Human BCAS3 Expression in Embryonic Stem Cells and = Vascular Precursors Suggests a Role in Human Embryogenesis and Tumor = Angiogenesis

Cancer is often associated with = multiple and=20 progressive genetic alterations in genes that are important for = normal=20 development. BCAS3 (Breast Cancer Amplified Sequence 3) is a gene = of=20 unknown function on human chromosome 17q23, a region associated = with=20 breakpoints of several neoplasms. The normal expression pattern of = BCAS3=20 has not been studied, though it is implicated in breast cancer=20 progression. Rudhira, a murine WD40 domain protein that is 98% = identical=20 to BCAS3 is expressed in embryonic stem (ES) cells, erythropoiesis = and=20 angiogenesis. This suggests that BCAS3 expression also may not be=20 restricted to mammary tissue and may have important roles in other = normal=20 as well as malignant tissues. We show that BCAS3 is also expressed = in=20 human ES cells and during their differentiation into blood = vascular=20 precursors. We find that BCAS3 is aberrantly expressed in = malignant human=20 brain lesions. In glioblastoma, hemangiopericytoma and brain = abscess we=20 note high levels of BCAS3 expression in tumor cells and some blood = vessels. BCAS3 may be associated with multiple cancerous and = rapidly=20 proliferating cells and hence the expression, function and = regulation of=20 this gene merits further investigation. We suggest that BCAS3 is=20 mis-expressed in brain tumors and could serve as a human ES cell = and tumor=20 marker.

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Abstract

"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>Introduction

Results

Discussion

Materials and=20 Methods

Supporting=20 Information

References

Introduction

Development of multicellular organisms requires controlled and=20 co-ordinated tissue growth. Misregulation of molecular pathways = that=20 control normal embryo or tissue development can result in aberrant = growth=20 and can lead to cancer [1].=20 Not surprisingly, several developmentally important molecules are = key=20 mediators of the cancer phenotype when aberrantly expressed [2],=20 [3].=20 Multiple and progressive genetic changes accompanied by = chromosomal=20 aberrations are often the underlying cause [4].=20 Human chromosome 17 has been well studied in this regard. Its = complex=20 rearrangement and duplication structure predispose it to = non-allelic=20 homologous recombinations that cause several micro-deletion = disorders [5],=20 [6].=20 Cruciform structures formed by direct and inverted repeats make it = susceptible to one of the most common somatic rearrangement events = characterized, isodicentric 17q, which is associated with several = cancers=20 and signifies poor prognosis [7].=20 17q23 amplification occurs in about 20% of primary breast tumors = [8]=E2=80=93[12].=20 Gain of chromosome arm 17q is the most frequent chromosomal change = in=20 neuroblastoma [13]=20 suggesting that this region includes genes critical for = tumorigenesis. An=20 increased dosage of genes on chromosome 17q are likely to provide=20 selective growth advantage to human ES cells for maintenance = in=20 vitro as human ES cells in culture show distinctive = chromosomal=20 abnormalities involving this region [14].=20 A comparative genomic hybridization analysis of medulloblastomas=20 identified chromosomal imbalances with high-level amplifications = involving=20 17q22-q24 and subsequent candidate gene analyses revealed = amplification of=20 RPS6KB1, APPBP2, PPM1D and = BCAS3 [15].

BCAS3 is a large gene located at 17q23 and encodes a = predicted=20 conserved WD40 domain protein 98% identical to murine Rudhira [16].=20 We have shown earlier that Rudhira is a cytoplasmic protein = expressed at=20 high levels in ES cells, blood islands and the erythroid lineage = during=20 embryonic development [16].=20 In both the embryo and the adult Rudhira expression is seen in = angiogenic=20 precursors. The spatio-temporal expression pattern of Rudhira is = well=20 characterized but its function is not known. The developmental = expression=20 of BCAS3, the human ortholog of rudhira is not = reported.=20 However BCAS3 is amplified in 9% of primary breast tumors = [17],=20 is expressed in tumor-derived cell lines like HeLa and MCF-7 and = is=20 implicated in breast cancer progression [16],=20 [18].=20 Given this result and the observation that many aberrations of = chromosome=20 17 map to the region of BCAS3, we analyzed its expression = during=20 normal development and in tumors. We used human ES cells and=20 differentiating embryoid bodies as models of early human embryonic = development and report BCAS3 expression in undifferentiated ES = cells and=20 in vascular precursors. We also show that BCAS3 is mis-expressed = in=20 different types of brain lesions that include a malignant glial = tumor, a=20 highly mitotic vascular tumor arising from meninges = (hemangiopericytoma)=20 and the newly formed channels in the wall of brain abcess. Our = results=20 suggest new roles for BCAS3 in human blood vascular development, = an=20 integral part of tumorigenesis and repair = mechanism.

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Introduction

"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>Results

Discussion

Materials and=20 Methods

Supporting=20 Information

References

Results

Expression of BCAS3 in human ES = cells and=20 vascular precursors

As the developmental expression of human = BCAS3=20 has not been reported due to obvious technical and ethical = reasons, we=20 began our analysis with human ES cells. Differentiation of human = ES cells=20 in culture affords a more tractable model for early human = development. We=20 found expression of BCAS3 in the cytoplasm of undifferentiated ES = cells=20 (Fig.=20 1 A=E2=80=93D). Flow cytometry analysis showed that more than = 90% of=20 undifferentiated ES cells express BCAS3 (Fig.=20 1I).

Figure=20 1

BCAS3 = expression in=20 human ES=20 = cells.

