafascicular queuing = in white=20 matter tracts of the corpus callosum and subpial infiltration,=20 perivascular satellitosis, and perineuronal satellitosis in areas = of=20 cortical invasion (Fig. 4).=20 The expression of exogenous PDGF in these tumors was verified by = positive=20 immunostaining for eGFP expression (data not shown).

Figure=20 3

Histologic analysis=20 of oligodendrogliomas induced from neural progenitors. = PDGF-induced=20 gliomas in Ntv-a mice with either = Ink4a=E2=80=93Arf^+/+=20 (A=E2=80=93C) or = Ink4a=E2=80=93Arf^{=E2=88=92/=E2=88=92} = (D=E2=80=93F)=20 genetic backgrounds. (A=20 (more ...)

Figure=20 4

Invasion = of normal=20 brain structures by mouse glioma cells. Similar to what is = seen in=20 human gliomas, these mouse tumors migrate along the white = matter=20 tracts (A), and surround neurons (B), and = collect=20 adjacent to the pial surface of the brain and blood=20 (more ...)

In the experiment reported = here, both=20 low- and high-grade tumors arose from PDGF gene transfer in vivo. = The=20 high-grade oligodendrogliomas, called anaplastic = oligodendrogliomas in the=20 current World Health Organization Classification of Tumours (WHO 2000), were characterized by dense cellularity = without=20 intervening neuropil, easily identifiable mitotic figures, = cellular and=20 nuclear pleomorphism and microvascular proliferation (Fig. 3D=E2=80=93F).=20 These anaplastic oligodendrogliomas frequently were additionally=20 characterized by the presence of foci of tumor necrosis with = surrounding=20 tumor cell pseudopalisading (Fig. 3F).=20 The majority of the PDGF-induced gliomas, arising in either Gtv-a = or Ntv-a=20 mice having a wild-type genetic background, were low-grade tumors = that=20 lacked the features just described for high-grade=20 oligodendrogliomas.

Loss of Ink4a=E2=80=93Arf = enhances tumor=20 initiation and tumor progression in Ntv-a transgenic 3D"

mice

The above data suggest = that=20 autocrine stimulation of PDGF signaling, in the absence of other=20 experimentally induced genetic alterations, could be sufficient to = induce=20 low-grade gliomas from neural progenitors. Human high-grade = gliomas have=20 additional mutations that result in disruption of cell cycle = arrest=20 pathways such as loss of Ink4a=E2=80=93Arf (Cairncross et al. 1998) To elucidate the roles of = disruption=20 of G1 cell cycle arrest pathway in PDGF-induced gliomagenesis, we = compared=20 the incidence and characteristics of gliomas occurring in both=20 Ink4a=E2=80=93Arf^+/+ and = Ink4a=E2=80=93Arf^{=E2=88=92/=E2=88=92}=20 mice. At 12 wk of age, 61% of = Ink4a=E2=80=93Arf^+/+ and 57% of=20 Ink4a=E2=80=93Arf^{=E2=88=92/=E2=88=92} mice = developed gliomas respectively (Fig.=20 5A).=20 All of these tumors were oligodendrogliomas according to the above = histopathological criteria and as described in the WHO 2000 classification. Although the overall = glioma=20 incidence was similar between these two groups, over half of the = gliomas=20 forming in Ink4a=E2=80=93Arf^+/+ mice were = low-grade and=20 asymptomatic at the 12-wk time point whereas only about 10% of = tumors=20 arising from = Ink4a=E2=80=93arf^{=E2=88=92/=E2=88=92} mice were low = grade. By=20 contrast, using the same criteria these = Ink4a=E2=80=93Arf^{=E2=88=92/=E2=88=92}=20 tumors not only were more likely to be malignant but were also = more likely=20 to be symptomatic, resulting in earlier sacrifice and analysis = (Fig. 5A,B).=20 Therefore, experimental disruption of the = Ink4a=E2=80=93Arf locus appears=20 not essential for the induction of these gliomas from = nestin-expressing=20 neural progenitors; however, it does either facilitate the = progression of=20 gliomas toward a more malignant phenotype, or it selects for a = more=20 aggressive tumor cell that outgrows the population in vivo.

