Evangelista Gabriela Coeli Menezes, Salvador Pollyanna Amaral, Soares Sara Malaguti Andrade, Barros Luciana Rodrigues Carvalho, Xavier Felipe Henrique da Cunha, Abdo Luiza Macedo, Gualberto Ana Cristina Moura, Macedo Gilson Costa, Clavijo-Salomon Maria Alejandra, Gameiro Jacy
Laboratory of Immunology of Infectious and Parasitic Diseases and Obesity, Department of Parasitology, Microbiology, and Immunology, Federal University of Juiz de Fora, Juiz de Fora, Brazil.
Laboratory of Tumor Immunology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Front Oncol. 2019 Sep 20;9:685. doi: 10.3389/fonc.2019.00685. eCollection 2019.
Breast cancer (BC) remains the leading cause of cancer-related deaths among women, and the chances to develop it are duplicated by obesity. Still, the impact of obesity during BC progression remains less understood. We investigated the role of obesity in tumor progression using the murine model of 4T1 mammary carcinoma in BALB/c female mice, previously high-fat-diet (HFD) fed. HFD induced obesity, metabolic impairment, and high serum and fat leptin levels. After injection of 4T1-cells, HFD-mice accelerated tumor progression and metastasis. 4T1-cells found within HFD-mice metastatic niches presented higher clonogenic potential. 4T1-cells treated with fat-conditioned medium derived from HFD-mice, increased migration capacity through CXCL12 and CCL25 gradients. In HFD-mice, the infiltration and activation of immune cells into tumor-sentinel lymph nodes was overall reduced, except for activated CD4 T cells expressing low CD25 levels. Within the bone marrow, the levels of haematopoiesis-related IL-6 and TNF-α decreased after 4T1-cells injection in HFD-mice whereas increased in the controls, suggesting that upregulation of both cytokines, regardless of the tumor, is disrupted by obesity. Finally, the expression of genes for leptin, CXCR4, and CCR9 (receptors of CXCL12 and CCL25, respectively) was negatively correlated with the infiltration of CD8 T cells in human triple-negative BC tumors from obese patients compared to non-obese. Together, our data present early evidence of systemic networks triggered by obesity that promote BC progression to the metastatic niches. Targeting these pathways might be useful to prevent the rapid BC progression observed among obese patients.
乳腺癌（BC）仍是女性癌症相关死亡的主要原因，肥胖会使患乳腺癌的几率翻倍。然而，肥胖在乳腺癌进展过程中的影响仍鲜为人知。我们使用先前喂食高脂饮食（HFD）的BALB/c雌性小鼠的4T1乳腺癌小鼠模型，研究了肥胖在肿瘤进展中的作用。HFD诱导了肥胖、代谢障碍以及血清和脂肪中瘦素水平升高。注射4T1细胞后，HFD小鼠的肿瘤进展和转移加速。在HFD小鼠转移龛中发现的4T1细胞具有更高的克隆形成潜力。用源自HFD小鼠的脂肪条件培养基处理的4T1细胞，通过CXCL12和CCL25梯度增加了迁移能力。在HFD小鼠中，免疫细胞向肿瘤前哨淋巴结的浸润和激活总体减少，但表达低水平CD25的活化CD4 T细胞除外。在骨髓中，HFD小鼠注射4T1细胞后造血相关的IL-6和TNF-α水平下降，而对照组则升高，这表明肥胖会破坏这两种细胞因子的上调，无论是否存在肿瘤。最后，与非肥胖患者相比，肥胖患者的人三阴性乳腺癌肿瘤中瘦素、CXCR4和CCR9（分别为CXCL12和CCL25的受体）基因的表达与CD8 T细胞的浸润呈负相关。总之，我们的数据提供了肥胖触发的促进乳腺癌进展至转移龛的全身网络的早期证据。靶向这些途径可能有助于预防肥胖患者中观察到的乳腺癌快速进展。
