■导管原位癌(DCIS),以乳腺导管内肿瘤细胞的增殖为特征,通过几乎不间断的肌上皮细胞(MEC)层和基底膜与周围的基质明显分离。脂肪微环境内的相互作用增强,特别是肥胖患者,可能在从DCIS到浸润性导管癌(IDC)的过渡中起关键作用,这吸引了人们对科学研究日益增长的兴趣。脂肪组织在肥胖中经历代谢变化,影响脂肪因子分泌和促进慢性炎症。本研究旨在评估DCIS之间的相互作用,包括原位癌细胞和MECs,及其炎性脂肪微环境的各种成分(脂肪细胞和巨噬细胞)。
■为此,使用双细胞双荧光DCIS样类肿瘤开发了3D共培养模型,脂肪细胞,和巨噬细胞来研究炎症脂肪微环境对DCIS进展的影响。
■3D共培养模型表明抑制了与细胞凋亡有关的基因的表达(BAX,BAG1、BCL2、CASP3、CASP8和CASP9),以及与细胞存活相关的基因增加(TP53,JUN,和TGFB1),炎症(TNF-α,PTGS2,IL-6R),在炎性条件与非炎性微环境下肿瘤样癌细胞的侵袭和转移(TIMP1和MMP-9)。相反,它证实了MEC的功能受损,导致它们对癌细胞的保护作用丧失。来自肥胖女性的脂肪细胞显示所有研究的肌成纤维细胞相关基因(myoCAFs)的表达显着增加,如FAP和α-SMA。相比之下,正常体重女性的脂肪细胞表达炎性成纤维细胞表型(iCAF)的标志物,其特征是LIF和炎性细胞因子如TNF-α的表达显着增加,IL-1β,IL-8和CXCL-10。这些变化也影响了巨噬细胞的极化,导致促炎M1表型。相比之下,肌CAF相关脂肪细胞,促进癌症的微环境将巨噬细胞极化为M2表型,以CD163受体高表达和IL-10和TGF-β分泌为特征。
■肿瘤及其微环境之间的相互作用,特别是在肥胖症中,导致脂肪细胞和巨噬细胞的转录变化,可能参与乳腺癌进展,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。
UNASSIGNED: Ductal carcinoma in situ (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 in situ cancer cells and MECs, and the various components of its inflammatory adipose microenvironment (adipocytes and macrophages).
UNASSIGNED: 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.
UNASSIGNED: The 3D co-culture model demonstrated an inhibition of the expression of genes involved in apoptosis (BAX, BAG1, BCL2, CASP3, CASP8, and CASP9), and an increase in genes related to cell survival (TP53, JUN, and TGFB1), inflammation (TNF-α, PTGS2, IL-6R), 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 FAP and α-SMA. In contrast, adipocytes from normal-weight women expressed markers of inflammatory fibroblast phenotypes (iCAF) characterized by a significant increase in the expression of LIF and inflammatory cytokines such as TNF-α, IL-1β, IL-8, and CXCL-10. 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.
UNASSIGNED: 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.