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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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Down-modulation of BST-2 in cancer cells reduces mammary cancer metastases. (A) Representative images of tumor cells tracked in vivo with IVIS imaging at different time points. Images show higher luciferase bioluminescence in 4T1 shControl-injected mice compared to sh413-injected mice. (B) Representative luciferase bioluminescence accompanied with abdominal and gastrointestinal tract (GI tract) gross images of uninjected (upper panel), shControl-implanted (middle panel), and sh413-implanted mice (lower panel). Arrow heads point to mammary tumors (middle column) and intestinal/mesenteric tumors (right column). Scale bar = 5 mm. (C) Number of secondary tumors in intestine/mesentery plotted as average of all mice. (D) Representative intestine/mesentery histology images from 4T1 shControl and sh413-injected mice confirming increased mesenteric tumors (arrows) in shControl mice compared to sh413-injected mice. A mesenteric lymph node is demarcated by an asterisk (not to be confused with a tumor mass). (E) Representative gross liver images of 4T1 shControl and sh413-injected mice. Arrows are pointing to tumors. (F) Representative gross images of lungs showing visible pulmonary nodules (arrows) in shControl-implanted mice. (G) Percent incidence of liver and lung metastases. (H) Lung histology from shControl (upper left) and sh413 (upper right) injected mice. Lung from the 4T1 shControl mice had multiple large tumors (tumors demonstrated by asterisk) and marked infiltration of the alveolar septa and alveolar spaces by neutrophils (yellow arrows). Boxed regions are shown at higher magnification (40X) for shControl (lower left) and sh413 (lower right). Error bars represent standard deviations and significance was taken at P <0.01**.
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Fig3: Down-modulation of BST-2 in cancer cells reduces mammary cancer metastases. (A) Representative images of tumor cells tracked in vivo with IVIS imaging at different time points. Images show higher luciferase bioluminescence in 4T1 shControl-injected mice compared to sh413-injected mice. (B) Representative luciferase bioluminescence accompanied with abdominal and gastrointestinal tract (GI tract) gross images of uninjected (upper panel), shControl-implanted (middle panel), and sh413-implanted mice (lower panel). Arrow heads point to mammary tumors (middle column) and intestinal/mesenteric tumors (right column). Scale bar = 5 mm. (C) Number of secondary tumors in intestine/mesentery plotted as average of all mice. (D) Representative intestine/mesentery histology images from 4T1 shControl and sh413-injected mice confirming increased mesenteric tumors (arrows) in shControl mice compared to sh413-injected mice. A mesenteric lymph node is demarcated by an asterisk (not to be confused with a tumor mass). (E) Representative gross liver images of 4T1 shControl and sh413-injected mice. Arrows are pointing to tumors. (F) Representative gross images of lungs showing visible pulmonary nodules (arrows) in shControl-implanted mice. (G) Percent incidence of liver and lung metastases. (H) Lung histology from shControl (upper left) and sh413 (upper right) injected mice. Lung from the 4T1 shControl mice had multiple large tumors (tumors demonstrated by asterisk) and marked infiltration of the alveolar septa and alveolar spaces by neutrophils (yellow arrows). Boxed regions are shown at higher magnification (40X) for shControl (lower left) and sh413 (lower right). Error bars represent standard deviations and significance was taken at P <0.01**.

Mentions: E0771 and 4T1 cells metastasize to liver, bone, lung, and intestine [29,31]. Thus, we investigated whether BST-2 enhances the metastatic potential of primary tumor cells. As expected, all mice implanted with BST-2-expressing shControl 4T1luc cells showed early onset and progressive increase in bioluminescence. The increase in bioluminescence signal intensity over time suggests progression and metastasis of cancer (Figure 3A, upper panel, Figure 3B, left, middle panel). Indeed, BST-2-expressing shControl cells formed primary tumors quickly and developed metastatic lesions that could be detected by bioluminescence imaging [32]. In striking contrast, BST-2-suppressed 4T1 cells (sh413) exhibited delayed onset of luciferase bioluminescence and disappearance of expression as measured over 45 days (Figure 3A, lower panel; Figure 3B, left, bottom panel). Unlike shControl-implanted mice that developed severe abdominal hemorrhage and intestinal/mesenteric tumors (Figure 3B, center, middle and right panels), sh413-implanted mice did not develop hemorrhage and had few intestinal/mesenteric tumors (compare Figure 3B, uninjected - upper panel with Figure 3B, sh413-injected - lower panel). Metastasis to the intestine and mesentery were significantly reduced from about 21 tumors in shControl mice (Figure 3B, middle right panel and Figure 3C) to six tumors in sh413 mice (Figure 3B, bottom right panel and Figure 3C). Histology confirmed increased intestinal/mesentery tumors in shControl-implanted mice compared to sh413-implanted mice (Figure 3D, arrows). These findings were confirmed with the highly metastatic E0771 cells. Mice (n = 10) implanted with BST-2-expressing E0771 cells (shControl) had higher bioluminescence and increased intestinal/mesenteric tumors compared to mice implanted with BST-2-suppressed sh413 cells (Figures S3B to S3D in Additional file 3).Figure 3


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)