Figure=20 5

Role of=20 Ink4a=E2=80=93Arf loss in PDGF-induced = gliomagenesis from neural=20 progenitors. (A) Tumor-free survival curve = indicating=20 percent of mice developing symptomatic tumors over time. All = mice=20 were sacrificed at 12 wk; clinically occult tumors are=20 indicated=20 (more ...)

Gene transfer of PDGF-B into=20 GFAP-expressing astrocytes induces either oligodendrogliomas or = mixed=20 oligoastrocytomas in 3D"

mice

The experiments = described thus far=20 were performed in Ntv-a mice, that is, gene transfer to = nestin-expressing=20 neural progenitors. To test the influence of cell of origin on=20 PDGF-induced gliomagenesis, we infected Gtv-a transgenic mice = (astrocytes)=20 with RCAS=E2=80=93PBIG. The total incidence of glioma = formation was=20 somewhat lower (~40%), and the tumors were either = oligodendrogliomas or=20 gliomas of mixed histology containing both oligodendroglioma and=20 astrocytoma components (oligoastrocytoma). Figure 6A=20 shows a representative example of an oligoastrocytoma in which = distinct=20 oligodendroglioma and astrocytoma components are present. The=20 oligodendroglioma component exhibits morphologic features = identical to=20 those seen in human oligodendrogliomas, including monotonous, = uniform=20 round nuclei and scant-to-nondetectable cytoplasm. By contrast, in = the=20 astrocytoma component the constituent tumor cells are more = pleomorphic and=20 atypical, with irregular nuclei and prominent eosinophilic = cytoplasm that=20 is strongly immunoreactive for GFAP (Fig. 6B,C).=20 In addition, multinucleated giant cells are intimately associated = with the=20 astrocytoma component (data not shown), as is sometimes seen in = human=20 astrocytomas. These gliomas arising in Gtv-a mice also occurred in = low-grade and malignant forms. However, over 70% of these tumors = were low=20 grade in mice with a wild-type Ink4a=E2=80=93Arf genetic = background.=20

Figure=20 6

Histology = of mixed=20 gliomas induced from GFAP-expressing astrocytes. = (A) Low=20 magnification of GFAP-immunostained section illustrates the=20 coexistence of both positive astrocytoma cells and negative=20 oligodendroglioma cells. (B) H&E-stained=20 section=20 (more ...)

In Gtv-a mice, loss of = Ink4a=E2=80=93Arf=20 increases tumor incidence and tumor 3D"

malignancy

To test the effects of = Ink4a=E2=80=93Arf loss on the formation of the mixed = gliomas arising from=20 astrocytes in Gtv-a mice, we compared PDGF-induced glioma = formation in=20 Gtv-a, Ink4a=E2=80=93Arf^+/+ and Gtv-a,=20 Ink4a=E2=80=93Arf^{=E2=88=92/=E2=88=92} mice. = Similar to the Ntv-a mice, gliomas=20 arising from Gtv-a mice with Ink4a=E2=80=93Arf deficiency = were of higher=20 grade and shorter latency than those in mice with an = Ink4a=E2=80=93Arf=20 wild-type background (Fig. 7A).=20 In contrast to Ntv-a mice, in which a higher percentage of animals = developed gliomas and no increase in tumor incidence was seen with = Ink4a=E2=80=93Arf loss, loss of = Ink4a=E2=80=93Arf in Gtv-a mice resulted=20 in a nearly twofold increase in the incidence of PDGF-induced = gliomas at=20 12 wk of age (Fig. 7A).=20 The most malignant gliomas with the shortest latency were seen = with the=20 combination of both neural progenitor cell of origin and loss of=20 Ink4a=E2=80=93Arf (Fig. 7B).=20

Figure=20 7

Role of=20 Ink4a=E2=80=93Arf loss, p53 loss in PDGF-induced = gliomagenesis from=20 Gtv-a mice. (A) Ink4a=E2=80=93Arf loss, = but not p53 loss,=20 resulted in a shortened tumor latency and an increased total = tumor=20 incidence (70% vs. 39%); (B) = Ink4a=E2=80=93Arf=20 (more ...)

