Macrophages mediate a switch between canonical and non-canonical Wnt pathways in canine mammary tumors

PLoS One. 2014 Jan 3;9(1):e83995. doi: 10.1371/journal.pone.0083995. eCollection 2014.

Abstract

Objective: 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.

Methods and results: 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.

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Coculture Techniques
  • Cytoskeleton / metabolism
  • Dogs
  • Epithelial-Mesenchymal Transition
  • Female
  • Gene Expression
  • Heterografts
  • Macrophages / metabolism*
  • Macrophages / pathology*
  • Male
  • Mammary Neoplasms, Animal / genetics
  • Mammary Neoplasms, Animal / metabolism*
  • Mammary Neoplasms, Animal / pathology*
  • Mice
  • MicroRNAs / genetics
  • Models, Biological
  • Protein Transport
  • Wnt Proteins / metabolism
  • Wnt Signaling Pathway*
  • beta Catenin / metabolism

Substances

  • MicroRNAs
  • Wnt Proteins
  • beta Catenin

Grants and funding

This work was supported by grant no. N N308012939 from the Ministry of Sciences and Higher Education. This work was performed owing to financial support of the Foundation for Polish Science (Start stipendium). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.