Macrophages Mediate a Switch between Canonical and Non-Canonical Wnt Pathways in Canine Mammary Tumors

• Published in: PloS one Vol. 9; no. 1; p. e83995
• Main Authors: Król, Magdalena, Mucha, Joanna, Majchrzak, Kinga, Homa, Agata, Bulkowska, Małgorzata, Majewska, Alicja, Gajewska, Małgorzata, Pietrzak, Marta, Perszko, Mikołaj, Romanowska, Karolina, Pawłowski, Karol, Manuali, Elisabetta, Hellmen, Eva, Motyl, Tomasz
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 03.01.2014; Public Library of Science (PLoS)
• Subjects: Activation; Animals; beta Catenin - metabolism; Biology; Breast cancer; Cancer; Cancer metastasis; Cancer treatment; Carcinoma; Cell culture; Cell cycle; Cell interactions; Cell Line, Tumor; Cell proliferation; Coculture Techniques; Conditioning; Cytoskeleton - metabolism; Development and progression; Dogs; Epithelial-Mesenchymal Transition; Female; Gene Expression; Growth patterns; Heterografts; Inhibitors; Invasiveness; Kinases; Life sciences; Macrophages; Macrophages - metabolism; Macrophages - pathology; Male; Mammary gland; Mammary Neoplasms, Animal - genetics; Mammary Neoplasms, Animal - metabolism; Mammary Neoplasms, Animal - pathology; Medical Bioscience; Medical prognosis; Medicine; Medicinsk biovetenskap; Mesenchyme; Metastases; Metastasis; Mice; MicroRNA; MicroRNAs - genetics; miRNA; Models, Biological; Molecular modelling; Physiology; Protein Transport; Ribonucleic acid; RNA; Signaling; Stem cells; Tissues; Tumor cells; Tumors; Veterinary medicine; Veterinary Science; Wnt protein; Wnt Proteins - metabolism; Wnt Signaling Pathway; Xenografts; Poland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0083995

According to the current hypothesis, tumor-associated macrophages (TAMs) are "corrupted" by cancer cells and subsequently facilitate, rather than inhibit, tumor metastasis. Because the molecular mechanisms of cancer cell-TAM interactions are complicated and controversial we aimed to better define this phenomenon. Using microRNA microarrays, Real-time qPCR and Western blot we showed that co-culture of canine mammary tumor cells with TAMs or treatment with macrophage-conditioned medium inhibited the canonical Wnt pathway and activated the non-canonical Wnt pathway in tumor cells. We also showed that co-culture of TAMs with tumor cells increased expression of canonical Wnt inhibitors in TAMs. Subsequently, we demonstrated macrophage-induced invasive growth patterns and epithelial-mesenchymal transition of tumor cells. Validation of these results in canine mammary carcinoma tissues (n = 50) and xenograft tumors indicated the activation of non-canonical and canonical Wnt pathways in metastatic tumors and non-metastatic malignancies, respectively. Activation of non-canonical Wnt pathway correlated with number of TAMs. We demonstrated that TAMs mediate a "switch" between canonical and non-canonical Wnt signaling pathways in canine mammary tumors, leading to increased tumor invasion and metastasis. Interestingly, similar changes in neoplastic cells were observed in the presence of macrophage-conditioned medium or live macrophages. These observations indicate that rather than being "corrupted" by cancer cells, TAMs constitutively secrete canonical Wnt inhibitors that decrease tumor proliferation and development, but as a side effect, they induce the non-canonical Wnt pathway, which leads to tumor metastasis. These data challenge the conventional understanding of TAM-cancer cell interactions.