Deletions of 1p, 19q, and 10q = are not=20 present in PDGF-induced 3D"

gliomas

It is not clear = whether PDGF=20 signaling is sufficient for the induction of oligodendrogliomas or = whether=20 additional chromosomal abnormalities during tumor initiation or=20 progression are required to cooperate with PDGF signaling in=20 gliomagenesis. We investigated this question by analyzing these = tumors for=20 allelic loss of the mouse chromosomes syntenic to regions that are = frequently lost in human gliomas. Approximately half of human=20 oligodendrogliomas demonstrate deletions of chromosomes 1p and = 19q, and=20 malignant gliomas often show loss of chromosome 10q (Ransom et al. 1992; Reifenberger et al. 1994; von Deimling et al. 1992; Bello et al. 1995; Maier et al. 1997). Such regions would be likely = candidates=20 for additional mutations that might be required for PDGF-induced = glioma=20 formation. We addressed this issue by using fluorescence in situ=20 hybridization (FISH) for murine loci that are syntenic to the = candidate=20 tumor suppressor regions on human chromosomal arms 1p, 10q, and = 19q.=20 Murine chromosomal arms (murine 3, 84.9 cM and murine 4, 46.6 and = 81.5 cM,=20 for human 1p; murine 7, 4=E2=80=935.5 and 23.0 cM for human 19q; = and murine 19,=20 26.0 cM for human 10q), and corresponding centromeres were studied = in 21=20 PDGF-induced gliomas of various grades. For each case at each = locus, the=20 chromosomal counts ranged from 1.71 and 2.08, satisfying the = criteria for=20 two chromosomal copies (Fig. 8).=20 Thus, in no case was there evidence for loss of any of these = regions.=20 Therefore, those common mutations implicated in human = oligodendrogliomas=20 appear not to be required for PDGF-induced glioma formation. These = data=20 may imply that PDGF signaling achieves the same biologic effect as = 1p and=20 19q loss and that there is no selective pressure for generating = these=20 mutations, or that that this model may simulate those human=20 oligodendrogliomas without such mutations.

Figure=20 8

Fluorescence in=20 situ hybridization analysis of PDGF-induced gliomas. = (A)=20 Two copies of murine chromosome 4 syntenic to human = chromosome 1p.=20 Green and red signals indicate the locus of murine = chromosome 4,=20 centromere and 81.5 cM, respectively. (B) = Two=20 (more ...)

Experimental loss of p53 does = not promote=20 PDGF-induced 3D"

gliomagenesis

The above data = indicate that some=20 of the common genetic alterations found in human gliomas do not = occur in=20 our PDGF-induced model for gliomas, potentially implying that = other=20 mutations are not required for PDGF-induced gliomagenesis. To = further=20 investigate the possibility that additional mutations might = enhance the=20 formation of PDGF-induced gliomas, we crossed the Gtv-a mice to a=20 p53^{=E2=88=92/=E2=88=92} background. Loss of p53 = has been shown to=20 induce chromosomal instability in some tumor model systems and = cultured=20 astrocytes (Donehower et al. 1995; Yahanda et al. 1995; Bertrand et al. 1997). Intriguingly, mice with a=20 p53^{=E2=88=92/=E2=88=92} genetic background = showed neither shortened=20 tumor latency nor increased incidence of PDGF-induced gliomas = relative to=20 wild type mice (Fig. 7A).=20 In fact, there appeared to be a somewhat lower tumor incidence in = these=20 p53^{=E2=88=92/=E2=88=92} mice. This result is consistent = with the finding that=20 TP53 mutations rarely occur in human oligodendrogliomas = (Ohgaki et al. 1993; Reifenberger et al. 1994; Bigner et al. 1999). In contrast, p53 loss = cooperates with combined activation of Ras and Akt pathways in = Gtv-a mice=20 to induce glioblastomas (E.C. Holland et al., unpubl.), which is = also=20 consistent with the high frequency of TP53 mutations in = human=20 astrocytic tumors (Louis et al. 1993; Wu et al. 1993; Weber et al. 1996). Therefore, although it remains = formally=20 possible that additional mutations are required for PDGF-induced = glioma=20 formation in mice, if such mutations exist they are not the common = ones=20 found in human oligodendrogliomas nor is their occurrence enhanced = by loss=20 of p53.

