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Heterogeneous activation of the TGFbeta pathway in glioblastomas identified by gene expression-based classification using TGFbeta-responsive genes.

Xu XL, Kapoun AM - J Transl Med (2009)

Bottom Line: Among glioblastomas, one of the most devastating human cancers, two subgroups were identified that showed distinct TGFbeta activation patterns as measured from transcriptional responses.Approximately 62% of glioblastoma samples analyzed showed strong TGFbeta activation, while the rest showed a weak TGFbeta transcriptional response.Our findings suggest heterogeneous TGFbeta activation in glioblastomas, which may cause potential differences in responses to anti-TGFbeta therapies in these two distinct subgroups of glioblastomas patients.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biomarker R&D, Scios Inc, Fremont, California, USA. lxu@its.jnj.com

ABSTRACT

Background: TGFbeta has emerged as an attractive target for the therapeutic intervention of glioblastomas. Aberrant TGFbeta overproduction in glioblastoma and other high-grade gliomas has been reported, however, to date, none of these reports has systematically examined the components of TGFbeta signaling to gain a comprehensive view of TGFbeta activation in large cohorts of human glioma patients.

Methods: TGFbeta activation in mammalian cells leads to a transcriptional program that typically affects 5-10% of the genes in the genome. To systematically examine the status of TGFbeta activation in high-grade glial tumors, we compiled a gene set of transcriptional response to TGFbeta stimulation from tissue culture and in vivo animal studies. These genes were used to examine the status of TGFbeta activation in high-grade gliomas including a large cohort of glioblastomas. Unsupervised and supervised classification analysis was performed in two independent, publicly available glioma microarray datasets.

Results: Unsupervised and supervised classification using the TGFbeta-responsive gene list in two independent glial tumor gene expression data sets revealed various levels of TGFbeta activation in these tumors. Among glioblastomas, one of the most devastating human cancers, two subgroups were identified that showed distinct TGFbeta activation patterns as measured from transcriptional responses. Approximately 62% of glioblastoma samples analyzed showed strong TGFbeta activation, while the rest showed a weak TGFbeta transcriptional response.

Conclusion: Our findings suggest heterogeneous TGFbeta activation in glioblastomas, which may cause potential differences in responses to anti-TGFbeta therapies in these two distinct subgroups of glioblastomas patients.

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Related in: MedlinePlus

The expression of TGFβ downstream targets SERPINE1 in glial tumors (the Freije dataset) shown in box plots. Y-axis is the expression level of SERPINE1 in log2 scale. The black arrow indicates the mean expression level of SERPINE1 in each type of gliomas. Red spots indicate the outlier samples. The table underneath of the box plots are the summary statistics (count, mean, standard deviation (StdDev), median) of the expression level of SERPINE1 by glioma types. A: Significant association of SERPINE1 expression and histology classification. SERPINE1 is significantly upregulated in glioblastoma (GBM) compared to anaplastic astrocytoma (Astro), anaplastic oligodendroglioma (Oligo) and mixed glioma, anaplastic oligoastrocytoma (Mix). The mean expression level of SERPINE1 is 6.1-fold higher in glioblastoma compared to anstrocytoma, 5.3-fold higher compared to mixed glioma and 1.9-folder higher compared to oligodendroglioma. P-value computed using ANOVA is indicated at the top right corner of the plot. B. Significant association of SERPINE1 expression and the grade of the tumor. SERPINE1 is significantly upregulated in grade IV tumors (GBM) compared to grade III tumors (Astro, Oligo, Mix). The mean expression level of SERPINE1 is 3.7-fold higher in grade IV tumors (GBM) than in grade III tumors. The P-value was computed using a t-test as indicated in the top left corner of the plot. C. The expression of SERPINE1 is highly correlated with FN1 expression in gliomas. The correlation coefficient (R) and P-value of correlation (p) were indicated in the plot. The histology types of the gliomas are indicated by colors (blue: GBM, red: Astro, pink: Mix, black: Oligo).
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Figure 2: The expression of TGFβ downstream targets SERPINE1 in glial tumors (the Freije dataset) shown in box plots. Y-axis is the expression level of SERPINE1 in log2 scale. The black arrow indicates the mean expression level of SERPINE1 in each type of gliomas. Red spots indicate the outlier samples. The table underneath of the box plots are the summary statistics (count, mean, standard deviation (StdDev), median) of the expression level of SERPINE1 by glioma types. A: Significant association of SERPINE1 expression and histology classification. SERPINE1 is significantly upregulated in glioblastoma (GBM) compared to anaplastic astrocytoma (Astro), anaplastic oligodendroglioma (Oligo) and mixed glioma, anaplastic oligoastrocytoma (Mix). The mean expression level of SERPINE1 is 6.1-fold higher in glioblastoma compared to anstrocytoma, 5.3-fold higher compared to mixed glioma and 1.9-folder higher compared to oligodendroglioma. P-value computed using ANOVA is indicated at the top right corner of the plot. B. Significant association of SERPINE1 expression and the grade of the tumor. SERPINE1 is significantly upregulated in grade IV tumors (GBM) compared to grade III tumors (Astro, Oligo, Mix). The mean expression level of SERPINE1 is 3.7-fold higher in grade IV tumors (GBM) than in grade III tumors. The P-value was computed using a t-test as indicated in the top left corner of the plot. C. The expression of SERPINE1 is highly correlated with FN1 expression in gliomas. The correlation coefficient (R) and P-value of correlation (p) were indicated in the plot. The histology types of the gliomas are indicated by colors (blue: GBM, red: Astro, pink: Mix, black: Oligo).