10.1371/journal.pone.0001202= .g001

Having established BCAS3 expression in pluripotent cells, we = examined=20 its expression in blood vessel precursors as is observed in the = case of=20 mouse rudhira. Human ES cells can also spontaneously=20 differentiate into blood islands which are precursors to embryonic = blood=20 vessels. This process is less efficient than in mouse ES cells and = is=20 often carried out under influence of growth factors. We allowed = human ES=20 cells to differentiate spontaneously into embryoid bodies (EB) = that=20 contain blood islands and nascent blood vessels. Earlier studies = indicate=20 that the maximal expression of vascular markers in human EBs is = detected=20 between week 1 and 2 of differentiation [19].=20 Hence we fixed EBs at 8, 10 and 14 days of differentiation and = analyzed=20 for expression of BCAS3 and cell surface markers for the blood = vascular=20 lineage.

VEGFRII expression indicates the presence of early vascular = precursors=20 such as hemangioblasts [20].=20 Both VEGFRII and Platelet Endothelial Cell Adhesion Molecule = (PECAM) are=20 expressed in blood islands which have endothelial and = hematopoietic=20 precursors. Differentiated endothelial cells also express the = adhesion=20 molecule ICAM2 [21],=20 [22].=20 We examined BCAS3 expression in differentiating EBS and = simultaneously=20 stained the cultures with VEGFRII or PECAM or ICAM2 to check for = any=20 co-localization with BCAS3. At day 8 of differentiation BCAS3 was = detected=20 in small clusters near the periphery of the EB. Staining for = vimentin=20 indicated that these were cells of mesodermal origin (Fig.=20 2 A=E2=80=93D). To examine whether these clusters were = vascular precursors we=20 double stained for VEGFRII. Expression of BCAS3 overlapped with = VEGFRII in=20 cell clusters resembling blood islands (Fig.=20 2 E=E2=80=93H) as well as in nascent vessels (fig.=20 2 I=E2=80=93L). Expression of BCAS3 was not uniform with some = cells expressing=20 higher BCAS3 level (Fig.=20 2E, H arrow). VEGFRII was also detected at day 10 in larger = clusters=20 which also expressed BCAS3 (Figure=20 3 A=E2=80=93D). BCAS3 expression was seen in day 10 EBs in = clusters of cells=20 expressing PECAM (Fig.=20 3 E=E2=80=93H). At day 14 BCAS3 expression was seen in few = PECAM-expressing=20 cells (Fig.=20 4 A=E2=80=93D) as well as in clusters of ICAM2-expressing = cells (Fig.=20 4 E=E2=80=93L). On closer examination at higher magnification = by confocal=20 microscopy we found that BCAS3 and ICAM2 were not co-expressed in = the same=20 cell (Fig.=20 4 I=E2=80=93L). ICAM-2 is also a marker of differentiated = endothelial cells of=20 nascent vessels. We saw expression of BCAS3 in a few vessels that = were=20 also expressing ICAM2. However cells co-expressing BCAS3 and ICAM2 = were=20 rarely seen (Fig.=20 4 M=E2=80=93P). Immunostaining for BCAS3 with the antibody was = compared to=20 control antibody staining at all stages analyzed (Fig.=20 2 M=E2=80=93P, 3Q-T and data not shown).

Figure=20 2

Expression of BCAS3=20 in embryoid bodies at day 8 of=20 = differentiation.

10.1371/journal.po= ne.0001202.g002

Figure=20 3

Expression of BCAS3=20 in embryoid bodies at day 10 of=20 = differentiation.

10.1371/journal.po= ne.0001202.g003

Figure=20 4

Expression of BCAS3=20 in embryoid bodies at day 14 of=20 = differentiation.

10.1371/journal.po= ne.0001202.g004

BCAS3 mRNA but not = protein is=20 expressed in the normal brain and in glioma cell lines

While = Rudhira=20 protein is not detected in mouse adult tissues, rudhira = RNA can=20 be detected in various adult tissues by RT-PCR. In particular, = multiple=20 splice variants are seen in the mouse brain [16].=20 To test whether this is so in human, we analyzed normal adult = brain cDNA=20 by PCR. BCAS3 amplicon was seen in cDNAs from all regions of the = brain (Fig.=20 5A). We also amplified BCAS3 from cDNA of various glioma cell = lines=20 that represent malignant human brain tumor cells (Fig.=20 5B). We then examined frozen sections of human frontal = cerebral cortex=20 for BCAS3 protein expression by immunofluorescence staining. = Details of=20 samples analyzed are listed in Table=20 1. BCAS3 was absent from control normal (non-malignant) brain = samples=20 (Fig.=20 6). This is in agreement with the observation that Rudhira = protein is=20 not detected in mouse brain.

Figure=20 5

BCAS3 RNA = expression in human brain and glioma cell=20 = lines.

10.1371/journal.pone.0001202= .g005

Figure=20 6

BCAS3 is = not=20 expressed in normal human frontal cerebral cortex (from two=20 = individuals).

10.1371/journal.pone.= 0001202.g006

Table=20 1

Details = of the=20 samples used for the=20 study.