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Abstract

Results

Materials=20 and methods

References

Discussion

Previous studies indicate = that PDGF=20 signaling functions during glial cell development by maintaining = glial=20 precursors in an undifferentiated and proliferating state. By = forcing the=20 overexpression of PDGF we have induced an autocrine signaling loop = in=20 cells that also express the PDGF receptor. In our experiments, the = alterations in proliferation rate, cell morphology, and gene = expression=20 pattern in cultured astrocytes infected with = RCAS=E2=80=93PBIG indicate=20 that PDGF autocrine stimulation can dedifferentiate = GFAP-expressing=20 astrocytes to glial progenitor-like cells. This process can be = reversed by=20 blocking the PDGF receptor kinase, indicating that these = PDGF-driven cells=20 continue to depend on signaling through the PDGF receptor in = culture, and=20 have not genetically evolved to be independent of these signaling=20 pathways.

The in vivo equivalent of this = dedifferentiation=20 effect of PDGF autocrine stimulation, and maintenance of glial = progenitors=20 in a proliferative capacity, appears to be the formation of = low-grade=20 gliomas. Depending on the cell of origin, these tumors are either=20 predominantly oligodendrogliomas from glial progenitors or=20 oligoastrocytomas from astrocytes. Similar to human gliomas, the = low-grade=20 mouse gliomas do not have Ink4a=E2=80=93Arf loss. = Additional=20 Ink4a=E2=80=93Arf loss in the mouse model results in = increased malignancy=20 but only a modest increase in tumor incidence. All of these data = are=20 consistent with the hypothesis that low-grade gliomas may = represent=20 collections of glial progenitors that are trapped in an = undifferentiated=20 and proliferating state. There could well be numerous mechanisms = that lead=20 to glial progenitors being unable to differentiate in vivo. PDGF = autocrine=20 stimulation models this phenomenon in mice and may be responsible = for a=20 subset of human oligodendrogliomas. The conversion of these tumors = to=20 high-grade neoplasms could be due to acquisition of additional = mutations,=20 such as Ink4a=E2=80=93Arf loss, and result in an = outgrowth of tumors with=20 increased malignancy. This hypothesis implies that low-grade = gliomas may=20 respond well to drugs that promote differentiation such as histone = deacetylase inhibitors and retinoic acid derivatives, and in some = cases=20 potentially PDGFR kinase inhibitors. High-grade gliomas that have=20 additional mutations may be more refractory to this strategy = alone.

The evidence presented in this paper = indicates=20 that PDGF signaling alone may be sufficient to induce glioma = formation.=20 The reversion of PDGF-induced phenotypes in vitro by blocking PDGF = signaling strongly implies that PDGF signaling is necessary and = sufficient=20 to maintain the transformed phenotypes of these cells in culture. = At least=20 in culture, these cells evolve to depend on the initiating event. = Although=20 it is possible in vivo that additional mutations occur that give = rise to=20 gliomas, the limited number of cells infected in each mouse and = the high=20 efficiency of glioma formation make the requirement for other = mutations=20 unlikely. The FISH data supports this idea by demonstrating that = some of=20 the common mutations found in human oligodendrogliomas, loss of = 1p, 19q,=20 and 10q, were not found in PDGF-induced oligodendrogliomas. = Furthermore,=20 p53 deficiency did not enhance the formation of these = tumors.=20 These data imply, but do not prove, that other mutations may not = be=20 required for the induction of low-grade gliomas induced by = autocrine PDGF=20 stimulation. It is possible that additional mutations do occur in = the=20 tumors in vivo; nevertheless, this would not necessarily indicate = that=20 such mutations are required for tumor initiation rather than = required for,=20 or a product of, tumor progression.

Other signaling molecules or = modeling=20 strategies may generate gliomas with an oligodendroglioma = histology=20 similar to the one presented in this paper. It would not be = surprising=20 that other such models may cooperate differently with specific = tumor=20 suppressor loss, or result in chromosomal abnormalities not found = in these=20 PDGF-induced gliomas in our model. Given the known varied clinical = responses to treatment and molecular genetic analyses of human = gliomas, it=20 would appear that there are multiple molecular subgroups within = each of=20 the glioma grades and types, including oligodendrogliomas (Cairncross et al. 1998; Ino et al. 2001). It is possible that different = modeling=20 approaches may effectively mimic different subgroups of = oligodendrogliomas=20 that are histologically similar, but are biologically and = clinically=20 distinct.

