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Inflammation Mediated Metastasis: Immune Induced Epithelial-To-Mesenchymal Transition in Inflammatory Breast Cancer Cells.

Cohen EN, Gao H, Anfossi S, Mego M, Reddy NG, Debeb B, Giordano A, Tin S, Wu Q, Garza RJ, Cristofanilli M, Mani SA, Croix DA, Ueno NT, Woodward WA, Luthra R, Krishnamurthy S, Reuben JM - PLoS ONE (2015)

Bottom Line: It is unknown whether immune cells associated to the IBC microenvironment play a role in this scenario to transiently promote epithelial to mesenchymal transition (EMT) in these cells.A combination of TNF-α, IL-6, and TGF-β was able to recapitulate EMT induction in IBC, and conditioned media preloaded with neutralizing antibodies against these factors exhibited decreased EMT.These data suggest that release of cytokines by activated immune cells may contribute to the aggressiveness of IBC and highlight these factors as potential target mediators of immune-IBC interaction.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America; The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America; The University of Texas Graduate School of Biomedical Sciences at Houston, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.

ABSTRACT
Inflammatory breast cancer (IBC) is the most insidious form of locally advanced breast cancer; about a third of patients have distant metastasis at initial staging. Emerging evidence suggests that host factors in the tumor microenvironment may interact with underlying IBC cells to make them aggressive. It is unknown whether immune cells associated to the IBC microenvironment play a role in this scenario to transiently promote epithelial to mesenchymal transition (EMT) in these cells. We hypothesized that soluble factors secreted by activated immune cells can induce an EMT in IBC and thus promote metastasis. In a pilot study of 16 breast cancer patients, TNF-α production by peripheral blood T cells was correlated with the detection of circulating tumor cells expressing EMT markers. In a variety of IBC model cell lines, soluble factors from activated T cells induced expression of EMT-related genes, including FN1, VIM, TGM2, ZEB1. Interestingly, although IBC cells exhibited increased invasion and migration following exposure to immune factors, the expression of E-cadherin (CDH1), a cell adhesion molecule, increased uniquely in IBC cell lines but not in non-IBC cell lines. A combination of TNF-α, IL-6, and TGF-β was able to recapitulate EMT induction in IBC, and conditioned media preloaded with neutralizing antibodies against these factors exhibited decreased EMT. These data suggest that release of cytokines by activated immune cells may contribute to the aggressiveness of IBC and highlight these factors as potential target mediators of immune-IBC interaction.

No MeSH data available.


Related in: MedlinePlus

Analysis of multiple cell lines by Fluidigm.Breast cancer cell lines were incubated with immune CM for 48 hours and mRNA was analyzed by qRT-PCR. Media control appears as a solid black line at 1 in the center of each plot, points falling outside the circle represent increased relative expression and lines inside are decreased. TCR-CM anti-CD3 induced EMT-related factors to varying degrees in all cell lines. Following treatment with TCR-CM, IBC cell lines with the exception of KPL4, had increased expression of E-cadherin.
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pone.0132710.g003: Analysis of multiple cell lines by Fluidigm.Breast cancer cell lines were incubated with immune CM for 48 hours and mRNA was analyzed by qRT-PCR. Media control appears as a solid black line at 1 in the center of each plot, points falling outside the circle represent increased relative expression and lines inside are decreased. TCR-CM anti-CD3 induced EMT-related factors to varying degrees in all cell lines. Following treatment with TCR-CM, IBC cell lines with the exception of KPL4, had increased expression of E-cadherin.

Mentions: A panel of 24 selected genes was analyzed for each condition using Fluidigm integrated fluidic circuit chips (Fig 3). Most cell lines showed increased expression of EMT-regulating genes following treatment with immune cell CM. Changes in response to LPS-CM were generally attenuated compared to TCR-CM, possibly due to the smaller relative number of monocytes than T cells in PBMC. ZEB1 and TGM2 were the most frequently, and highly induced EMT-related factors, along with inflammatory factors prostaglandin E synthase 2 (PTGES2) and IL-8 (CXCL8). Consistent with induction of EMT in epithelial cells, epithelial cell adhesion molecule (EpCAM) expression decreased with TCR-CM treatment in every cell line except SUM149. However, in the other IBC cell lines, although EpCAM expression was reduced, this down-regulation was attenuated compared to the non-IBC cell lines (p = 0.0197). Likewise, although the non-IBC cell lines showed no change in E-cadherin expression at this time point, 3 of the 4 IBC cell lines (SUM149, SUM190, and IBC3, but not KPL4) showed the paradoxical increase in E-cadherin expression noted previously (p = 0.0411). While these data confirm that immune induction of EMT is common among a range of breast cancer subtypes, IBC cells had an abnormal response characterized by a shift toward EMT expression concurrent with maintained or increased E-cadherin expression.