BCAS3 is expressed in human = brain tumors=20 of different cell lineage and inflammatory brain = abscess

Having=20 established the expression of BCAS3 in glioma cell lines in=20 vitro, we looked for similar expression in brain tumor tissue = and=20 wall of brain abscess rich in vasculature (Table=20 1). We found a large number of BCAS3- expressing cells in = different=20 types of brain lesions including glioblastoma, hemangiopericytoma = and wall=20 of an abscess. Eight samples showed strong immunoreactivity for = BCAS3;=20 over 50% of the cells being BCAS3⁺ (five glioblastomas, = two=20 hemangiopericytomas and one abscess) (Fig.=20 7I). In all the cases, BCAS3 localized to the cytoplasm (Fig.=20 7). Negative controls in which primary antibodies were omitted = did not=20 show any specific immunostaining. The expression of BCAS3 in the = cells was=20 rather random and showed a distinct association to vascular = component of=20 neoplasms of various cell lineages and inflammatory lesions. The = labeling=20 was noted along the endothelial aspect and the adjacent pericytes = of small=20 arterioles and endothelium of some of the larger blood vessels but = not the=20 smooth muscle cells. Labeling was seen in vascular sprouts in the = wall of=20 the brain abcess (one case) (Fig.=20 7A), the newly formed vessels in five cases of glioblastoma = multiforme=20 (high-grade astrocytic tumor) (Fig.=20 7B, D, F, G, H) and two cases of hemangiopericytoma = (mesenchymal tumor=20 of meningio-vascular origin) (Fig.=20 7C, E). In addition, the undifferentiated glial tumor cells in = glioblastoma multiforme (grade IV) also revealed cytoplasmic = labeling. The=20 cells in most low-grade glial tumors of different cell lineages = (grade=20 I=E2=80=93III) failed to show expression of BCAS3 protein. BCAS3 = positive cells in=20 the tumors co-expressed GFAP (Glial Fibrillar Acidic Protein), a = marker of=20 the glial cells (Fig.=20 8).

Figure=20 7

BCAS3 = expression in=20 human brain=20 = lesions.

10.1371/journal.pone.00012= 02.g007

Figure=20 8

BCAS3 is = expressed=20 in glial cells in glioblastoma=20 = multiforme.

10.1371/journal.pone.00= 01202.g008

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Results

"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>Discussion

Materials and=20 Methods

Supporting=20 Information

References

Discussion

Several cancers result from the mis-regulated expression of=20 developmentally important genes. While there is obvious benefit in = studying human tumor biology and tumor progression, elucidating = gene=20 function is often hindered by the lack of a suitable model to = study the=20 developmental and pathogenetic role of the tumor-associated genes. = In this=20 regard animal models of cancer have been extremely valuable in = elucidating=20 molecular pathways and mechanisms of disease progression. However = several=20 differences are seen in development and stem cell differentiation = in=20 humans compared to that in animal models and their cultured = derivatives.=20 Till recently, studies on developmental and pathological human = gene=20 expression have been restricted to tissues from fixed aborted = fetuses, or=20 cell- and tissue- cultures derived from them. The advent of human = ES cell=20 technology has opened up new avenues of investigation and now = allows one=20 to address developmental roles of human disease genes. We have = taken=20 advantage of this system to analyze the developmental and = pathological=20 expression of BCAS3 a gene known to be important in breast cancer. = Our=20 analysis suggests new conserved roles for BCAS3 in tumor = manifestation and=20 progression and in tissue healing.

BCAS3 is a conserved,=20 developmentally expressed gene

Expression of BCAS3 = mRNA in=20 medulloblastoma of cerebellum and BCAS3 protein in breast cancer = has been=20 reported [15],=20 [18].=20 Such an expression profile suggests that BCAS3 expression is not=20 restricted to a specific tissue. The function of BCAS3 is not = known either=20 in embryogenesis or during tumor progression. Our study suggests = that=20 BCAS3 may have a role during embryogenesis and in = tumorigenesis=20 like many other genes that were discovered for their oncogenic = role and=20 found to be key players in embryogenesis. For example, Smad4/Dpc4, = a=20 signaling molecule of TGF-=CE=B2- related pathways required for = gastrulation=20 and anterior development of the mouse embryo is involved in 50% of = pancreatic cancers [23].=20 Similarly expression of BRCA-1, an infamous breast cancer gene, is = associated with embryonic cellular proliferation and with = differentiation=20 of ectodermally- and mesodermally- derived tissues in the mouse [24],=20 [25].

BCAS3 is expressed in = developmental and=20 pathological angiogenesis

The kinetics of vascular marker = gene=20 expression during mouse EB differentiation is well documented and = allows=20 the detection of successive maturation steps [20].=20 Similar analysis done on human EBs showed that the early vascular = markers=20 VEGFRII and PECAM/CD31 appeared by the first week of = differentiation [19].=20 The majority of early vascular markers peak between week 1 and 2 = of=20 differentiation. Hence we restricted our analysis till day 14 of=20 differentiation. We observe that like in mouse EBs, human EBs also = express=20 BCAS3 in early stages of vascular development as indicated by = VEGFRII and=20 PECAM expression. BCAS3 expression at later stages in seen only in = a few=20 differentiated ICAM2+ endothelial cells indicating that BCAS3 = expression=20 in the vasculature is downregulated in later stages of vascular=20 development. As seen for Rudhira in mouse EBs and mouse tissues [16]=20 cells that co-express BCAS3 and ICAM2 are rarely detected. This = suggests=20 that the sequence of vascular gene expression in human EBs = parallels that=20 in mouse EBs. As in mouse vascular development Rudhira/BCAS3 is = expressed=20 transiently in differentiated human endothelial cells during human = vascular development. This suggests an important role for BCAS3 in = human=20 angiogenesis.

BCAS3 RNA is expressed in the normal human brain and also in = glial cell=20 lines. In case of the normal brain, the cDNA represented the = entire tissue=20 including the blood vessels. Hence, the amplicon may represent RNA = from=20 the few blood vessels that express BCAS3 as seen in mouse embryos = and=20 models of angiogenesis. Rudhira is also expressed during normal=20 physiological angiogenesis though it is not detected in = differentiated=20 endothelium. Greater the neo-vascularisation in tumors, greater is = their=20 chance of metastatic spread. As BCAS3 expression is associated = with=20 vascular precursors derived from human ES cells, it is possible = that BCAS3=20 plays a role in the formation of tumor vessels.