Materials and methods

Construction of RCAS = vectors

pSM-1, human = PDGF-B/c-sis cDNA=20 clone, was digested with BamHI and SspI = restriction=20 enzymes. The 927-bp fragment including the entire coding sequence = of=20 PDGF-B chain was subcloned into RCAS vector with and without the = IRES=E2=80=93EGFP=20 sequence. These vectors are referred to as = RCAS=E2=80=93PB and=20 RCAS=E2=80=93PBIG, respectively.

Transfection of DF-1 3D"

cells

DF-1 cells were grown = in DMEM=20 medium complemented with 10% fetal calf serum. = RCAS=E2=80=93PB,=20 RCAS=E2=80=93PBIG, RCAS=E2=80=93MTA, and = RCAS=E2=80=93lacZ plasmid DNAs=20 were transfected into chicken DF-1 cells by using calcium = phosphate=20 precipitation methods and the vectors were allowed to replicate = within the=20 producer cell population.

Tv-a transgenic mice

The Gtv-a mouse line = that=20 expresses tv-a from the GFAP promoter and the Ntv-a mouse line = that=20 expresses tv-a from the nestin promoter have been published (Holland and Varmus 1998; Holland et al. 1998a). The mice are a mixed = genetic=20 background including contribution from C57Bl6, 129, Balb/C, and=20 FVB/N.

Primary brain cell = cultures

Newborn tv-a = transgenic mice were=20 sacrificed and the whole brains were mechanically dissociated into = small=20 pieces in sterile PBS, Ca²⁺, Mg²⁺ free (pH = 7.4),=20 followed by digestion with 1 mL of 0.25% Trypsin=E2=80=931 mM EDTA = in HBSS (GIBCO=20 BRL) in sterile tubes and incubation in 37=C2=B0C water bath for = 15 min with=20 gentle shaking. After incubation, fresh medium was added to = terminate=20 Trypsin digestion and large debris was settled. The single cells = were=20 pelleted, resuspended in DMEM with 10% fetal calf serum (GIBCO = BRL), and=20 plated.

Infection of primary brain cell = culture=20 and growth rate 3D"

analysis

The supernatants = containing=20 various RCAS virons from DF-1 cell cultures transfected with = various RCAS=20 vectors were collected using sterile syringes and filtered through = 0.22 =CE=BCm=20 filters, followed by transferring into 70%=E2=80=9380% confluent = primary brain=20 cell cultures that had been plated and grown in DMEM with 10% = fetal calf=20 serum. Infections were repeated 3 times with 12-h intervals. After = infection, the proliferation rates were measured. Briefly, the = cells were=20 harvested by trypsin digestion and counted using a hemocytometer. = Total=20 1 3D"

=C3=97

10⁵ cells were replated and grown in DMEM = with 10%=20 fetal calf serum until the cells reached confluence; the same = procedure=20 was repeated over time. Finally, the total accumulated cell = numbers were=20 calculated and plotted as growth curves.

Fluorescence microscopy

DF-1 cells transfected = with=20 RCAS=E2=80=93PBIG and primary brain cell cultures = infected with the same=20 vector were seeded and grown on sterilized glass coverslips. = First, the=20 cells were fixed by immersing the coverslips in 2 mL of 4%=20 paraformaldehyde in PBS (pH 7.4) for 30 min at room temperature. = After=20 washing with PBS three times, the coverslips were mounted on = slides using=20 Fluoromount G (EMS) and visualized under fluorescence microscope = (Nikon=20 Eclipse) using conventional FITC filter sets (Nikon B-1E, = EX470=E2=80=93490,=20 DM505, BA520=E2=80=93560) for green fluorescence. The red = fluorescence of brain=20 sections stained with anti-GFP antibody (Santa Cruz Biotech) was=20 visualized by using Texas Red filter set (Nikon G-1B, EX540/10, = DM580,=20 BA590).

