Université Clermont-Auvergne, INRAE, UNH, Clermont-Ferrand, France.
Université Clermont-Auvergne, Centre d'Imagerie Cellulaire Santé (CCIS), Clermont-Ferrand, France.
Front Immunol. 2024 Jul 12;15:1384354. doi: 10.3389/fimmu.2024.1384354. eCollection 2024.
Ductal carcinoma (DCIS), characterized by a proliferation of neoplastic cells confined within the mammary ducts, is distinctly isolated from the surrounding stroma by an almost uninterrupted layer of myoepithelial cells (MECs) and by the basement membrane. Heightened interactions within the adipose microenvironment, particularly in obese patients, may play a key role in the transition from DCIS to invasive ductal carcinoma (IDC), which is attracting growing interest in scientific research. Adipose tissue undergoes metabolic changes in obesity, impacting adipokine secretion and promoting chronic inflammation. This study aimed to assess the interactions between DCIS, including cancer cells and MECs, and the various components of its inflammatory adipose microenvironment (adipocytes and macrophages).
To this end, a 3D co-culture model was developed using bicellular bi-fluorescent DCIS-like tumoroids, adipose cells, and macrophages to investigate the influence of the inflammatory adipose microenvironment on DCIS progression.
The 3D co-culture model demonstrated an inhibition of the expression of genes involved in apoptosis (, and ), and an increase in genes related to cell survival (, , and ), inflammation (), invasion and metastasis (TIMP1 and MMP-9) in cancer cells of the tumoroids under inflammatory conditions versus a non-inflammatory microenvironment. On the contrary, it confirmed the compromised functionality of MECs, resulting in the loss of their protective effects against cancer cells. Adipocytes from obese women showed a significant increase in the expression of all studied myofibroblast-associated genes (myoCAFs), such as and . In contrast, adipocytes from normal-weight women expressed markers of inflammatory fibroblast phenotypes (iCAF) characterized by a significant increase in the expression of and inflammatory cytokines such as , and . These changes also influenced macrophage polarization, leading to a pro-inflammatory M1 phenotype. In contrast, myoCAF-associated adipocytes, and the cancer-promoting microenvironment polarized macrophages towards an M2 phenotype, characterized by high CD163 receptor expression and IL-10 and TGF-β secretion.
Reciprocal interactions between the tumoroid and its microenvironment, particularly in obesity, led to transcriptomic changes in adipocytes and macrophages, may participate in breast cancer progression while disrupting the integrity of the MEC layer. These results underlined the importance of adipose tissue in cancer progression.
导管癌（DCIS）的特征是肿瘤细胞在乳腺导管内增殖，被一层几乎连续的肌上皮细胞（MEC）和基底膜与周围的基质明显隔开。在肥胖患者中，脂肪微环境中的相互作用增强，特别是在肥胖患者中，可能在从 DCIS 向浸润性导管癌（IDC）的转变中发挥关键作用，这在科学研究中引起了越来越多的关注。脂肪组织在肥胖中发生代谢变化，影响脂肪因子的分泌并促进慢性炎症。本研究旨在评估 DCIS（包括癌细胞和 MEC）与炎症性脂肪微环境的各种成分（脂肪细胞和巨噬细胞）之间的相互作用。
为此，使用双细胞双荧光 DCIS 样肿瘤样体、脂肪细胞和巨噬细胞开发了 3D 共培养模型，以研究炎症性脂肪微环境对 DCIS 进展的影响。
3D 共培养模型显示，在炎症条件下，与非炎症微环境相比，肿瘤样体中的癌细胞的凋亡相关基因（、和）表达受到抑制，与细胞存活相关的基因（、、和）表达增加，炎症（），侵袭和转移（TIMP1 和 MMP-9）。相反，它证实了 MEC 功能受损，导致其对癌细胞失去保护作用。来自肥胖女性的脂肪细胞表现出所有研究的肌成纤维细胞相关基因（myoCAFs）的表达显著增加，如和。相比之下，来自正常体重女性的脂肪细胞表现出炎症成纤维细胞表型（iCAF）的标志物，其特征是表达的显著增加和炎症细胞因子如、和。这些变化还影响巨噬细胞极化，导致促炎 M1 表型。相反，myoCAF 相关脂肪细胞和促进癌症的微环境使巨噬细胞向特征在于高 CD163 受体表达和 IL-10 和 TGF-β 分泌的 M2 表型极化。
肿瘤样体与其微环境之间的相互作用，特别是在肥胖中，导致脂肪细胞和巨噬细胞的转录组发生变化，可能参与乳腺癌的进展，同时破坏 MEC 层的完整性。这些结果强调了脂肪组织在癌症进展中的重要性。