We report that the protein encoded by BCAS3 is = mis-expressed=20 in brain neo plastic and reparative lesions like glioma, abscess = and=20 hemangiopericytoma. The vessels in an abscess express enhanced = levels of=20 adhesion molecules like ICAM-1 (intercellular cell adhesion = molecule) and=20 PECAM (platelet endothelial cell adhesion molecule) which are not=20 expressed in the normal brain and are thought to be involved in = guiding=20 the immune cells to the abscess [26].=20 BCAS3 is not detected in low grade tumors indicating a temporal = and=20 spatial association of BCAS3 to highly mitotic undifferentiated = tumor=20 cells and neo-angiogenesis. Similarly, many of the vascular = sprouts in the=20 wall of an abcess also showed constitutive expression, reflecting = that the=20 angiogenesis in the wall of inflammatory lesion is essentially = similar to=20 tumor blood vessels, ontologically. The vascular component- either = arterioles or capillaries- in normal cerebral cortex did not show=20 expression of BCAS3 indicating the blood vessels in normal brain = are=20 quiescent, of low turn over and the biology is distinct from = vessels in=20 tumors or active inflammatory lesions.

Blood vessels are composed of two interacting cell types. = Endothelial=20 cells form the inner lining of the vessel wall and perivascular = cells=20 referred to as pericytes, vascular smooth muscle cells (SMCs) or = mural=20 cells. Depending on their location during embryogenesis, pericytes = can=20 arise from neural crest cells or mesenchymal cells [27],=20 [28].=20 Vessels associated with tumors have abnormal wall structure and = branching=20 patterns. These perivascular cells are loosely associated with the = endothelium [29].=20 A tumor arising from these pericytes could be arising from = progenitor=20 mesenchymal cells, thus expressing BCAS3.

BCAS3 could serve as a marker = of tumor=20 progression

BCAS3 is expressed in the neo-angiogenic = component of=20 glioblastoma, hemangiopericytoma and brain abcess wall. In = addition, its=20 expression is noted in some of the neoplastic cells of glial = lineage=20 (grade IV). Cell lines are a more homogenous population and BCAS3=20 expression in glioma lines is suggestive of expression in = non-vascular=20 neuroectodermal cells. This suggests that the expression of = BCAS3=20 RNA and constitutive presence in the tumor cells and newly formed = blood=20 vessels but not in the capillary endothelium of the normal brain = is=20 related either to the proliferative nature or an event associated = with the=20 undifferentiated and multipotent nature of the cells. The gene = controlling=20 this is probably turned off with maturation. In view of this, = BCAS3 could=20 be a surrogate marker for angiogenesis in a reparative healing = process or=20 tumor progression to higher grade of malignancy, a common = phenomenon in=20 cell biology.

BCAS3 is located in a chromosomal region that carries = several=20 oncogenes. It is a target gene of metastasis-associated protein1 = (MTA1) [18].=20 MTA1 is a component of the nucleosome remodeling and deacetylating = (NURD)=20 complex that contains both histone deacetylase and nucleosome = remodeling=20 activity. By expression profiling, MTA1 was identified as a target = of the=20 c-MYC oncoprotein in primary human cells and has been implicated = in=20 cellular transformation through its ability to regulate the = epithelial to=20 mesenchymal transition and metastasis [30].=20 MTA1 binds to estrogen response elements (ERE) on the enhancer 12 = kbp=20 downstream of the transcription start site of BCAS3. = Breast=20 cancer patients with high BCAS3 expression and ER/PR positive = expression=20 show impaired response to tamoxifen [31].=20 Hence, a study of the expression of BCAS3 can help in assessing=20 prognosis.

We also find that most samples expressing BCAS3 are grade III = and IV=20 brain tumors though not all high-grade samples showed expression. = This=20 reflects the heterogeneity in the neoplastic cell population of = brain=20 tumors and a probable role of BCAS3 in tumor progression as seen = in the=20 breast tumors [18].

Whether expression of BCAS3 is a cause or an effect of = the=20 general transformation and metastasis of tumors requires further = studies.=20 This is the first report on BCAS3 expression during development = and in=20 brain malignancies. The expression profile suggests that BCAS3 may = play a=20 role during both embryogenesis and tumorigenesis. An in- depth = study of=20 BCAS3 regulation and its role in progression of tumors of = different organs=20 may reveal correlation with prognosis and disease recurrence.

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Discussion

"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>Materials and=20 Methods

Supporting=20 Information

References

Materials and = Methods

Culture and differentiation of = Human ES=20 cells

Human ES cells (HUES9) [32]=20 (hES facility, Harvard University, Cambridge, MA, http://www.pubmedcentral.nih.gov/redirect3.cgi?&&= ;auth=3D0wcT_3hH00-1JO67VHoVrfcJJv9UVbBOAymLlb9IQXk&reftype=3Dextlink= &artid=3D2075367&iid=3D152676&jid=3D440&FROM=3DArticle%7C= Body&TO=3DExternal%7CLink%7CURI&article-id=3D2075367&journal-= id=3D440&rendering-type=3Dnormal&&http://mcb.harvard.edu/melt= on/hues)=20 were grown on irradiated mouse embryonic fibroblasts (MEFs) in = medium=20 containing 80% DMEM, 20% knockout serum, 2 mM L-glutamine, 0.1 mM=20 =CE=B2-mercaptoethanol, 1% non-essential amino acids and 4 ng/ml = basic=20 fibroblast growth factor (bFGF). For differentiation, the colonies = were=20 cut and maintained in the EB medium on bacteriological dishes = without=20 feeders. EB medium is similar to ES cell medium except the = following: it=20 is without bFGF, knockout serum is replaced by fetal calf serum, = and=20 glutamine is 4 mM. The floating EBs were allowed to attach on = tissue=20 culture dishes and fixed at different days post-attachment.

