Introduction: Tumor microenvironment plays a key role in the development and progression of tumors. Although adipose tissue is a predominant component of tumor microenvironment in mammary tissue, and secretes various cytokines, chemokines and growth factors, roles of adipocytes in the breast cancers remain to be elucidated.
Methods: In this study, we identified adipsin, an adipokine predominantly expressed in the adipose-derived stem cells (ADSCs) of breast cancer patients, enhanced the clonogenicity, proliferation, and cancer stem cell-like properties of human breast cancer patient-derived xenograft (PDX) cells. Human breast cancer PDXs were established by the engraftment of surgical specimens of the breast cancer patients into immunodeficient mice. Human mammary adipose-derived stem cells (ADSCs) were isolated from the enzymatically dissociated adipose tissues of the surgical specimens of breast cancer patients.
Results: When ADSCs with diverse patient backgrounds were co-cultured with human breast cancer PDX cells, ADSCs significantly enhanced the clonogenicity of breast cancer PDX cells (n = 9; p < 0.05). We found that adipsin, an adipokine that is involved in the generation of C3a and C3b in the complement alternative pathway, was highly expressed in the cultured supernatants of ADSCs when compared to those of breast cancer PDX cells (n = 9; p < 0.05). Accordingly, the amount of C3a was significantly higher in the cultured supernatants of ADSCs when compared to those of breast cancer PDX cells (n = 9; p < 0.05). Suppression of adipsin by a specific inhibitor or knockdown in mammary ADSCs significantly suppressed the sphere-forming abilities of breast cancer PDX cells; reduced the mRNA expression levels of the cancer stem cell marker CD44 and the chemokine receptor CXCR4 (p < 0.01); and reduced the cell surface expression of CD44 in breast cancer PDX cells, suggesting that cancer stem cell-like properties were regulated by adipsin. Although the suppression of CXCR4 by a specific inhibitor showed a tendency to suppress the sphere-forming abilities of breast cancer PDX cells, the dual suppression of adipsin/C3a and CXCR4 by their specific inhibitors showed no additive effects on the suppression of the clonogenicity of breast cancer PDX cells.
Conclusion: These observations suggest that ADSCs are important components of tumor microenvironment in human breast cancers, and secrete adipsin that functions as regulators of the clonogenicity, proliferation, and cancer stem cell-like properties of human breast cancer cells.
Citation Format: Hideaki Goto, Yohei Shimono, Toru Mukohara, Yohei Funakoshi, Yoshinori Imamura, Seishi Kono, Shintaro Takao, Akira Suzuki, Hironobu Minami. Adipsin enhanced clonogenicity and proliferation of human breast cancer patient-derived xenograft cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1006.