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Conserved Molecular Underpinnings and Characterization of a Role for Caveolin-1 in the Tumor Microenvironment of Mature T-Cell Lymphomas.

Herek TA, Shew TD, Spurgin HN, Cutucache CE - PLoS ONE (2015)

Bottom Line: Neoplasms of extra-thymic T-cell origin represent a rare and difficult population characterized by poor clinical outcome, aggressive presentation, and poorly defined molecular characteristics.From these results, we sought to characterize a role for caveolin-1 (CAV1), a gene with previous description in the progression of both solid and hematological tumors.Taken together, these results demonstrate a role for CAV1 in the tumor microenvironment of mature T-cell malignancies and point toward potential prognostic implications.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of Nebraska at Omaha, Omaha, Nebraska, United States of America.

ABSTRACT
Neoplasms of extra-thymic T-cell origin represent a rare and difficult population characterized by poor clinical outcome, aggressive presentation, and poorly defined molecular characteristics. Much work has been done to gain greater insights into distinguishing features among malignant subtypes, but there also exists a need to identify unifying characteristics to assist in rapid diagnosis and subsequent potential treatment. Herein, we investigated gene expression data of five different mature T-cell lymphoma subtypes (n = 187) and found 21 genes to be up- and down-regulated across all malignancies in comparison to healthy CD4(+) and CD8(+) T-cell controls (n = 52). From these results, we sought to characterize a role for caveolin-1 (CAV1), a gene with previous description in the progression of both solid and hematological tumors. Caveolin-1 was upregulated, albeit with a heterogeneous nature, across all mature T-cell lymphoma subtypes, a finding confirmed using immunohistochemical staining on an independent sampling of mature T-cell lymphoma biopsies (n = 65 cases). Further, stratifying malignant samples in accordance with high and low CAV1 expression revealed that higher expression of CAV1 in mature T-cell lymphomas is analogous with an enhanced inflammatory and invasive gene expression profile. Taken together, these results demonstrate a role for CAV1 in the tumor microenvironment of mature T-cell malignancies and point toward potential prognostic implications.

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T-cell lymphomas can be divided into CAV1-High and CAV-1 Low subgroups.(A) Boxplot of normalized 212097_at (CAV1) probe signal between pooled healthy controls and malignant samples. Continuous line represents median value, discontinuous line represents mean. Red line represents threshold for CAV1-High or CAV1-Low expression determination and is set 2 standard deviations above the healthy T-cell mean value. (B) Classification of CAV1-High and CAV1-Low samples according to expression threshold. Solid bars and above-bar values represent percentage of CAV1-High samples per subtype. 67% (125/187) of all malignant samples were classified as CAV1-High. 77% (33/43) of AITL samples, 47% (21/45) of ALCL samples, 85% (11/13) of ATLL samples, 75% (6/8) of HSTL samples, 69% (54/78) of PTCL-NOS samples.
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pone.0142682.g002: T-cell lymphomas can be divided into CAV1-High and CAV-1 Low subgroups.(A) Boxplot of normalized 212097_at (CAV1) probe signal between pooled healthy controls and malignant samples. Continuous line represents median value, discontinuous line represents mean. Red line represents threshold for CAV1-High or CAV1-Low expression determination and is set 2 standard deviations above the healthy T-cell mean value. (B) Classification of CAV1-High and CAV1-Low samples according to expression threshold. Solid bars and above-bar values represent percentage of CAV1-High samples per subtype. 67% (125/187) of all malignant samples were classified as CAV1-High. 77% (33/43) of AITL samples, 47% (21/45) of ALCL samples, 85% (11/13) of ATLL samples, 75% (6/8) of HSTL samples, 69% (54/78) of PTCL-NOS samples.

Mentions: As previously reported, higher CAV1 expression in B-cell lymphomas leads to a more aggressive disease [15, 16] with an inferior overall survival among patients with higher CAV1 expression [15]. Therefore, we decided to further investigate the differences between CAV1-High and CAV1-Low expressing mature T-cell lymphoma samples in an effort to characterize the impact of CAV1 on the tumor microenvironment (TME). Analysis of CAV1 expression using 212097_at probe signal intensity revealed that all mature T-cell lymphoma subtypes analyzed have a higher mean expression of CAV1 (p < 0.001, FDR < 0.001) as compared to healthy CD4+ and CD8+ T-cell controls (Fig 1C). However, as expected, there exists a heterogeneous expression of CAV1 amongst the malignant samples. To stratify samples into the abovementioned groups, healthy controls and malignant samples were pooled, respectively. Moreover, a CAV1-Low expression threshold was calculated based on the distribution of CAV1 expression in healthy samples (Fig 2A). Using this threshold, 67% (125/187) of mature T-cell lymphoma samples were classified as CAV1-High (Fig 2B). For each T-cell lymphoma subtype: 77% (33/43) of AITL samples, 47% (21/45) of ALCL samples, 85% (11/13) of ATLL samples, 75% (6/8) of HSTL samples, and 69% (54/78) of PTCL-NOS samples were classified as CAV1-High.