Culture of glioma cells = lines

U87MG,=20 U373MG, LN18 and LN229 -glioma cell lines (Kind gift from M.R.S. = Rao,=20 JNCASR) were grown in DMEM containing 10% serum and 2 mM = L-glutamine.=20 Cells were scraped out of the culture dish and RNA was isolated.

Human brain = cDNAs

Marathon-Ready=20 human brain cDNAs were obtained from Clontech (kind gift from A. = Anand,=20 JNCASR).

Clinical = material=E2=80=93collection and=20 processing

Forty-six surgically resected formalin-fixed = pathological=20 tissue samples were obtained from the archives of human brain = tissue=20 repository (Human Brain Bank=E2=80=93a National Research facility, = Department of=20 Neuropathology, National Institute of Mental Health and = Neurosciences=20 (NIMHANS), Bangalore, India). The brains have been collected with = informed=20 consent from the close relatives after the death of the patients. = This is=20 in line with legally and ethically approved practice in India. The = consent=20 form has been approved by Institutional Scientific Ethics = Committee-=20 NIMHANS for the use of Human Biological Material for Scientific = Research=20 and Archiving.

The samples were subsequently cryopreserved in 30% sucrose = solution.=20 Cryosections 10 =C2=B5m thick were picked on gelatin- coated = slides for=20 immunostaining and stored at =E2=88=9270=C2=B0C. The age of the = patients ranged between=20 4 years and 65 years (M 3D[ratio]=20 F 3D" =3D 3D" 2521). Relatively normal control samples for comparison = were=20 cerebral cortical tissue resected during epilepsy surgery, which = were free=20 of pathology on detailed histological evaluation and were obtained = with=20 informed consent. The consent forms and the biological samples for = research have been approved by Institutional Scientific Ethics = Committee=20 for the use of Human Biological Material for Scientific Research = and=20 Archiving- NIMHANS, Bangalore, India. The samples have been coded = to=20 maintain the confidentiality of the patients. The sample numbers = used in=20 the manuscript are coded and the original data is not accessible = to the=20 investigating scientist, the number indicated is used only for the = purpose=20 of this study and it cannot be tied to any other information to = trace the=20 individual. Thus the strict confidentiality is preserved as per = the policy=20 of the Human Brain Bank, NIMHANS, Bangalore. The histological = diagnosis of=20 the tissues examined is indicated in the Table=20 1. The brain tumors were reviewed and graded according to WHO=20 classification for degree of malignancy.

Reverse = Transcription=E2=80=93Polymerase Chain=20 Reaction (RT-PCR)

2 =C2=B5g total RNA from cultured glioma = cell lines was=20 reverse transcribed using Superscript II (GIBCO) and random = primers,=20 according to the manufacturer's instructions. PCR was performed = using the=20 following BCAS3-specific primers: 466-1F 5=E2=80=B2=20 GAATTCCATGGAGAGCGTCGTGACTTTTCTG 3=E2=80=B2; 466-1R 5=E2=80=B2=20 GAGCTCGAGGGACTGGTGACAGCGAATCAGC 3=E2=80=B2

Immunostaining and=20 imaging

Monoclonal antibodies raised against Rudhira were = used for=20 the study [16].=20 As mouse Rudhira and human BCAS3 proteins are 98% identical, the=20 anti-Rudhira antibody could be used for detecting the human = protein.=20 Antibody specificity was tested by blocking with immunogen (see Figure=20 S1 of Text=20 S1). Antibody was used at a dilution of 1 3D[ratio]=20

10. Marker antibodies used were anti-Vimentin, = anti-Flk-1,=20 anti-PECAM and anti-ICAM2 from BD Pharmingen, GFAP (Glial = fibrillar acidic=20 protein) from Sigma Chemical Co., USA and SSEA4 from Chemicon (all = at=20 1 3D[ratio]=20

50 dilution). Alexa Fluor-conjugated secondary = antibodies=20 (Molecular Probes, USA) were used at a dilution of 1 3D[ratio]=20

400 to immuno-localize the binding of the primary = antibody.

Frozen sections of various brain lesions were thawed to room=20 temperature, washed in PBS, permeabilized with 0.3% Triton X 100 = and=20 blocked for non-specific binding sites in 3% skimmed milk powder = in PBS=20 for 1 hr. Sections were incubated in monoclonal antibody (110) overnight in a humid chamber. After washing off the = primary=20 antibody, the immuno-labeling of BCAS3 protein was visualized by=20 incubating with fluorescent- labeled secondary antibody (Rabbit = anti-Mouse=20 IgG tagged to Alexa Fluor 488 1 3D[ratio]=20 400) for 1 hr at RT. Sections were mounted in glycerol = containing=20 DAPI, to stain the nucleus. Adjacent sections (10 =C2=B5m) were = stained with=20 hematoxylin and eosin. The fluorescent immunostained sections were = viewed=20 under a Carl-Zeiss LSM 510 Meta confocal microscope and the image = analysis=20 and processing was carried out with LSM 5 Image Browser software.=20 Quantitation was done using MicroImage software (Roper Scientific, = USA)=20 and percentage of BCAS3-expressing (green) cells out of total = number of=20 cells (DAPI stained nuclei) in a sampled area was estimated. At = least 500=20 cells were analyzed for each sample. Cultured cells were imaged = using an=20 Olympus IX70 fluorescence microscope and CoolSNAP-PROcf=20 camera.

