PDF(Pubmed)
Abstract：
BACKGROUND: Obesity is a risk factor for breast cancer, and women with obesity that develop breast cancer have a worsened prognosis. Within the mammary gland, obesity causes chronic, macrophage-driven inflammation and adipose tissue fibrosis. Weight loss is a recommended intervention to resolve obesity, but the impact of weight loss on the mammary gland microenvironment and in tumors has not been well identified.
METHODS: To examine the effects of weight loss following obesity, mice were fed a high-fat diet for 16 weeks to induce obesity, then switched to a low-fat diet for 6 weeks. We examined changes in immune cells, including fibrocytes, which are myeloid lineage cells that have attributes of both macrophages and myofibroblasts, and collagen deposition within the mammary glands of non-tumor-bearing mice and within the tumors of mice that were transplanted with estrogen receptor alpha positive TC2 tumor cells.
RESULTS: In formerly obese mice, we observed reduced numbers of crown-like structures and fibrocytes in mammary glands, while collagen deposition was not resolved with weight loss. Following transplant of TC2 tumor cells into the mammary glands of lean, obese, and formerly obese mice, diminished collagen deposition and cancer-associated fibroblasts were observed in tumors from formerly obese mice compared to obese mice. Within tumors of obese mice, increased myeloid-derived suppressor cells and diminished CD8+ T cells were identified, while the microenvironment of tumors of formerly obese mice were more similar to tumors from lean mice. When TC2 tumor cells were mixed with CD11b+CD34+ myeloid progenitor cells, which are the cells of origin for fibrocytes, and transplanted into mammary glands of lean and obese mice, collagen deposition within the tumors of both lean and obese was significantly greater than when tumor cells were mixed with CD11b+CD34- monocytes or total CD45+ immune cells.
CONCLUSIONS: Overall, these studies demonstrate that weight loss resolved some of the microenvironmental conditions within the mammary gland that may contribute to tumor progression. Additionally, fibrocytes may contribute to early collagen deposition in mammary tumors of obese mice leading to the growth of desmoplastic tumors.
METHODS: To examine the effects of weight loss following obesity, mice were fed a high-fat diet for 16 weeks to induce obesity, then switched to a low-fat diet for 6 weeks. We examined changes in immune cells, including fibrocytes, which are myeloid lineage cells that have attributes of both macrophages and myofibroblasts, and collagen deposition within the mammary glands of non-tumor-bearing mice and within the tumors of mice that were transplanted with estrogen receptor alpha positive TC2 tumor cells.
RESULTS: In formerly obese mice, we observed reduced numbers of crown-like structures and fibrocytes in mammary glands, while collagen deposition was not resolved with weight loss. Following transplant of TC2 tumor cells into the mammary glands of lean, obese, and formerly obese mice, diminished collagen deposition and cancer-associated fibroblasts were observed in tumors from formerly obese mice compared to obese mice. Within tumors of obese mice, increased myeloid-derived suppressor cells and diminished CD8+ T cells were identified, while the microenvironment of tumors of formerly obese mice were more similar to tumors from lean mice. When TC2 tumor cells were mixed with CD11b+CD34+ myeloid progenitor cells, which are the cells of origin for fibrocytes, and transplanted into mammary glands of lean and obese mice, collagen deposition within the tumors of both lean and obese was significantly greater than when tumor cells were mixed with CD11b+CD34- monocytes or total CD45+ immune cells.
CONCLUSIONS: Overall, these studies demonstrate that weight loss resolved some of the microenvironmental conditions within the mammary gland that may contribute to tumor progression. Additionally, fibrocytes may contribute to early collagen deposition in mammary tumors of obese mice leading to the growth of desmoplastic tumors.
摘要：
背景：肥胖是乳腺癌的危险因素，患乳腺癌的肥胖女性预后恶化。在乳腺内，肥胖导致慢性，巨噬细胞驱动的炎症和脂肪组织纤维化。减肥是解决肥胖的推荐干预措施，但是减肥对乳腺微环境和肿瘤的影响尚未得到很好的鉴定。
方法：为了检查肥胖后体重减轻的影响，给小鼠喂食16周高脂饮食诱导肥胖，然后改用低脂饮食6周。我们检查了免疫细胞的变化，包括纤维细胞,它们是骨髓谱系细胞，具有巨噬细胞和肌成纤维细胞的属性，和胶原沉积在非荷瘤小鼠的乳腺内和移植有雌激素受体α阳性TC2肿瘤细胞的小鼠的肿瘤内。
结果：在以前的肥胖小鼠中，我们观察到乳腺中的冠状结构和纤维细胞数量减少，而胶原蛋白沉积并未随体重减轻而解决。在将TC2肿瘤细胞移植到瘦乳腺中之后，肥胖，和以前肥胖的老鼠，与肥胖小鼠相比,在先前肥胖小鼠的肿瘤中观察到胶原沉积和癌症相关成纤维细胞减少.在肥胖小鼠的肿瘤中，发现髓源性抑制细胞增加和CD8+T细胞减少，而以前肥胖小鼠的肿瘤微环境更类似于瘦小鼠的肿瘤。当TC2肿瘤细胞与CD11b+CD34+骨髓祖细胞混合时，是纤维细胞的起源细胞，移植到瘦和肥胖小鼠的乳腺中，瘦和肥胖的肿瘤内胶原沉积显著大于当肿瘤细胞与CD11b+CD34-单核细胞或总CD45+免疫细胞混合时.
结论：总体而言，这些研究表明，体重减轻解决了乳腺内可能导致肿瘤进展的一些微环境条件。此外,纤维细胞可能有助于肥胖小鼠乳腺肿瘤的早期胶原沉积，导致促纤维增生性肿瘤的生长。
方法：为了检查肥胖后体重减轻的影响，给小鼠喂食16周高脂饮食诱导肥胖，然后改用低脂饮食6周。我们检查了免疫细胞的变化，包括纤维细胞,它们是骨髓谱系细胞，具有巨噬细胞和肌成纤维细胞的属性，和胶原沉积在非荷瘤小鼠的乳腺内和移植有雌激素受体α阳性TC2肿瘤细胞的小鼠的肿瘤内。
结果：在以前的肥胖小鼠中，我们观察到乳腺中的冠状结构和纤维细胞数量减少，而胶原蛋白沉积并未随体重减轻而解决。在将TC2肿瘤细胞移植到瘦乳腺中之后，肥胖，和以前肥胖的老鼠，与肥胖小鼠相比,在先前肥胖小鼠的肿瘤中观察到胶原沉积和癌症相关成纤维细胞减少.在肥胖小鼠的肿瘤中，发现髓源性抑制细胞增加和CD8+T细胞减少，而以前肥胖小鼠的肿瘤微环境更类似于瘦小鼠的肿瘤。当TC2肿瘤细胞与CD11b+CD34+骨髓祖细胞混合时，是纤维细胞的起源细胞，移植到瘦和肥胖小鼠的乳腺中，瘦和肥胖的肿瘤内胶原沉积显著大于当肿瘤细胞与CD11b+CD34-单核细胞或总CD45+免疫细胞混合时.
结论：总体而言，这些研究表明，体重减轻解决了乳腺内可能导致肿瘤进展的一些微环境条件。此外,纤维细胞可能有助于肥胖小鼠乳腺肿瘤的早期胶原沉积，导致促纤维增生性肿瘤的生长。
