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Stat3 orchestrates interaction between endothelial and tumor cells and inhibition of Stat3 suppresses brain metastasis of breast cancer cells.

Lee HT, Xue J, Chou PC, Zhou A, Yang P, Conrad CA, Aldape KD, Priebe W, Patterson C, Sawaya R, Xie K, Huang S - Oncotarget (2015)

Bottom Line: WP1066 inhibited Stat3 activation in tumor-associated endothelial cells, reducing their infiltration and angiogenesis.WP1066 also inhibited breast cancer cell invasion.Our results indicate that WP1066 can inhibit tumor angiogenesis and brain metastasis mediated by Stat3 in endothelial and tumor cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

ABSTRACT
Brain metastasis is a major cause of morbidity and mortality in patients with breast cancer. Our previous studies indicated that Stat3 plays an important role in brain metastasis. Here, we present evidence that Stat3 functions at the level of the microenvironment of brain metastases. Stat3 controlled constitutive and inducible VEGFR2 expression in tumor-associated brain endothelial cells. Furthermore, inhibition of Stat3 by WP1066 decreased the incidence of brain metastases and increased survival in a preclinical model of breast cancer brain metastasis. WP1066 inhibited Stat3 activation in tumor-associated endothelial cells, reducing their infiltration and angiogenesis. WP1066 also inhibited breast cancer cell invasion. Our results indicate that WP1066 can inhibit tumor angiogenesis and brain metastasis mediated by Stat3 in endothelial and tumor cells.

No MeSH data available.


Related in: MedlinePlus

Stat3 activation in breast cancer brain metastases and WP1066 inhibited brain metastasis(A) pStat3, Stat3, and β-actin protein expression levels in MDA-MB-231 and BT-474 cells. (B) Expression levels of pStat3 in 90 IDC and 89 breast cancer brain metastasis specimens. ***, P<0.001. (C) MDA-MB-231BR cells and BT-474BR cells were treated with 1 μM WP1066 (wp) for the indicated times, and whole-cell lysates were subjected to western blotting for pStat3 (Tyr705), Stat3 and β-actin. (D) Concentration of WP1066 in mouse brain tissue and plasma after WP1066 treatment for 72 hours. (E) The effect of WP1066 on the brain metastases of MDA-MB231-BR cell in vivo. 5×105 MDA-M-B231-BR cells were injected into the Left ventricle of the heart of nude mice. Results were shown for one representative experiment of two. **, P<0.01, ***, P<0.001. (F) HE-stained sections of brain metastases of MDA-MB-231BR cells in mice. (G) Survival of mice injected with MDA-MB-231BR cells and given later WP1066 treatment. Data are presented from the day of injection to day 100. Survival of mice was evaluated by Kaplan-Meier analysis. ***, P<0.001.
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Figure 1: Stat3 activation in breast cancer brain metastases and WP1066 inhibited brain metastasis(A) pStat3, Stat3, and β-actin protein expression levels in MDA-MB-231 and BT-474 cells. (B) Expression levels of pStat3 in 90 IDC and 89 breast cancer brain metastasis specimens. ***, P<0.001. (C) MDA-MB-231BR cells and BT-474BR cells were treated with 1 μM WP1066 (wp) for the indicated times, and whole-cell lysates were subjected to western blotting for pStat3 (Tyr705), Stat3 and β-actin. (D) Concentration of WP1066 in mouse brain tissue and plasma after WP1066 treatment for 72 hours. (E) The effect of WP1066 on the brain metastases of MDA-MB231-BR cell in vivo. 5×105 MDA-M-B231-BR cells were injected into the Left ventricle of the heart of nude mice. Results were shown for one representative experiment of two. **, P<0.01, ***, P<0.001. (F) HE-stained sections of brain metastases of MDA-MB-231BR cells in mice. (G) Survival of mice injected with MDA-MB-231BR cells and given later WP1066 treatment. Data are presented from the day of injection to day 100. Survival of mice was evaluated by Kaplan-Meier analysis. ***, P<0.001.

Mentions: We first examined Stat3 activity in MDA-MB-231 and BT-474 cell lines and in brain metastatic cell lines MDA-MB-231BR and BT-474BR. Stat3 activity is significantly higher in MDA-MB-231BR and BT-474BR cells than in their wild-type counterparts (Fig. 1A), indicating that Stat3 was constitutively activated at higher levels in brain metastatic breast cancer cells.