Down-modulation of BST-2 in cancer cells reduces mammary cancer metastases. (A) Representative images of tumor cells tracked in vivo with IVIS imaging at different time points. Images show higher luciferase bioluminescence in 4T1 shControl-injected mice compared to sh413-injected mice. (B) Representative luciferase bioluminescence accompanied with abdominal and gastrointestinal tract (GI tract) gross images of uninjected (upper panel), shControl-implanted (middle panel), and sh413-implanted mice (lower panel). Arrow heads point to mammary tumors (middle column) and intestinal/mesenteric tumors (right column). Scale bar = 5 mm. (C) Number of secondary tumors in intestine/mesentery plotted as average of all mice. (D) Representative intestine/mesentery histology images from 4T1 shControl and sh413-injected mice confirming increased mesenteric tumors (arrows) in shControl mice compared to sh413-injected mice. A mesenteric lymph node is demarcated by an asterisk (not to be confused with a tumor mass). (E) Representative gross liver images of 4T1 shControl and sh413-injected mice. Arrows are pointing to tumors. (F) Representative gross images of lungs showing visible pulmonary nodules (arrows) in shControl-implanted mice. (G) Percent incidence of liver and lung metastases. (H) Lung histology from shControl (upper left) and sh413 (upper right) injected mice. Lung from the 4T1 shControl mice had multiple large tumors (tumors demonstrated by asterisk) and marked infiltration of the alveolar septa and alveolar spaces by neutrophils (yellow arrows). Boxed regions are shown at higher magnification (40X) for shControl (lower left) and sh413 (lower right). Error bars represent standard deviations and significance was taken at P <0.01**.
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Related In: Results  -  Collection

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Fig3: Down-modulation of BST-2 in cancer cells reduces mammary cancer metastases. (A) Representative images of tumor cells tracked in vivo with IVIS imaging at different time points. Images show higher luciferase bioluminescence in 4T1 shControl-injected mice compared to sh413-injected mice. (B) Representative luciferase bioluminescence accompanied with abdominal and gastrointestinal tract (GI tract) gross images of uninjected (upper panel), shControl-implanted (middle panel), and sh413-implanted mice (lower panel). Arrow heads point to mammary tumors (middle column) and intestinal/mesenteric tumors (right column). Scale bar = 5 mm. (C) Number of secondary tumors in intestine/mesentery plotted as average of all mice. (D) Representative intestine/mesentery histology images from 4T1 shControl and sh413-injected mice confirming increased mesenteric tumors (arrows) in shControl mice compared to sh413-injected mice. A mesenteric lymph node is demarcated by an asterisk (not to be confused with a tumor mass). (E) Representative gross liver images of 4T1 shControl and sh413-injected mice. Arrows are pointing to tumors. (F) Representative gross images of lungs showing visible pulmonary nodules (arrows) in shControl-implanted mice. (G) Percent incidence of liver and lung metastases. (H) Lung histology from shControl (upper left) and sh413 (upper right) injected mice. Lung from the 4T1 shControl mice had multiple large tumors (tumors demonstrated by asterisk) and marked infiltration of the alveolar septa and alveolar spaces by neutrophils (yellow arrows). Boxed regions are shown at higher magnification (40X) for shControl (lower left) and sh413 (lower right). Error bars represent standard deviations and significance was taken at P <0.01**.
Mentions: E0771 and 4T1 cells metastasize to liver, bone, lung, and intestine [29,31]. Thus, we investigated whether BST-2 enhances the metastatic potential of primary tumor cells. As expected, all mice implanted with BST-2-expressing shControl 4T1luc cells showed early onset and progressive increase in bioluminescence. The increase in bioluminescence signal intensity over time suggests progression and metastasis of cancer (Figure 3A, upper panel, Figure 3B, left, middle panel). Indeed, BST-2-expressing shControl cells formed primary tumors quickly and developed metastatic lesions that could be detected by bioluminescence imaging [32]. In striking contrast, BST-2-suppressed 4T1 cells (sh413) exhibited delayed onset of luciferase bioluminescence and disappearance of expression as measured over 45 days (Figure 3A, lower panel; Figure 3B, left, bottom panel). Unlike shControl-implanted mice that developed severe abdominal hemorrhage and intestinal/mesenteric tumors (Figure 3B, center, middle and right panels), sh413-implanted mice did not develop hemorrhage and had few intestinal/mesenteric tumors (compare Figure 3B, uninjected - upper panel with Figure 3B, sh413-injected - lower panel). Metastasis to the intestine and mesentery were significantly reduced from about 21 tumors in shControl mice (Figure 3B, middle right panel and Figure 3C) to six tumors in sh413 mice (Figure 3B, bottom right panel and Figure 3C). Histology confirmed increased intestinal/mesentery tumors in shControl-implanted mice compared to sh413-implanted mice (Figure 3D, arrows). These findings were confirmed with the highly metastatic E0771 cells. Mice (n = 10) implanted with BST-2-expressing E0771 cells (shControl) had higher bioluminescence and increased intestinal/mesenteric tumors compared to mice implanted with BST-2-suppressed sh413 cells (Figures S3B to S3D in Additional file 3).Figure 3

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