The Impact of Tumor-Associated Macrophages Found at Mammary Carcinoma Sites is Dependent Upon the Tumor Type

Abstract

ABSTRACT Background Previously, we reported that tumor-associated macrophages (TAM) at early sites of mammary carcinoma showed a decrease in ATP production rate and a higher dependence on oxidative phosphorylation. Methods Since these changes can result from activation of AMP-activated protein kinase (AMPK) and glucose transporter 1 (Glut1) during metabolic stress, we investigated whether the TAM showed increased expression of ampk and glut1, as well as another indicator of metabolic stress, pkm2. Indeed, the TAM exhibited significant expression of pkm2, glut1, and ampk. Results Bone marrow-derived macrophages (BMDM) co-cultured with 4T1, EMT6, and 168 in vitro similarly showed increased expression of pkm2, glut1, and ampk. Moreover, lactate, which is expressed at significant levels by all three tumors, induced expression of these same genes in BMDM suggesting that lactate may induce a metabolic stress response in these TAM. Yet, the three different mammary carcinoma models benefited from different targeting strategies. Macrophage depletion studies revealed that the TAM contributed to growth of the EMT6 tumor and metastasis of the 4T1 tumor. Targeting the stress response with the Integrated Stress Response Inhibitor (ISRIB), which targets eIF2, impacted 168 tumor progression, and ISRIB as well as FX-11, which targets lactate dehydrogenase, impacted 4T1 tumor progression and metastasis. Conclusions Collectively, these data demonstrate that targeting TAM or metabolism at early tumor sites can impact tumor progression. However, variability in the responses underscore the fact that the impact of macrophages differs even within three different syngeneic mammary carcinoma models.