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Bone marrow stromal antigen 2 expressed in cancer cells promotes mammary tumor growth and metastasis.

Mahauad-Fernandez WD, DeMali KA, Olivier AK, Okeoma CM - Breast Cancer Res. (2014)

Bottom Line: In vivo, we examined the effect of knockdown of BST-2 in two different murine carcinoma cells on tumor growth, metastasis, and survival.In mice, orthotopic implantation of mammary tumor cells lacking BST-2 increased tumor latency, decreased primary tumor growth, reduced metastases to distal organs, and prolonged host survival.Furthermore, we found that the cellular basis for the role of BST-2 in promoting tumorigenesis include BST-2-directed enhancement in cancer cell adhesion, anchorage-independency, migration, and invasion.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, 51 Newton Road, Iowa City, IA, 52242-1109, USA. wadiedaniel-mahauadfernandez@uiowa.edu.

ABSTRACT

Introduction: Several innate immunity genes are overexpressed in human cancers and their roles remain controversial. Bone marrow stromal antigen 2 (BST-2) is one such gene whose role in cancer is not clear. BST-2 is a unique innate immunity gene with both antiviral and pro-tumor functions and therefore can serve as a paradigm for understanding the roles of other innate immunity genes in cancers.

Methods: Meta-analysis of tumors from breast cancer patients obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets were evaluated for levels of BST-2 expression and for tumor aggressiveness. In vivo, we examined the effect of knockdown of BST-2 in two different murine carcinoma cells on tumor growth, metastasis, and survival. In vitro, we assessed the effect of carcinoma cell BST-2 knockdown and/or overexpression on adhesion, anchorage-independent growth, migration, and invasion.

Results: BST-2 in breast tumors and mammary cancer cells is a strong predictor of tumor size, tumor aggressiveness, and host survival. In humans, BST-2 mRNA is elevated in metastatic and invasive breast tumors. In mice, orthotopic implantation of mammary tumor cells lacking BST-2 increased tumor latency, decreased primary tumor growth, reduced metastases to distal organs, and prolonged host survival. Furthermore, we found that the cellular basis for the role of BST-2 in promoting tumorigenesis include BST-2-directed enhancement in cancer cell adhesion, anchorage-independency, migration, and invasion.

Conclusions: BST-2 contributes to the emergence of neoplasia and malignant progression of breast cancer. Thus, BST-2 may (1) serve as a biomarker for aggressive breast cancers, and (2) be a novel target for breast cancer therapeutics.

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Suppression of BST-2 in cancer cells increases tumor latency and decreases tumor massin vivo.(A) Knockdown of endogenous BST-2 expression in 4T1 cells increases tumor latency computed as (number of tumor-free injected mice/number of injected mice) x100. (B) Tumor volume (TV) computed as TV = 0.5 (length*width2) over time is significantly reduced when BST-2 is suppressed in 4T1 cells. (C) Tumor cells tracked in vivo with IVIS imaging system show significant reduction in luciferase expression in BST-2-suppressed sh413 compared to BST-2-expressing shControl injected mice. (D) Loss of BST-2 in cancer cells reduced tumor mass. Tumor weight (numbers, g) and gross images obtained at necropsy are shown. All mice implanted with 4T1 shControl or sh413 cells developed mammary tumors with variation in size. Numbers represent average ± SEM. Scale bar = 5 mm.
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Fig2: Suppression of BST-2 in cancer cells increases tumor latency and decreases tumor massin vivo.(A) Knockdown of endogenous BST-2 expression in 4T1 cells increases tumor latency computed as (number of tumor-free injected mice/number of injected mice) x100. (B) Tumor volume (TV) computed as TV = 0.5 (length*width2) over time is significantly reduced when BST-2 is suppressed in 4T1 cells. (C) Tumor cells tracked in vivo with IVIS imaging system show significant reduction in luciferase expression in BST-2-suppressed sh413 compared to BST-2-expressing shControl injected mice. (D) Loss of BST-2 in cancer cells reduced tumor mass. Tumor weight (numbers, g) and gross images obtained at necropsy are shown. All mice implanted with 4T1 shControl or sh413 cells developed mammary tumors with variation in size. Numbers represent average ± SEM. Scale bar = 5 mm.

Mentions: To determine the effect of BST-2 in primary mammary tumor development, we inoculated BST-2-expressing shControl and BST-2-suppressed sh413 4T1 cells into the mammary fat pads of BALB/c mice and evaluated tumor growth. 4T1 cells formed primary tumors in the mammary fat pad prior to metastasis [30]. We observed increased mammary tumor latency (Figure 2A) and delayed mammary tumor onset (Figure 2B) in mice implanted with BST-2-suppressed sh413 cells compared to shControl cells. Tumor volume over time was significantly lower in sh413 tumors compared to shControl tumors (Figure 2B). Because 4T1 cells were tagged with luciferase, we tracked cancer cells in vivo by IVIS imaging. As expected, luciferase intensity (photons/sec) was much lower in mice implanted with sh413 cells compared to shControl-implanted mice at the site of injection (Figure 2C). Inoculation of mice (n = 15) with BST-2-expressing shControl cells resulted in massive mammary tumors with an average tumor mass of 1.11 g ± 0.24 (Figure 2D). This result was in stark contrast to mice (n = 15) inoculated with BST-2-suppressed sh413 cells that developed significantly smaller tumors averaging 0.37 g ± 0.12 in weight (Figure 2D).Figure 2


Bone marrow stromal antigen 2 expressed in cancer cells promotes mammary tumor growth and metastasis.

