A Subpopulation of CD44+/CD25-/CD100+ Cells Contributes to the Development of Basal Epithelial-Like Metaplastic Breast Cancer in Adiponectin-Deficient MMTV-PyVT Mice
FASEB JOURNAL（2016）
Univ Hong Kong
Abstract
Cancer development depends on the interactions between epithelial carcinoma cells and the stromal microenvironment. The present study investigated the role of adiponectin, an adipokine with potent tumor‐suppressive activities, in modulating the stromal microenvironment during breast cancer development in mice. Trans‐implantation of the stromal vascular fractions (SVF) of mammary adipose tissue from adiponectin‐deficient MMTV‐PyVT mice promotes the development of MDA‐MB‐231 human breast cancers in NOD/SCID mice, which exhibit the aggressive metaplastic basal epithelial‐like molecular features. In MMTV‐PyVT mammary tumors, adiponectin deficiency significantly decreases the density of CD3+ tumor‐infiltrating lymphocytes and enhances the SVF composition of CD44+/CD25−/CD100+ cells that are originated from thymus. Adiponectin plays an important role in T‐cell development and maturation partly by modulating the epithelial stromal microenvironment of thymus. Adiponectin deficiency prevents the positive selection of CD3+ T‐cells and the negative selection of CD44+CD25−CD100+ T‐cells by thymic nurse cells (TNCs). Thus, reduced production of CD3+ T‐cells as well as enhanced release of CD44+/CD25−/CD100+ cells from thymus into the circulation give rise to a tumor‐permissive microenvironment in mammary tissues of MMTV‐PyVT mice lacking adiponectin. Moreover, CD44+/CD25−/CD100+ cells represent a major metaplastic component contributing to the development of more aggressive basal epithelial‐like mammary tumors in MMTV‐PyVT or NOD/SCID mice implanted with human MDA‐MB‐231 breast cancer cells. Treatment with adiponectin restores thymic T‐cell maturation/selection process and prevents the development of metaplastic basal epithelial‐like breast cancer in MMTV‐PyVT mice. In summary, the present study reveals that adiponectin acts as an immunomodulatory stromal factor in both the thymus and mammary tumor microenvironment to elicit the multifaceted anti‐tumorigenic functions. Support or Funding Information This work was supported in part by grants from Seeding Funds for basic research of the University of Hong Kong, Research Grant Council Grants (17121714, HKU779712M, HKU780613M) of Hong Kong; And the National Basic Research Program of China (973 program 2015CB553603).
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Tumor Development
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