Stat3 orchestrates interaction between endothelial and tumor cells and inhibition of Stat3 suppresses brain metastasis of breast cancer cells.

Lee HT, Xue J, Chou PC, Zhou A, Yang P, Conrad CA, Aldape KD, Priebe W, Patterson C, Sawaya R, Xie K, Huang S - Oncotarget (2015)

Stat3 activation in breast cancer brain metastases and WP1066 inhibited brain metastasis(A) pStat3, Stat3, and β-actin protein expression levels in MDA-MB-231 and BT-474 cells. (B) Expression levels of pStat3 in 90 IDC and 89 breast cancer brain metastasis specimens. ***, P<0.001. (C) MDA-MB-231BR cells and BT-474BR cells were treated with 1 μM WP1066 (wp) for the indicated times, and whole-cell lysates were subjected to western blotting for pStat3 (Tyr705), Stat3 and β-actin. (D) Concentration of WP1066 in mouse brain tissue and plasma after WP1066 treatment for 72 hours. (E) The effect of WP1066 on the brain metastases of MDA-MB231-BR cell in vivo. 5×105 MDA-M-B231-BR cells were injected into the Left ventricle of the heart of nude mice. Results were shown for one representative experiment of two. **, P<0.01, ***, P<0.001. (F) HE-stained sections of brain metastases of MDA-MB-231BR cells in mice. (G) Survival of mice injected with MDA-MB-231BR cells and given later WP1066 treatment. Data are presented from the day of injection to day 100. Survival of mice was evaluated by Kaplan-Meier analysis. ***, P<0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496337&req=5

Figure 1: Stat3 activation in breast cancer brain metastases and WP1066 inhibited brain metastasis(A) pStat3, Stat3, and β-actin protein expression levels in MDA-MB-231 and BT-474 cells. (B) Expression levels of pStat3 in 90 IDC and 89 breast cancer brain metastasis specimens. ***, P<0.001. (C) MDA-MB-231BR cells and BT-474BR cells were treated with 1 μM WP1066 (wp) for the indicated times, and whole-cell lysates were subjected to western blotting for pStat3 (Tyr705), Stat3 and β-actin. (D) Concentration of WP1066 in mouse brain tissue and plasma after WP1066 treatment for 72 hours. (E) The effect of WP1066 on the brain metastases of MDA-MB231-BR cell in vivo. 5×105 MDA-M-B231-BR cells were injected into the Left ventricle of the heart of nude mice. Results were shown for one representative experiment of two. **, P<0.01, ***, P<0.001. (F) HE-stained sections of brain metastases of MDA-MB-231BR cells in mice. (G) Survival of mice injected with MDA-MB-231BR cells and given later WP1066 treatment. Data are presented from the day of injection to day 100. Survival of mice was evaluated by Kaplan-Meier analysis. ***, P<0.001.
Mentions: We first examined Stat3 activity in MDA-MB-231 and BT-474 cell lines and in brain metastatic cell lines MDA-MB-231BR and BT-474BR. Stat3 activity is significantly higher in MDA-MB-231BR and BT-474BR cells than in their wild-type counterparts (Fig. 1A), indicating that Stat3 was constitutively activated at higher levels in brain metastatic breast cancer cells.

Bottom Line: WP1066 inhibited Stat3 activation in tumor-associated endothelial cells, reducing their infiltration and angiogenesis.WP1066 also inhibited breast cancer cell invasion.Our results indicate that WP1066 can inhibit tumor angiogenesis and brain metastasis mediated by Stat3 in endothelial and tumor cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

ABSTRACT
Brain metastasis is a major cause of morbidity and mortality in patients with breast cancer. Our previous studies indicated that Stat3 plays an important role in brain metastasis. Here, we present evidence that Stat3 functions at the level of the microenvironment of brain metastases. Stat3 controlled constitutive and inducible VEGFR2 expression in tumor-associated brain endothelial cells. Furthermore, inhibition of Stat3 by WP1066 decreased the incidence of brain metastases and increased survival in a preclinical model of breast cancer brain metastasis. WP1066 inhibited Stat3 activation in tumor-associated endothelial cells, reducing their infiltration and angiogenesis. WP1066 also inhibited breast cancer cell invasion. Our results indicate that WP1066 can inhibit tumor angiogenesis and brain metastasis mediated by Stat3 in endothelial and tumor cells.

No MeSH data available.


Related in: MedlinePlus