《生命科学》 2026, 38(5): 836-845
乳腺癌中脂肪组织的特异性作用
摘 要：
乳腺癌的发生和发展受周围脂肪组织微环境的深刻影响。脂肪组织不仅为乳腺癌细胞提供机械支撑，而且由于乳腺癌细胞与脂肪细胞间紧密的解剖学接触，使得其局部的肿瘤相关脂肪细胞数量和雌激素水平都较其他恶性实体肿瘤显著升高。本文系统综述了脂肪组织促进恶性肿瘤进展的普遍机制，并重点阐述了其在乳腺癌微环境中的特异性作用。通过与其他肥胖相关癌症进行对比分析，本文旨在深化对“脂肪-癌细胞”互作网络的理解，为乳腺癌的精准治疗提供新的理论依据。
通讯作者：梁俊青 , Email:liang_junqing@126.com
Abstract:
Breast cancer has surpassed lung cancer to become the most prevalent malignancy worldwide, characterized by high heterogeneity and complex pathological mechanisms. Epidemiological evidence firmly establishes obesity as a significant risk factor for breast cancer, particularly in postmenopausal women, correlating with poor prognosis and increased metastasis. Adipose tissue, far from being merely an energy storage depot, is recognized as the body′s largest endocrine organ. While adipose tissue contributes to the progression of various cancers including hepatic, colorectal, and pancreatic cancers through shared mechanisms such as chronic inflammation and metabolic dysregulation, the breast presents a uniqueanatomical landscape where epithelial cells are deeply embedded within a fat-rich stroma. This review aims to synthesize the general mechanisms by which adipose tissue promotes tumorigenesis and, more importantly, to dissect the specific, intimate crosstalk between breast cancer cells and the surrounding adipose microenvironment, highlighting the distinct roles of cancerassociated adipocytes (CAAs) and local estrogen biosynthesis. Adipose tissue exerts a pro-tumorigenic influence across multiple cancer types through systemic low-grade chronic inflammation, insulin/IGF-1 signaling dysregulation, and altered adipokine secretion (e.g., increased leptin and decreased adiponectin). However, adipose-tumor crosstalk in breast cancer is uniquely direct and sustained. Specifically, breast cancer cells induce adjacent mature adipocytes to undergo de-differentiation into CAAs. This process, regulated by factors such as Wnt, TGF-β, and adrenomedullin (AM), transforms adipocytes into
fibroblast-like cells with reduced lipid droplets and activated pro-inflammatory phenotypes. CAAs undergo metabolic reprogramming, accelerating lipolysis via ATGL and HSL activation to release free fatty acids (FFAs). These FFAs are taken up by cancer cells for β-oxidation, fueling rapid proliferation and membrane synthesis. Furthermore, CAAs secrete a myriad of cytokines (e.g., IL-6, CCL2), which not only activate STAT3 and ERK1/2 pathways to enhance tumor invasiveness but also recruit immune cells, notably promoting the polarization of macrophages towards the immunosuppressive M2 phenotype. A defining feature of the breast cancer-adipose nexus, particularly in ER-positive postmenopausal cases, is the profound upregulation of local estrogen synthesis. Adipose tissue serves as the primary source of estrogen via the aromatase enzyme (CYP19A1). This process is amplified by intricate positive feedback loops within the tumor microenvironment: obesityinduced inflammation elevates PGE2 and TNF-α, while tumor-derived oncostatin M (OSM) activates the JAK/STAT3 pathway in adipocytes. These signals converge to upregulate CYP19A1 expression, resulting in significantly higher level of local estrogen than circulating system, thereby driving hormone-dependent tumor growth. Current clinical translation efforts, including microphysiological systems (MPS) and 3D bioprinting, are improving our ability to model these interactions, while radiomic tools like MRI proton density fat fraction (PDFF) offer non-invasive risk assessment. Despite these advances, the causal hierarchy and dynamic regulation of the adipose-tumor dialogue remain to be fully elucidated. Future research must leverage single-cell multi-omics and spatial transcriptomics to map the heterogeneity of the tumoradipose interface and clarify the metabolic fate of adipocyte-derived lipids. Ultimately, targeting the specific signaling axes of CAAs, such as the blockage of pro-inflammatory cytokines or the inhibition of specific metabolic enzymes, without disrupting systemic metabolic homeostasis, represents a promising frontier for developing novel, personalized therapeutic strategies for breast cancer.
Communication Author：LIANG Jun-Qing , Email:liang_junqing@126.com
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