Abstract
Innate immune cells strongly influence cancer growth and progression via multiple mechanisms including regulation of epithelial to mesenchymal transition (EMT). In this study, we investigated whether expression of the metabolic gene, heme oxygenase-1 (HO-1) in tumor microenvironment imparts significant effects on prostate cancer progression.We showed that HO-1 is expressed in MARCO-positive macrophages in prostate cancer (PCa) xenografts and human prostate cancers. We demonstrated that macrophage specific (LyzM-Cre) conditional deletion of HO-1 suppressed growth of PC3 xenografts in vivo and delayed progression of prostate intraepithelial neoplasia (PIN) in TRAMP mice. However, initiation and progression of cancer xenografts in the presence of macrophages lacking HO-1 resulted in loss of E-cadherin, a known marker of poor prognosis as well as EMT. Application of CO, a product of HO-1 catalysis, increased levels of E-cadherin in the adherens junctions between cancer cells. We further showed that HO-1-driven expression of E-cadherin in cancer cells cultured in the presence of macrophages is dependent on mitochondrial activity of cancer cells.In summary, these data suggest that HO-1-derived CO from tumor-associated macrophages influences, in part, E-cadherin expression and thus tumor initiation and progression.
Highlights
The tumor microenvironment provides unique conditions to regulate cellular transformation and cancer growth [1, 2]
Others and we have previously demonstrated that heme oxygenase-1 (HO-1) is highly expressed in prostate cancer [14, 15] and that HO-1 in cancer cells is targeted to the nucleus and remains enzymatically inactive to drive a malignant cell phenotype [25]
We found that in addition to nuclear HO-1 in cancer cells in tumor xenografts, HO-1 is expressed in stromal cells, in the cytoplasm of MARCO positive macrophages in tumors (Figure 1A)
Summary
The tumor microenvironment provides unique conditions to regulate cellular transformation and cancer growth [1, 2]. EMT generally occurs at the invasive front of metastatic tumors where TAMs accumulate [8] and has been linked to high expression of Twist and Snail [9], changes in mitochondrial activity, reactive oxygen species (ROS) production, and modulation of glucose and lipid metabolism [10, 11]. Knockdown of mitochondrial complex I increased ROS production and led to enhanced migration, invasion, and spheroid formation [12]. A mutation in the NADH dehydrogenase subunit 6 generates a deficiency in respiratory complex I, leading to ROS overproduction and enhanced metastatic potential of cancer cells [13]. The link between regulation of cancer metabolism and how heme degradation pathways influence tumor-associated macrophages and EMT in cancer cells remains poorly defined
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