Flow cytometry = analysis

Cultured=20 cells were washed twice with PBS, trypsinized to get single cell=20 suspension and transferred to FACS tubes. Trypsin was inactivated = with 5%=20 fetal calf serum, cells were fixed and permeabilized = simultaneously with=20 cold methanol for 1 min then washed with PBS. Non-specific binding = of=20 antibody was blocked with staining media (3% serum in PBS) for 45 = min at=20 room temperature. Staining media was then replaced with primary = antibody,=20 incubated at 4=C2=B0C overnight and unbound antibody was removed = with wash=20 solution (2% serum in PBS). Cells were then incubated with=20 fluorescent-tagged secondary antibody (Alexa Fluor 488 goat = anti-mouse=20 IgG, at 1 3D[ratio]=20

400 dilution in staining media), washed and finally = resuspended=20 in 0.5 ml of PBS and run through a flow cytometer (Becton = Dickinson FACS=20 Calibur=E2=84=A2 system). The data was analyzed using BD CellQuest = Pro software.

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Abstract

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Results

Discussion

Materials and=20 Methods

"=20 = src=3D"http://www.pubmedcentral.nih.gov/corehtml/pmc/pmcgifs/square.gif" = border=3D0>Supporting=20 Information

References

Supporting Information

Figure S1

Immunostaining is abolished by pre-incubation of antibody with = the=20 immunogen. (A,C,E,G) Phase contrast and (B,D,F,H) fluorescent = (red) images=20 of HEK293 cells stained with antibody preincubated with (A,B) 0 = microgram=20 (C,D) 20 microgram (E,F) 40 microgram and (G,H) 80 microgram of=20 immunogen.

(4.96 MB TIF)

Click=20 here for additional data file.^{=20
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Text S1

Blocking of antibody binding 50 microliters of undiluted = monoclonal=20 anti-Rudhira/BCAS3 antibody was pre-incubated with 0, 10, 20, 40 = and 80=20 microgram of the immunogen and at 4 oC for 12 hours, centrifuged = to remove=20 any antigen-antibody complex, diluted 1 3D[ratio]=20 10 and used to stain HEK293 cells.

(0.02 MB DOC)

Click=20 here for additional data file.^{=20
(24K)}

Acknowledgments

We thank Suma B.S. for help with confocal microscopy; R. = UdayKumar and=20 laboratory members for help with flow cytometry.

Footnotes

Competing Interests: The = authors=20 have declared that no competing interests exist.

Funding: This work was supported = by the=20 Jawaharlal Nehru Centre for Advanced Scientific Research, and = Department=20 of Biotechnology, Government of India. KS was supported by a = fellowship=20 from University Grants Commission.

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Abstract

Introduction

Results

Discussion

Materials and=20 Methods

Supporting=20 Information

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<= /TD>

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Hanahan D, Weinberg RA. The hallmarks of = cancer. Cell.=20 2000;100:57=E2=80=9370. = [Pu= bMed]