Giemsa staining of cultured 3D"

cells

The medium was = aspirated from=20 cells at 80% confluence and the cells were washed with PBS (pH = 7.4),=20 followed by fixing in methanol at room temperature for 10 min. = Then, 1 mL=20 of Giemsa stain (LabChem Inc) was applied for 5 min. The stain was = discarded and the cells were washed with PBS several times and = visualized=20 under a bright field microscope.

Immunocytochemistry

The cells infected = with=20 RCAS=E2=80=93PBIG or RCAS=E2=80=93lacZ were = fixed in either 4%=20 paraformaldehyde in PBS (pH 7.4) or cold methanol. The dishes were = blocked=20 by using 5% normal horse serum diluted in PBS (pH 7.4) for 1 h at = room=20 temperature with shaking. Monoclonal anti-A2B5 antibody = (Chemicon),=20 polyclonal anti-NG2 antibody (Chemicon), monoclonal anti-O4 = antibody=20 (Chemicon), monoclonal anti-GFAP antibody (Boehringer Mannheim),=20 monoclonal anti-NeuN antibody (Chemicon), and monoclonal=20 anti-neurofilament antibody (Boehringer Mannheim) were used as = primary=20 antibodies. Appropriate biotinylated secondary antibodies and=20 avidin-conjugated peroxidase were purchased from Vector Lab. The = signal=20 was visualized by using DAB substrate kit (Vector Lab) and = examined under=20 microscopy.

Blocking of PDGF 3D"

signaling

The cells infected = with=20 RCAS=E2=80=93PBIG were cultured in DMEM supplemented with = 10% FCS. Cells=20 (1 3D"

=C3=97

10⁵) were plated and the experiment groups = were=20 treated with PTK787 (stock solution dissolved in DMSO) with the = final=20 concentration of 1 =CE=BCM for 2 wk. The control groups were = treated with the=20 same volume of DMSO. After two wk, the cell numbers were counted, = and the=20 morphology was visualized by Giemsa staining.

Western analysis

Whole-cell protein = extracts were=20 prepared by using cold lysis buffer consisting of: 100 mM NaCl, 30 = mM=20 Tris-HCl (pH 7.6), 1% NP-40, 30 mM sodium fluoride, 1 mM EDTA, 1 = mM sodium=20 vanadate, 0.5 mM PMSF, and protease inhibitor cocktail tablets = (Boerhinger=20 Mannheim). Samples were incubated on ice for 30 min and = supernatants were=20 recovered by centrifuging at 14,000 rpm at 4=C2=B0C for 20 min. = Protein=20 concentrations were determined by BCA method (Pierce Biochemical). = Proteins were separated on 10% SDS-PAGE and transferred to = nitrocellulose=20 membrane (Osmonics). Blocking reagent was 5% non-fat dry milk in = TBS (pH=20 7.4). Washing buffer was TBS (pH 7.4) with 0.1% Tween-20. = Polyclonal=20 rabbit anti-PLP (Oncogene Research), polyclonal rabbit = anti-PDGFR=CE=B1 and =CE=B2=20 (Upstate Biotech), polyclonal goat anti-vimentin (Chemicon), = polyclonal=20 rabbit anti-Id4 (Santa Cruz Biotech), polyclonal rabbit anti-GFP = (Santa=20 Cruz Biotech), and monoclonal anti-=CE=B1-tubulin (Sigma) were = used as primary=20 antibodies. Respective HRP-conjugated secondary antibodies were = purchased=20 from Boehringer Mannheim. Signals were visualized by using ECL=20 chemiluminescence (Amersham) and Kodak X-OMAT films.

Infection of = tv-a-transgenic 3D"

mice

DF-1 cells producing = various RCAS=20 virons were trypsinized and pelleted by centrifugation; the = pellets were=20 resuspended in ~50 =CE=BCL of DMEM medium and placed on ice before = injection.=20 Using a 10 =CE=BCL gas-tight Hamilton syringe, a single = intracranial injection=20 of 1 =CE=BCL of cell suspension (~10⁴ cells) was made = in the right=20 frontal region of newborn mice, with the tip of the needle just = touching=20 the skull base.