Mahauad-Fernandez WD, DeMali KA, Olivier AK, Okeoma CM - Breast Cancer Res. (2014)

Suppression of BST-2 in cancer cells increases tumor latency and decreases tumor massin vivo.(A) Knockdown of endogenous BST-2 expression in 4T1 cells increases tumor latency computed as (number of tumor-free injected mice/number of injected mice) x100. (B) Tumor volume (TV) computed as TV = 0.5 (length*width2) over time is significantly reduced when BST-2 is suppressed in 4T1 cells. (C) Tumor cells tracked in vivo with IVIS imaging system show significant reduction in luciferase expression in BST-2-suppressed sh413 compared to BST-2-expressing shControl injected mice. (D) Loss of BST-2 in cancer cells reduced tumor mass. Tumor weight (numbers, g) and gross images obtained at necropsy are shown. All mice implanted with 4T1 shControl or sh413 cells developed mammary tumors with variation in size. Numbers represent average ± SEM. Scale bar = 5 mm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4308845&req=5

Fig2: Suppression of BST-2 in cancer cells increases tumor latency and decreases tumor massin vivo.(A) Knockdown of endogenous BST-2 expression in 4T1 cells increases tumor latency computed as (number of tumor-free injected mice/number of injected mice) x100. (B) Tumor volume (TV) computed as TV = 0.5 (length*width2) over time is significantly reduced when BST-2 is suppressed in 4T1 cells. (C) Tumor cells tracked in vivo with IVIS imaging system show significant reduction in luciferase expression in BST-2-suppressed sh413 compared to BST-2-expressing shControl injected mice. (D) Loss of BST-2 in cancer cells reduced tumor mass. Tumor weight (numbers, g) and gross images obtained at necropsy are shown. All mice implanted with 4T1 shControl or sh413 cells developed mammary tumors with variation in size. Numbers represent average ± SEM. Scale bar = 5 mm.
Mentions: To determine the effect of BST-2 in primary mammary tumor development, we inoculated BST-2-expressing shControl and BST-2-suppressed sh413 4T1 cells into the mammary fat pads of BALB/c mice and evaluated tumor growth. 4T1 cells formed primary tumors in the mammary fat pad prior to metastasis [30]. We observed increased mammary tumor latency (Figure 2A) and delayed mammary tumor onset (Figure 2B) in mice implanted with BST-2-suppressed sh413 cells compared to shControl cells. Tumor volume over time was significantly lower in sh413 tumors compared to shControl tumors (Figure 2B). Because 4T1 cells were tagged with luciferase, we tracked cancer cells in vivo by IVIS imaging. As expected, luciferase intensity (photons/sec) was much lower in mice implanted with sh413 cells compared to shControl-implanted mice at the site of injection (Figure 2C). Inoculation of mice (n = 15) with BST-2-expressing shControl cells resulted in massive mammary tumors with an average tumor mass of 1.11 g ± 0.24 (Figure 2D). This result was in stark contrast to mice (n = 15) inoculated with BST-2-suppressed sh413 cells that developed significantly smaller tumors averaging 0.37 g ± 0.12 in weight (Figure 2D).Figure 2

Bottom Line: In vivo, we examined the effect of knockdown of BST-2 in two different murine carcinoma cells on tumor growth, metastasis, and survival.In mice, orthotopic implantation of mammary tumor cells lacking BST-2 increased tumor latency, decreased primary tumor growth, reduced metastases to distal organs, and prolonged host survival.Furthermore, we found that the cellular basis for the role of BST-2 in promoting tumorigenesis include BST-2-directed enhancement in cancer cell adhesion, anchorage-independency, migration, and invasion.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, 51 Newton Road, Iowa City, IA, 52242-1109, USA. wadiedaniel-mahauadfernandez@uiowa.edu.

ABSTRACT

Introduction: Several innate immunity genes are overexpressed in human cancers and their roles remain controversial. Bone marrow stromal antigen 2 (BST-2) is one such gene whose role in cancer is not clear. BST-2 is a unique innate immunity gene with both antiviral and pro-tumor functions and therefore can serve as a paradigm for understanding the roles of other innate immunity genes in cancers.

Methods: Meta-analysis of tumors from breast cancer patients obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets were evaluated for levels of BST-2 expression and for tumor aggressiveness. In vivo, we examined the effect of knockdown of BST-2 in two different murine carcinoma cells on tumor growth, metastasis, and survival. In vitro, we assessed the effect of carcinoma cell BST-2 knockdown and/or overexpression on adhesion, anchorage-independent growth, migration, and invasion.

Results: BST-2 in breast tumors and mammary cancer cells is a strong predictor of tumor size, tumor aggressiveness, and host survival. In humans, BST-2 mRNA is elevated in metastatic and invasive breast tumors. In mice, orthotopic implantation of mammary tumor cells lacking BST-2 increased tumor latency, decreased primary tumor growth, reduced metastases to distal organs, and prolonged host survival. Furthermore, we found that the cellular basis for the role of BST-2 in promoting tumorigenesis include BST-2-directed enhancement in cancer cell adhesion, anchorage-independency, migration, and invasion.

Conclusions: BST-2 contributes to the emergence of neoplasia and malignant progression of breast cancer. Thus, BST-2 may (1) serve as a biomarker for aggressive breast cancers, and (2) be a novel target for breast cancer therapeutics.

Show MeSH
Related in: MedlinePlus