Mentions: As a first step towards characterizing the TGFβ-responsive gene set in gliomas, we examined the expression of a classic TGFβ target gene SERPINE1 in glial tumors within the Freije data set. The expression of SERPINE1, also called PAI-1, has been shown to be regulated by TGFβ in several reports [31]. Multiple TGFβ-responsive elements have been identified at the promoter region of the SERPINE1 gene [32,33]. The protein products of the SERPINE1 gene play important roles in TGFβ-mediated biological processes such as fibrosis and wound healing [34]. The induction of SERPINE1 expression by TGFβ was abolished by agents that interfered with TGFβ signaling [17]. Our ANOVA analysis of the Freije study suggested that there was no significant association between SERPINE1 expression and age or gender. However, SERPINE1 expression was significantly associated with the following histological types: glioblastoma (GBM), anaplastic astrocytoma (Astro), anaplastic oligodendroglioma (Oligo) and mixed glioma, anaplastic oligoastrocytoma (Mix)(p < 1.52 × 10-5), as well as grades (III and IV) (p < 7.87 × 10-6). SERPINE1 expression was significantly upregulated in glioblastoma (grade IV) compared to other grade III glial tumors (anaplastic astrocytoma, anaplastic oligodendroglioma and mixed glioma, anaplastic oligoastrocytoma, Figure 2A and Figure 2B). Similar results were found in another TGFβ target FN1 (Additional file 2). Moreover, the expressions of SERPINE1 and FN1 were highly correlated among the high-grade gliomas (correlation coefficient r = 0.687, Figure 2C), suggesting the activation of TGFβ pathway [35]. We also found similar expression patterns in a second independent glioma dataset, the Nutt study [28].


Heterogeneous activation of the TGFbeta pathway in glioblastomas identified by gene expression-based classification using TGFbeta-responsive genes.

Xu XL, Kapoun AM - J Transl Med (2009)