Brain sectioning, H&E = staining,=20 and 3D"

immunohistochemistry

Mice were sacrificed = before=20 (because of early symptoms) or at 12 wk of age and the whole = brains were=20 fixed in 4% formaldehyde in PBS for at least 36 h with shaking. = Five=20 sections of each brain were cut and embedded in paraffin, 5-micron = sections were cut with a Leica microtome. The sections were = stained with=20 H&E. Immunostaining was performed using ABC kits (Vector Lab). = Briefly, deparaffinized slides were first treated with antigen = unmasking=20 reagent (Vector Lab) with heating in a steamer for 30 min, = followed by=20 immersing in 10% hydrogen peroxide in methanol for 20 min to = inactivate=20 the endogenous peroxidases. Then the sections were blocked with = 1.5%=20 normal horse serum in PBS (pH 7.4) for 1 h at room temperature. = Monoclonal=20 anti-GFAP (Boehringer Mannheim), monoclonal anti-NeuN (Chemicon),=20 polyclonal rabbit anti-synaptophysin (Biomeda), and polyclonal = rabbit=20 anti-GFP (Santa Cruz Biotech) were diluted in ChemMate antibody = dilution=20 buffer (Ventana Medical Systems) and incubated with sections at = 37=C2=B0C for 1=20 h. After washing with PBS/0.05% Tween 20, appropriate biotinylated = secondary antibodies (Vector Lab) diluted in the same antibody = dilution=20 buffer were incubated with sections at 37=C2=B0C for 30 min. Then, = after=20 washing, avidin-conjugated peroxidase or alkaline phosphatase = (Vector Lab)=20 diluted in PBS containing 1.5% normal horse serum was incubated = with=20 sections for 30 min at room temperature. Finally, after exclusive = PBS-T=20 washing, DAB or alkaline phosphatase red substrate (Vector Lab) = was added=20 to develop the color. After terminating the staining reaction, the = sections were counterstained with hematoxylin and mounted. The = negative=20 controls were included with the same procedure except replacing = primary=20 antibodies with antibody dilution buffer.

FISH

The following BACs = (Research=20 Genetics, Huntsville, AL) were used to assay for chromosomal loss = at=20 murine regions syntenic to human glioma tumor suppressor regions=20 (human/mouse homology maps are available at http://www.pubmedcentral.nih.gov/redirect3.cgi?&&= ;auth=3D0ZWT06WqaBGsutpQ4HUPzjak-EEqH3FtHvssk4QXU&reftype=3Dextlink&a= mp;article-id=3D312748&issue-id=3D9227&journal-id=3D101&FROM=3D= Article%7CBody&TO=3DExternal%7CLink%7CURI&rendering-type=3Dnormal= &&http://www.ncbi.nlm.nih.gov/Homology/index.html=20 and http://www.pubmedcentral.nih.gov/redirect3.cgi?&&= ;auth=3D0vsFTA_oxMtssXjrB2pANd9CNZoykBlJ110myU52Q&reftype=3Dextlink&a= mp;article-id=3D312748&issue-id=3D9227&journal-id=3D101&FROM=3D= Article%7CBody&TO=3DExternal%7CLink%7CURI&rendering-type=3Dnormal= &&http://greengenes.llnl.gov/mouse/):=20 for regions syntenic to human 1p, BAC 432-H-2 (murine chromosome = 3, 84.9=20 cM) (Korenberg et al. 1999), BAC 150-L-24 (murine = chromosome 4,=20 46.6 cM) (Chua et al. 1996), and BAC 362-D-3 (murine = chromosome 4, 81.5=20 cM) (Korenberg er al. 1999); for regions syntenic to = human=20 19q13.3, BACs 305-J-2 (murine chromosome 7, 4=E2=80=935.5 cM) and = 419-I-21 (murine=20 chromosome 7, 23.0 cM); for the Pten locus, BAC 371-O-8 (murine = chromosome=20 19, 26 cM) (Hansen and Justice 1999). Centromeric BACs were = also used to=20 confirm copy numbers for chromosomes 3, 4, 7, and 19 (BAC 52-H-9,=20 chromosome 3; BAC 39-B-18, chromosome 4; BAC 43-A-19, chromosome = 7; and=20 BAC 26-B-5, chromosome 19) (Korenberg et al. 1999). Purified BAC DNA was = fluorescently=20 labeled with SpectrumOrange or SpectrumGreen (Vysis Inc., Downers = Grove,=20 IL) by nick translation and applied to slide-mounted tissue = sections that=20 had been dewaxed, rehydrated, and treated in 10 mM sodium citrate = for 30=20 min at 80=C2=B0C and pepsin (4 mg/mL in saline, pH is adjusted to = 1.5 with HCl)=20 for 15 min. Following denaturation for 10 min at 80=C2=B0C, the = sections were=20 incubated overnight at 37=C2=B0C. After washing in buffers at = 45=C2=B0C (2=C3=97 3D"