Conserved Molecular Underpinnings and Characterization of a Role for Caveolin-1 in the Tumor Microenvironment of Mature T-Cell Lymphomas.

Herek TA, Shew TD, Spurgin HN, Cutucache CE - PLoS ONE (2015)

T-cell lymphomas can be divided into CAV1-High and CAV-1 Low subgroups.(A) Boxplot of normalized 212097_at (CAV1) probe signal between pooled healthy controls and malignant samples. Continuous line represents median value, discontinuous line represents mean. Red line represents threshold for CAV1-High or CAV1-Low expression determination and is set 2 standard deviations above the healthy T-cell mean value. (B) Classification of CAV1-High and CAV1-Low samples according to expression threshold. Solid bars and above-bar values represent percentage of CAV1-High samples per subtype. 67% (125/187) of all malignant samples were classified as CAV1-High. 77% (33/43) of AITL samples, 47% (21/45) of ALCL samples, 85% (11/13) of ATLL samples, 75% (6/8) of HSTL samples, 69% (54/78) of PTCL-NOS samples.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4643970&req=5

pone.0142682.g002: T-cell lymphomas can be divided into CAV1-High and CAV-1 Low subgroups.(A) Boxplot of normalized 212097_at (CAV1) probe signal between pooled healthy controls and malignant samples. Continuous line represents median value, discontinuous line represents mean. Red line represents threshold for CAV1-High or CAV1-Low expression determination and is set 2 standard deviations above the healthy T-cell mean value. (B) Classification of CAV1-High and CAV1-Low samples according to expression threshold. Solid bars and above-bar values represent percentage of CAV1-High samples per subtype. 67% (125/187) of all malignant samples were classified as CAV1-High. 77% (33/43) of AITL samples, 47% (21/45) of ALCL samples, 85% (11/13) of ATLL samples, 75% (6/8) of HSTL samples, 69% (54/78) of PTCL-NOS samples.
Mentions: As previously reported, higher CAV1 expression in B-cell lymphomas leads to a more aggressive disease [15, 16] with an inferior overall survival among patients with higher CAV1 expression [15]. Therefore, we decided to further investigate the differences between CAV1-High and CAV1-Low expressing mature T-cell lymphoma samples in an effort to characterize the impact of CAV1 on the tumor microenvironment (TME). Analysis of CAV1 expression using 212097_at probe signal intensity revealed that all mature T-cell lymphoma subtypes analyzed have a higher mean expression of CAV1 (p < 0.001, FDR < 0.001) as compared to healthy CD4+ and CD8+ T-cell controls (Fig 1C). However, as expected, there exists a heterogeneous expression of CAV1 amongst the malignant samples. To stratify samples into the abovementioned groups, healthy controls and malignant samples were pooled, respectively. Moreover, a CAV1-Low expression threshold was calculated based on the distribution of CAV1 expression in healthy samples (Fig 2A). Using this threshold, 67% (125/187) of mature T-cell lymphoma samples were classified as CAV1-High (Fig 2B). For each T-cell lymphoma subtype: 77% (33/43) of AITL samples, 47% (21/45) of ALCL samples, 85% (11/13) of ATLL samples, 75% (6/8) of HSTL samples, and 69% (54/78) of PTCL-NOS samples were classified as CAV1-High.

Bottom Line: Neoplasms of extra-thymic T-cell origin represent a rare and difficult population characterized by poor clinical outcome, aggressive presentation, and poorly defined molecular characteristics.From these results, we sought to characterize a role for caveolin-1 (CAV1), a gene with previous description in the progression of both solid and hematological tumors.Taken together, these results demonstrate a role for CAV1 in the tumor microenvironment of mature T-cell malignancies and point toward potential prognostic implications.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, University of Nebraska at Omaha, Omaha, Nebraska, United States of America.

ABSTRACT
Neoplasms of extra-thymic T-cell origin represent a rare and difficult population characterized by poor clinical outcome, aggressive presentation, and poorly defined molecular characteristics. Much work has been done to gain greater insights into distinguishing features among malignant subtypes, but there also exists a need to identify unifying characteristics to assist in rapid diagnosis and subsequent potential treatment. Herein, we investigated gene expression data of five different mature T-cell lymphoma subtypes (n = 187) and found 21 genes to be up- and down-regulated across all malignancies in comparison to healthy CD4(+) and CD8(+) T-cell controls (n = 52). From these results, we sought to characterize a role for caveolin-1 (CAV1), a gene with previous description in the progression of both solid and hematological tumors. Caveolin-1 was upregulated, albeit with a heterogeneous nature, across all mature T-cell lymphoma subtypes, a finding confirmed using immunohistochemical staining on an independent sampling of mature T-cell lymphoma biopsies (n = 65 cases). Further, stratifying malignant samples in accordance with high and low CAV1 expression revealed that higher expression of CAV1 in mature T-cell lymphomas is analogous with an enhanced inflammatory and invasive gene expression profile. Taken together, these results demonstrate a role for CAV1 in the tumor microenvironment of mature T-cell malignancies and point toward potential prognostic implications.

Show MeSH
Related in: MedlinePlus