The expression of TGFβ downstream targets SERPINE1 in glial tumors (the Freije dataset) shown in box plots. Y-axis is the expression level of SERPINE1 in log2 scale. The black arrow indicates the mean expression level of SERPINE1 in each type of gliomas. Red spots indicate the outlier samples. The table underneath of the box plots are the summary statistics (count, mean, standard deviation (StdDev), median) of the expression level of SERPINE1 by glioma types. A: Significant association of SERPINE1 expression and histology classification. SERPINE1 is significantly upregulated in glioblastoma (GBM) compared to anaplastic astrocytoma (Astro), anaplastic oligodendroglioma (Oligo) and mixed glioma, anaplastic oligoastrocytoma (Mix). The mean expression level of SERPINE1 is 6.1-fold higher in glioblastoma compared to anstrocytoma, 5.3-fold higher compared to mixed glioma and 1.9-folder higher compared to oligodendroglioma. P-value computed using ANOVA is indicated at the top right corner of the plot. B. Significant association of SERPINE1 expression and the grade of the tumor. SERPINE1 is significantly upregulated in grade IV tumors (GBM) compared to grade III tumors (Astro, Oligo, Mix). The mean expression level of SERPINE1 is 3.7-fold higher in grade IV tumors (GBM) than in grade III tumors. The P-value was computed using a t-test as indicated in the top left corner of the plot. C. The expression of SERPINE1 is highly correlated with FN1 expression in gliomas. The correlation coefficient (R) and P-value of correlation (p) were indicated in the plot. The histology types of the gliomas are indicated by colors (blue: GBM, red: Astro, pink: Mix, black: Oligo).
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Figure 2: The expression of TGFβ downstream targets SERPINE1 in glial tumors (the Freije dataset) shown in box plots. Y-axis is the expression level of SERPINE1 in log2 scale. The black arrow indicates the mean expression level of SERPINE1 in each type of gliomas. Red spots indicate the outlier samples. The table underneath of the box plots are the summary statistics (count, mean, standard deviation (StdDev), median) of the expression level of SERPINE1 by glioma types. A: Significant association of SERPINE1 expression and histology classification. SERPINE1 is significantly upregulated in glioblastoma (GBM) compared to anaplastic astrocytoma (Astro), anaplastic oligodendroglioma (Oligo) and mixed glioma, anaplastic oligoastrocytoma (Mix). The mean expression level of SERPINE1 is 6.1-fold higher in glioblastoma compared to anstrocytoma, 5.3-fold higher compared to mixed glioma and 1.9-folder higher compared to oligodendroglioma. P-value computed using ANOVA is indicated at the top right corner of the plot. B. Significant association of SERPINE1 expression and the grade of the tumor. SERPINE1 is significantly upregulated in grade IV tumors (GBM) compared to grade III tumors (Astro, Oligo, Mix). The mean expression level of SERPINE1 is 3.7-fold higher in grade IV tumors (GBM) than in grade III tumors. The P-value was computed using a t-test as indicated in the top left corner of the plot. C. The expression of SERPINE1 is highly correlated with FN1 expression in gliomas. The correlation coefficient (R) and P-value of correlation (p) were indicated in the plot. The histology types of the gliomas are indicated by colors (blue: GBM, red: Astro, pink: Mix, black: Oligo).
Mentions: As a first step towards characterizing the TGFβ-responsive gene set in gliomas, we examined the expression of a classic TGFβ target gene SERPINE1 in glial tumors within the Freije data set. The expression of SERPINE1, also called PAI-1, has been shown to be regulated by TGFβ in several reports [31]. Multiple TGFβ-responsive elements have been identified at the promoter region of the SERPINE1 gene [32,33]. The protein products of the SERPINE1 gene play important roles in TGFβ-mediated biological processes such as fibrosis and wound healing [34]. The induction of SERPINE1 expression by TGFβ was abolished by agents that interfered with TGFβ signaling [17]. Our ANOVA analysis of the Freije study suggested that there was no significant association between SERPINE1 expression and age or gender. However, SERPINE1 expression was significantly associated with the following histological types: glioblastoma (GBM), anaplastic astrocytoma (Astro), anaplastic oligodendroglioma (Oligo) and mixed glioma, anaplastic oligoastrocytoma (Mix)(p < 1.52 × 10-5), as well as grades (III and IV) (p < 7.87 × 10-6). SERPINE1 expression was significantly upregulated in glioblastoma (grade IV) compared to other grade III glial tumors (anaplastic astrocytoma, anaplastic oligodendroglioma and mixed glioma, anaplastic oligoastrocytoma, Figure 2A and Figure 2B). Similar results were found in another TGFβ target FN1 (Additional file 2). Moreover, the expressions of SERPINE1 and FN1 were highly correlated among the high-grade gliomas (correlation coefficient r = 0.687, Figure 2C), suggesting the activation of TGFβ pathway [35]. We also found similar expression patterns in a second independent glioma dataset, the Nutt study [28].

Bottom Line: Among glioblastomas, one of the most devastating human cancers, two subgroups were identified that showed distinct TGFbeta activation patterns as measured from transcriptional responses.Approximately 62% of glioblastoma samples analyzed showed strong TGFbeta activation, while the rest showed a weak TGFbeta transcriptional response.Our findings suggest heterogeneous TGFbeta activation in glioblastomas, which may cause potential differences in responses to anti-TGFbeta therapies in these two distinct subgroups of glioblastomas patients.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biomarker R&D, Scios Inc, Fremont, California, USA. lxu@its.jnj.com

ABSTRACT

Background: TGFbeta has emerged as an attractive target for the therapeutic intervention of glioblastomas. Aberrant TGFbeta overproduction in glioblastoma and other high-grade gliomas has been reported, however, to date, none of these reports has systematically examined the components of TGFbeta signaling to gain a comprehensive view of TGFbeta activation in large cohorts of human glioma patients.

Methods: TGFbeta activation in mammalian cells leads to a transcriptional program that typically affects 5-10% of the genes in the genome. To systematically examine the status of TGFbeta activation in high-grade glial tumors, we compiled a gene set of transcriptional response to TGFbeta stimulation from tissue culture and in vivo animal studies. These genes were used to examine the status of TGFbeta activation in high-grade gliomas including a large cohort of glioblastomas. Unsupervised and supervised classification analysis was performed in two independent, publicly available glioma microarray datasets.

Results: Unsupervised and supervised classification using the TGFbeta-responsive gene list in two independent glial tumor gene expression data sets revealed various levels of TGFbeta activation in these tumors. Among glioblastomas, one of the most devastating human cancers, two subgroups were identified that showed distinct TGFbeta activation patterns as measured from transcriptional responses. Approximately 62% of glioblastoma samples analyzed showed strong TGFbeta activation, while the rest showed a weak TGFbeta transcriptional response.

Conclusion: Our findings suggest heterogeneous TGFbeta activation in glioblastomas, which may cause potential differences in responses to anti-TGFbeta therapies in these two distinct subgroups of glioblastomas patients.

Show MeSH
Related in: MedlinePlus