RESUMEN
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.
RESUMEN
BACKGROUND: Treatment of invasive breast cancer has an alarmingly high rate of failure because effective targets have not been identified. One potential target is mitochondrial generated reactive oxygen species (ROS) because ROS production has been associated with changes in substrate metabolism and lower concentration of anti-oxidant enzymes in tumor and stromal cells and increased metastatic potential. METHODS: Transgenic mice expressing a human catalase gene (mCAT) were crossed with MMTV-PyMT transgenic mice that develop metastatic breast cancer. All mice (33 mCAT positive and 23 mCAT negative) were terminated at 110 days of age, when tumors were well advanced. Tumors were histologically assessed for invasiveness, proliferation and metastatic foci in the lungs. ROS levels and activation status of p38 MAPK were determined. RESULTS: PyMT mice expressing mCAT had a 12.5 per cent incidence of high histological grade primary tumor invasiveness compared to a 62.5 per cent incidence in PyMT mice without mCAT. The histological grade correlated with incidence of metastasis with 56 per cent of PyMT mice positive for mCAT showing evidence of pulmonary metastasis compared to 85.4 per cent of PyMT mice negative for mCAT with pulmonary metastasis (p ≤ 0.05). PyMT tumor cells expressing mCAT had lower ROS levels and were more resistant to hydrogen peroxide-induced oxidative stress than wild type tumor cells, suggesting that mCAT has the potential of quenching intracellular ROS and subsequent invasive behavior. The metastatic tumor burden in PyMT mice expressing mCAT was 0.1 mm2/cm2 of lung tissue compared with 1.3 mm2/cm2 of lung tissue in PyMT mice expressing the wild type allele (p ≤ 0.01), indicating that mCAT could play a role in mitigating metastatic tumor progression at a distant organ site. Expression of mCAT in the lungs increased resistance to hydrogen peroxide-induced oxidative stress that was associated with decreased activation of p38MAPK suggesting ROS signaling is dependent on p38MAPK for at least some of its downstream effects. CONCLUSION: Targeting catalase within mitochondria of tumor cells and tumor stromal cells suppresses ROS-driven tumor progression and metastasis. Therefore, increasing the antioxidant capacity of the mitochondrial compartment could be a rational therapeutic approach for invasive breast cancer.