Inflammation Mediated Metastasis: Immune Induced Epithelial-To-Mesenchymal Transition in Inflammatory Breast Cancer Cells.

Cohen EN, Gao H, Anfossi S, Mego M, Reddy NG, Debeb B, Giordano A, Tin S, Wu Q, Garza RJ, Cristofanilli M, Mani SA, Croix DA, Ueno NT, Woodward WA, Luthra R, Krishnamurthy S, Reuben JM - PLoS ONE (2015)

Analysis of multiple cell lines by Fluidigm.Breast cancer cell lines were incubated with immune CM for 48 hours and mRNA was analyzed by qRT-PCR. Media control appears as a solid black line at 1 in the center of each plot, points falling outside the circle represent increased relative expression and lines inside are decreased. TCR-CM anti-CD3 induced EMT-related factors to varying degrees in all cell lines. Following treatment with TCR-CM, IBC cell lines with the exception of KPL4, had increased expression of E-cadherin.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4514595&req=5

pone.0132710.g003: Analysis of multiple cell lines by Fluidigm.Breast cancer cell lines were incubated with immune CM for 48 hours and mRNA was analyzed by qRT-PCR. Media control appears as a solid black line at 1 in the center of each plot, points falling outside the circle represent increased relative expression and lines inside are decreased. TCR-CM anti-CD3 induced EMT-related factors to varying degrees in all cell lines. Following treatment with TCR-CM, IBC cell lines with the exception of KPL4, had increased expression of E-cadherin.
Mentions: A panel of 24 selected genes was analyzed for each condition using Fluidigm integrated fluidic circuit chips (Fig 3). Most cell lines showed increased expression of EMT-regulating genes following treatment with immune cell CM. Changes in response to LPS-CM were generally attenuated compared to TCR-CM, possibly due to the smaller relative number of monocytes than T cells in PBMC. ZEB1 and TGM2 were the most frequently, and highly induced EMT-related factors, along with inflammatory factors prostaglandin E synthase 2 (PTGES2) and IL-8 (CXCL8). Consistent with induction of EMT in epithelial cells, epithelial cell adhesion molecule (EpCAM) expression decreased with TCR-CM treatment in every cell line except SUM149. However, in the other IBC cell lines, although EpCAM expression was reduced, this down-regulation was attenuated compared to the non-IBC cell lines (p = 0.0197). Likewise, although the non-IBC cell lines showed no change in E-cadherin expression at this time point, 3 of the 4 IBC cell lines (SUM149, SUM190, and IBC3, but not KPL4) showed the paradoxical increase in E-cadherin expression noted previously (p = 0.0411). While these data confirm that immune induction of EMT is common among a range of breast cancer subtypes, IBC cells had an abnormal response characterized by a shift toward EMT expression concurrent with maintained or increased E-cadherin expression.

Bottom Line: It is unknown whether immune cells associated to the IBC microenvironment play a role in this scenario to transiently promote epithelial to mesenchymal transition (EMT) in these cells.A combination of TNF-α, IL-6, and TGF-β was able to recapitulate EMT induction in IBC, and conditioned media preloaded with neutralizing antibodies against these factors exhibited decreased EMT.These data suggest that release of cytokines by activated immune cells may contribute to the aggressiveness of IBC and highlight these factors as potential target mediators of immune-IBC interaction.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America; The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America; The University of Texas Graduate School of Biomedical Sciences at Houston, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.

ABSTRACT
Inflammatory breast cancer (IBC) is the most insidious form of locally advanced breast cancer; about a third of patients have distant metastasis at initial staging. Emerging evidence suggests that host factors in the tumor microenvironment may interact with underlying IBC cells to make them aggressive. It is unknown whether immune cells associated to the IBC microenvironment play a role in this scenario to transiently promote epithelial to mesenchymal transition (EMT) in these cells. We hypothesized that soluble factors secreted by activated immune cells can induce an EMT in IBC and thus promote metastasis. In a pilot study of 16 breast cancer patients, TNF-α production by peripheral blood T cells was correlated with the detection of circulating tumor cells expressing EMT markers. In a variety of IBC model cell lines, soluble factors from activated T cells induced expression of EMT-related genes, including FN1, VIM, TGM2, ZEB1. Interestingly, although IBC cells exhibited increased invasion and migration following exposure to immune factors, the expression of E-cadherin (CDH1), a cell adhesion molecule, increased uniquely in IBC cell lines but not in non-IBC cell lines. A combination of TNF-α, IL-6, and TGF-β was able to recapitulate EMT induction in IBC, and conditioned media preloaded with neutralizing antibodies against these factors exhibited decreased EMT. These data suggest that release of cytokines by activated immune cells may contribute to the aggressiveness of IBC and highlight these factors as potential target mediators of immune-IBC interaction.

No MeSH data available.


Related in: MedlinePlus