15 min in 1.5 M urea/0.1=C3=97 SSC, 5 min in 2=C3=97 = SSC, 5 min in 2=C3=97=20 SSC/0.1% NP-40), the slides were counterstained with=20 4,6-diaminidino-2-pheny-indol (DAPI), covered with coverslips and=20 evaluated by fluorescence microscopy. Nuclear signals were counted = from a=20 total of 100 cells in areas of solid tumor. Cells were considered = to have=20 two copies of the chromosome when the signal average was between = 1.7 and=20 2.3. The region was judged to be hemizygously deleted when the = signal=20 average ranged from 0.7=E2=80=931.3, and homozygously deleted when = the average was=20 below 0.3.

Acknowledgments

We thank Yi Li (Memorial Sloan = Kettering Cancer=20 Center) for the RCAS=E2=80=93LacZ vector and Dr. Timothy = S. Schaefer (MD=20 Anderson Cancer Center, Houston, TX) for the pSM-1 clone. Mice = with=20 targeted deletions of Ink4a=E2=80=93Arf were obtained from Ron = DePinho (Dana=20 Farber Cancer Center) and those with targeted deletions for p53 = were=20 obtained from Larry Donehower (Baylor University). The PDGF = receptor=20 kinase inhibitor PTK787/ZK222584 was a gift of Jeanette Wood = (Novartis).=20 This work was supported by NIH grant UO1CA894314-1 and the Searles = Scholars Program.

The publication costs of this article = were=20 defrayed in part by payment of page charges. This article must = therefore=20 be hereby marked =E2=80=9Cadvertisement=E2=80=9D in accordance = with 18 USC section 1734=20 solely to indicate this fact.

Footnotes

E-MAIL hollande/at/mskcc.org ; FAX (646) 422-2062.

Article and publication are at=20 = http://www.genesdev.org/cgi/doi/10.1101/gad.903001.

Materials=20 and methods

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Articles=20 from Genes &=20 Development are provided here courtesy of
Cold = Spring Harbor=20 Laboratory Press

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(elmnts.item(i).className.indexOf(className, " ") = !=3D -1)=0A= {=0A= elmnts.item(i).innerHTML =3D innerHTML;=0A= unObscuredEmails[className] =3D true=0A= =0A= }=0A= }=0A= }=0A= }=0A= catch(e){=0A= }=0A= }=0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function pubMedDbLinkSubmit(control) {=0A= try{=0A= if (control.pubmedOption)=0A= control =3D control.pubmedOption=0A= if (control.options)=0A= location.href =3D = control.options[control.options.selectedIndex].value;=0A= }=0A= catch(e){}=0A= return false;=0A= }=0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= // elements "a", "area" with "ref" attribute report to redirect utility = before dereferencing link=0A= //=0A= function initRedirectClicks(report_url) {=0A= if (report_url && jQuery)=0A= jQuery(document).click(function(e) {=0A= //=0A= if (!e) return true;=0A= //=0A= if (e.shiftKey || e.altKey || e.ctrlKey) return true;=0A= //=0A= var target =3D jQuery(e.target).closest("a[ref], area[ref]");=0A= if (!target || target.length =3D=3D 0) return true;=0A= //=0A= var ref =3D target.attr("ref");=0A= // append ref with value of href if 'redirect-to-url' is = missing in ref.=0A= if (ref.indexOf('redirect-to-url') =3D=3D -1)=0A= ref =3D ref + '&redirect-to-url=3D' + = encodeURIComponent(target.attr("href"))=0A= =0A= //=0A= jQuery.ajax({=0A= type: "HEAD",=0A= url: report_url + '?' + ref,=0A= timeout: 1000,=0A= async: false=0A= });=0A= =0A= return true;=0A= });=0A= };=0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= 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