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Articles=20 from PLoS ONE = are provided=20 here courtesy of
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DIV.panel DT IMG { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; PADDING-BOTTOM: 0px; MARGIN: = 0px; PADDING-TOP: 0px } DIV.panel DL { FLOAT: left; WIDTH: 100% } DIV.panel DL DD { FLOAT: right } DIV.panel DL DT { FLOAT: left; BACKGROUND-IMAGE: url(i/loading_bg.gif) } .scale-pmc { MARGIN: auto; WIDTH: 32px; PADDING-TOP: 0em } .scale-pmc A { PADDING-RIGHT: 1px; DISPLAY: block; PADDING-LEFT: 1px; FONT-SIZE: 3px; = BACKGROUND-IMAGE: url(i/toolbar.png); PADDING-BOTTOM: 1px; MARGIN: 0px; = PADDING-TOP: 1px; BACKGROUND-REPEAT: no-repeat; HEIGHT: 16px; = TEXT-DECORATION: none; _background-image: url(i/toolbar.gif) } .scale-pmc A:hover { BACKGROUND-REPEAT: no-repeat; BACKGROUND-COLOR: transparent; = TEXT-DECORATION: none } .scale-pmc A.scale-up { MARGIN: 2px auto; WIDTH: 22px; HEIGHT: 22px } .scale-pmc A.scale-up-disabled { MARGIN: 2px auto; WIDTH: 22px; HEIGHT: 22px } .scale-pmc A.scale-down-disabled { MARGIN: 2px auto; WIDTH: 22px; HEIGHT: 22px } .scale-pmc A.scale-down { MARGIN: 2px auto; WIDTH: 22px; HEIGHT: 22px } .scale-pmc A.scale-up { BACKGROUND-POSITION: 4px -26px } .scale-pmc A.scale-up:hover { BACKGROUND-POSITION: -76px -26px } .scale-pmc A.scale-up-disabled { BACKGROUND-POSITION: -36px -26px; CURSOR: default } .scale-pmc A.scale-down { BACKGROUND-POSITION: 4px -226px } .scale-pmc A.scale-down:hover { BACKGROUND-POSITION: -76px -226px } .scale-pmc A.scale-down-disabled { BACKGROUND-POSITION: -36px -226px; CURSOR: default } .scale-pmc A.scale-1 { BACKGROUND-POSITION: 3px -57px } .scale-pmc A.scale-1:hover { BACKGROUND-POSITION: -77px -57px } .scale-pmc A.selected-1 { BACKGROUND-POSITION: -37px -57px; CURSOR: default } .scale-pmc A.selected-1:hover { BACKGROUND-POSITION: -37px -57px; CURSOR: default } .scale-pmc A.scale-2 { BACKGROUND-POSITION: 3px -77px } .scale-pmc A.scale-2:hover { BACKGROUND-POSITION: -77px -77px } .scale-pmc A.selected-2 { BACKGROUND-POSITION: -37px -77px; CURSOR: default } .scale-pmc A.selected-2:hover { BACKGROUND-POSITION: -37px -77px; CURSOR: default } .scale-pmc A.scale-3 { BACKGROUND-POSITION: 3px -97px } .scale-pmc A.scale-3:hover { BACKGROUND-POSITION: -77px -97px } .scale-pmc A.selected-3 { BACKGROUND-POSITION: -37px -97px; CURSOR: default } .scale-pmc A.selected-3:hover { BACKGROUND-POSITION: -37px -97px; CURSOR: default } .scale-pmc A.scale-4 { BACKGROUND-POSITION: 3px -117px } .scale-pmc A.scale-4:hover { BACKGROUND-POSITION: -77px -117px } .scale-pmc A.selected-4 { BACKGROUND-POSITION: -37px -117px; CURSOR: default } .scale-pmc A.selected-4:hover { BACKGROUND-POSITION: -37px -117px; CURSOR: default } .scale-pmc A.scale-5 { BACKGROUND-POSITION: 3px -137px } .scale-pmc A.scale-5:hover { BACKGROUND-POSITION: -77px -137px } .scale-pmc A.selected-5 { BACKGROUND-POSITION: -37px -137px; CURSOR: default } .scale-pmc A.selected-5:hover { BACKGROUND-POSITION: -37px -137px; CURSOR: default } .scale-pmc A.scale-6 { BACKGROUND-POSITION: 3px -157px } .scale-pmc A.scale-6:hover { BACKGROUND-POSITION: -77px -157px } .scale-pmc A.selected-6 { BACKGROUND-POSITION: -37px -157px; CURSOR: default } .scale-pmc A.selected-6:hover { BACKGROUND-POSITION: -37px -157px; CURSOR: default } .scale-pmc A.scale-7 { BACKGROUND-POSITION: 3px -177px } .scale-pmc A.scale-7:hover { BACKGROUND-POSITION: -77px -177px } .scale-pmc A.selected-7 { BACKGROUND-POSITION: -37px -177px; CURSOR: default } .scale-pmc A.selected-7:hover { BACKGROUND-POSITION: -37px -177px; CURSOR: default } .scale-pmc A.scale-8 { BACKGROUND-POSITION: 3px -207px } .scale-pmc A.scale-8:hover { BACKGROUND-POSITION: -77px -207px } .scale-pmc A.selected-8 { BACKGROUND-POSITION: -37px -207px; CURSOR: default } .scale-pmc A.selected-8:hover { BACKGROUND-POSITION: -37px -207px; CURSOR: default } ------=_NextPart_000_0006_01C83427.2CBB4B20 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://www.pubmedcentral.nih.gov/corehtml/pmc/js/common.js // Called from many places to handle links.=0A= // Params:=0A= // link: URL. 'this' to reuse same window, else ""=0A= // windowname: Reference name for window=0A= // additional: Attributes for window.open, from:=0A= // width, height, resizable, scrollbars, toolbar, location, = directories,=0A= // status, menubar, copyhistory.=0A= // Notes: Book version always provides menubar, toolbar, etc.=0A= //=0A= function startTargetBook(link,windowname,width,height,additional) =0A= {=0A= if(! window.focus)=0A= return;=0A= var sizestring =3D ",width=3D" + width + ",height=3D" + height;=0A= var opt =3D = "menubar=3Dyes,toolbar=3Dyes,status=3Dyes,scrollbars,resizable,dependent=3D= yes";=0A= var allOptions =3D opt + sizestring;=0A= if (additional) { allOptions =3D allOptions + additional; }=0A= //alert("In startTargetBook, additional: " + additional);=0A= =0A= w =3D window.open("",windowname, allOptions);=0A= w.focus();=0A= link.target=3Dwindowname;=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 startTarget(link,windowname,width,height) =0A= {=0A= if(! window.focus)=0A= return;=0A= var sizestring =3D ",width=3D" + width + ",height=3D" + height;=0A= w =3D = window.open("",windowname,"scrollbars,resizable,dependent=3Dyes" + = sizestring);=0A= w.focus();=0A= link.target=3Dwindowname;=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 focuswin(windowname) =0A= {=0A= w =3D = window.open("",windowname,"menubar=3Dyes,scrollbars=3Dyes,toolbar=3Dyes,l= ocation=3Dyes,status=3Dyes,directories=3Dyes,resizable=3Dyes");=0A= w.focus();=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= =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 reverseString (inStr)=0A= {=0A= var outStr =3D ''=0A= =0A= for (i =3D0; i <=3D inStr.length; i++)=0A= {=0A= outStr =3D inStr.charAt(i) + outStr=0A= }=0A= =0A= return outStr=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 reverseAndReplaceString (inStr, findStr, newStr)=0A= {=0A= return reverseString(inStr).replace(findStr, newStr)=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 initUnObscureEmail (className, innerHTML)=0A= {=0A= =0A= try{=0A= if (window.addEventListener)=0A= window.addEventListener('load', function() {unObscureEmail = (className, innerHTML)}, false)=0A= else if (window.attachEvent)=0A= window.attachEvent('onload', function() {unObscureEmail = (className, innerHTML)})=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 unObscureEmail (className, innerHTML)=0A= {=0A= try {=0A= if (typeof(unObscuredEmails) =3D=3D 'undefined')=0A= unObscuredEmails =3D new Array()=0A= =0A= if (! unObscuredEmails[className])=0A= {=0A= =0A= var elmnts =3D document.getElementsByTagName("span")=0A= for (var i =3D 0, len =3D elmnts.length; i < len; i++)=0A= {=0A= if (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= ------=_NextPart_000_0006_01C83427.2CBB4B20 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://www.ncbi.nlm.nih.gov/corehtml/jsutils/utils.1.js // $Id: utils.1.js,v 1.7 2007/03/28 15:33:23 sponomar Exp $=0A= var utils=3D{=0A= KeyCode_TAB:9,=0A= KeyCode_DELETE:46,=0A= KeyCode_BACKSPACE:8,=0A= KeyCode_LEFT_ARROW:37,=0A= KeyCode_RIGHT_ARROW:39,=0A= KeyCode_HOME:36,=0A= KeyCode_END:35,=0A= KeyCode_PAGE_UP:33,=0A= KeyCode_PAGE_DOWN:34,=0A= KeyCode_UP_ARROW:38,=0A= KeyCode_DOWN_ARROW:40,=0A= KeyCode_ESC:27,=0A= KeyCode_ENTER:13,=0A= KeyCode_SPACE:32,=0A= KeyCode_SHIFT_KEY:16,=0A= KeyCode_CTRL_KEY:17,=0A= KeyCode_ALT_KEY:18,=0A= KeyCode_LEFT_MS_WINDOWS_KEY:91,=0A= KeyCode_RIGHT_MS_WINDOWS_KEY:92,=0A= KeyCode_MS_MENU_KEY:93,=0A= isObject: function(a) { return (a && typeof a =3D=3D 'object'); 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oThis.iScaleIndex < = oMetadata.aView.length - 1; oThis.iScaleIndex++) {=0A= var s =3D oMetadata.aView[oThis.iScaleIndex].W / W;=0A= if (s <=3D 0.5 || s < 1.36) break;=0A= }=0A= } else =0A= oThis.iScaleIndex =3D 0;=0A= =0A= =0A= =0A= // var W =3D oThis.oPanorama.img.width;=0A= // var H =3D oThis.oPanorama.img.height;=0A= // console.info(W, H);=0A= // Set array scale data=0A= for (var i =3D 0; i < oMetadata.aView.length; i++) {=0A= // if (oMetadata.aView[i].W > oThis.oViewport.w || = oMetadata.aView[i].H > oThis.oViewport.h) {=0A= var v =3D oMetadata.aView[i].W / W;=0A= oThis.oScales[i] =3D {n:oMetadata.aView[i].sName, v:v};=0A= // } else =0A= // oThis.oScales[i] =3D null;=0A= =0A= if (oMetadata.aView[i].W =3D=3D oMetadata.aView[i].w =0A= && oMetadata.aView[i].H =3D=3D oMetadata.aView[i].h) {=0A= var v =3D oMetadata.aView[i].W / W;=0A= oThis.oScales[i] =3D {n:oMetadata.aView[i].sName, v:v};=0A= break;=0A= }=0A= }=0A= =0A= x_Update(oMetadata, oThis.iScaleIndex);=0A= }, null);=0A= =0A= =0A= this.oNotifier.setListener(this, "scale", function(oListener, = oComment) {=0A= // save previous scale index=0A= // skip unneccessary scales (if tiled picture less viewport)=0A= oThis.iScaleIndexPrevious =3D oThis.iScaleIndex;=0A= switch (oComment) {=0A= case "up":=0A= if (oThis.iScaleIndex < 1) return;=0A= oThis.iScaleIndex--;=0A= while (!oThis.oScales[oThis.iScaleIndex]) {=0A= oThis.iScaleIndex--;=0A= if (oThis.iScaleIndex < 1) break;=0A= }=0A= break;=0A= case "down":=0A= if (oThis.oScales.length - 1 <=3D oThis.iScaleIndex) return;=0A= oThis.iScaleIndex++;=0A= while (oThis.oScales[oThis.iScaleIndex] =3D=3D null) {=0A= oThis.iScaleIndex++;=0A= if (oThis.oScales.length - 1 <=3D oThis.iScaleIndex) = break;=0A= }=0A= break;=0A= default:=0A= oThis.iScaleIndex =3D oComment;=0A= break;=0A= }=0A= x_Update(oThis.oMetadata, oThis.iScaleIndex);=0A= }, null);=0A= =0A= =0A= setTimeout(function() {=0A= oDataProvider.Request();=0A= }, 5);=0A= }=0A= =0A= TileDataDb.prototype =3D new TileData();=0A= =0A= TileDataDb.prototype.Parse =3D function(arr) {=0A= var tmp;=0A= if (arr.indexOf("p=3D") =3D=3D 0) {=0A= tmp =3D arr.split("=3D");=0A= this.sProjectId =3D tmp[1];=0A= =0A= } else if (arr.indexOf("id=3D") =3D=3D 0) {=0A= tmp =3D arr.split("=3D");=0A= this.sPictureId =3D tmp[1];=0A= =0A= }=0A= }=0A= =0A= =0A= TileDataDb.prototype.GetTileUrl =3D function(row, col) {=0A= return this.sUrl + "?p=3D" + this.sProjectId =0A= + "&id=3D" + this.sTileDbId + "&s=3D" + this.sSat=0A= + "&r=3D" + (row + 1) + "&c=3D" + (col + 1);=0A= }=0A= =0A= =0A= TileDataDb.prototype.GetFitUrl =3D function() {=0A= return this.sUrl + "?p=3D" + this.sProjectId =0A= + "&id=3D" + this.oMetadata.aView[this.oMetadata.aView.length - = 1].sId =0A= + "&s=3D" + this.sSat + "&r=3D1&c=3D1";=0A= }=0A= ------=_NextPart_000_0006_01C83427.2CBB4B20--