Am J Cancer Res 2013;3(2):196-210
Original Article
Breast tumor cells primed by endoplasmic reticulum stress remodel
macrophage phenotype
Sarah J Cullen, Soroosh Fatemie, Warren Ladiges
Department of Comparative Medicine, University of Washington, Seattle WA 98195, USA
Received March 7, 2013; Accepted March 27, 2013; Epub April 3, 2013; Published April 13, 2013
Abstract: In the pathogenesis of breast cancer, tumor-associated macrophages have the capacity to impinge upon clinical
outcomes. In light of this, reconciling mechanisms by which macrophages are primed to facilitate tumor growth and progression
provide clinically relevant therapeutic targets. Given the recent linkage between activation of the endoplasmic reticulum (ER)
stress response and breast cancer progression, we postulated that, similar to other carcinomas, mammary carcinoma cells
undergoing ER stress re-program macrophages in order to foster both tumor cell growth and survival, and tumor angiogenesis.
To test this, we modeled the interaction between ER-stressed tumor cells and macrophages in the tumor microenvironment by
culturing macrophages in the conditioned medium of mammary carcinoma cells undergoing ER stress. In response to these
stimuli, macrophages not only invoked a similar stress response but also adopted a pro-inflammatory phenotype. Additionally,
macrophages produced the pro-angiogenic molecule, vascular endothelial growth factor (VEGF), thereby establishing the
macrophage phenotype invoked by ER-stressed breast cancer cells as being pro-angiogenic. In aggregate, these findings
delineate a role for ER stress-dependent cross-talk between breast tumor cells and TAMs as a potential catalyst for tumor cell
growth and tumor-associated angiogenesis. Hence, by suggesting that mammary carcinoma cells cope with ER stress by
influencing TAM functionality, we have partially elucidated why enhanced tumor progression and angiogenesis accompany the
ER stress response in breast cancer. (AJCR0000186)
Keywords: Breast cancer, macrophages, endoplasmic reticulum stress, angiogenesis
Address correspondence to: Dr. Warren C Ladiges, Department of Comparative Medicine, University of Washington, Seattle,
WA 98195, BOX 357190. Tel: 206-685-3260; Fax: 206-685-3006; E-mail: wladiges@u.washington.edu
Original Article
Breast tumor cells primed by endoplasmic reticulum stress remodel
macrophage phenotype
Sarah J Cullen, Soroosh Fatemie, Warren Ladiges
Department of Comparative Medicine, University of Washington, Seattle WA 98195, USA
Received March 7, 2013; Accepted March 27, 2013; Epub April 3, 2013; Published April 13, 2013
Abstract: In the pathogenesis of breast cancer, tumor-associated macrophages have the capacity to impinge upon clinical
outcomes. In light of this, reconciling mechanisms by which macrophages are primed to facilitate tumor growth and progression
provide clinically relevant therapeutic targets. Given the recent linkage between activation of the endoplasmic reticulum (ER)
stress response and breast cancer progression, we postulated that, similar to other carcinomas, mammary carcinoma cells
undergoing ER stress re-program macrophages in order to foster both tumor cell growth and survival, and tumor angiogenesis.
To test this, we modeled the interaction between ER-stressed tumor cells and macrophages in the tumor microenvironment by
culturing macrophages in the conditioned medium of mammary carcinoma cells undergoing ER stress. In response to these
stimuli, macrophages not only invoked a similar stress response but also adopted a pro-inflammatory phenotype. Additionally,
macrophages produced the pro-angiogenic molecule, vascular endothelial growth factor (VEGF), thereby establishing the
macrophage phenotype invoked by ER-stressed breast cancer cells as being pro-angiogenic. In aggregate, these findings
delineate a role for ER stress-dependent cross-talk between breast tumor cells and TAMs as a potential catalyst for tumor cell
growth and tumor-associated angiogenesis. Hence, by suggesting that mammary carcinoma cells cope with ER stress by
influencing TAM functionality, we have partially elucidated why enhanced tumor progression and angiogenesis accompany the
ER stress response in breast cancer. (AJCR0000186)
Keywords: Breast cancer, macrophages, endoplasmic reticulum stress, angiogenesis
Address correspondence to: Dr. Warren C Ladiges, Department of Comparative Medicine, University of Washington, Seattle,
WA 98195, BOX 357190. Tel: 206-685-3260; Fax: 206-685-3006; E-mail: wladiges@u.washington.edu
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American Journal of Cancer Research
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