ACM Advances in Clinical Medicine 2161-8712 Scientific Research Publishing 10.12677/ACM.2023.131154 ACM-60936 ACM20230100000_65640714.pdf 医药卫生 FABP4：肥胖相关乳腺癌诊疗新方向 FABP4: A New Direction for the Diagnosis and Treatment of Obesity-Related Breast Cancer 郇 喻淇 1 2 孔 滨 3 1 青岛大学附属医院，山东 青岛 null 青岛大学，山东 青岛 04 01 2023 13 01 1118 1123 © Copyright 2014 by authors and Scientific Research Publishing Inc. 2014 This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

乳腺癌因其高发病率及高死亡率成为威胁全球女性健康的主要问题，肥胖患者有更高的转移率和病死率，表现出更差的预后，然而目前针对肥胖影响乳腺癌的潜在机制仍未明确。近年来有研究表明，FABP4与肥胖相关乳腺癌的发生发展有关，提示我们FABP4在未来可能成为研究肥胖相关乳腺癌，改善乳腺癌患者预后的新方向。本文通过回顾FABP4及肥胖相关乳腺癌的相关文献报道，探讨FABP4在乳腺癌早期诊疗、预测预后及治疗等方面的应用前景。 Breast cancer has become a major threat to women’s health worldwide due to its high incidence and mortality. Patients with obesity have a higher metastasis rate and mortality, and show a worse prognosis. However, the underlying mechanism of obesity affecting breast cancer is still unclear. Recently, some studies have shown that FABP4 is related to the occurrence and development of obesity-related breast cancer, suggesting that FABP4 may become a new direction for studying obe-sity-related breast cancer and improving the prognosis of patients with breast cancer in the future. This article reviews the literature reports on FABP4 and obesity-related breast cancer, and dis-cusses the application prospect of FABP4 in the early diagnosis and treatment of breast cancer, predicting prognosis and treatment.

肥胖，乳腺癌，脂肪酸结合蛋白，脂肪酸结合蛋白4, Obesity Breast Cancer Fatty Acid Binding Proteins (FABP) FABP4 摘要

乳腺癌因其高发病率及高死亡率成为威胁全球女性健康的主要问题，肥胖患者有更高的转移率和病死率，表现出更差的预后，然而目前针对肥胖影响乳腺癌的潜在机制仍未明确。近年来有研究表明，FABP4与肥胖相关乳腺癌的发生发展有关，提示我们FABP4在未来可能成为研究肥胖相关乳腺癌，改善乳腺癌患者预后的新方向。本文通过回顾FABP4及肥胖相关乳腺癌的相关文献报道，探讨FABP4在乳腺癌早期诊疗、预测预后及治疗等方面的应用前景。

 关键词

肥胖，乳腺癌，脂肪酸结合蛋白，脂肪酸结合蛋白4

 FABP4: A New Direction for the Diagnosis and Treatment of Obesity-Related Breast Cancer<sup> </sup>

Yuqi Huan1*, Bin Kong2#

1Qingdao University, Qingdao Shandong

2The Affiliated Hospital of Qingdao University, Qingdao Shandong

Received: Dec. 28th, 2022; accepted: Jan. 21st, 2023; published: Jan. 31st, 2023

 ABSTRACT

Breast cancer has become a major threat to women’s health worldwide due to its high incidence and mortality. Patients with obesity have a higher metastasis rate and mortality, and show a worse prognosis. However, the underlying mechanism of obesity affecting breast cancer is still unclear. Recently, some studies have shown that FABP4 is related to the occurrence and development of obesity-related breast cancer, suggesting that FABP4 may become a new direction for studying obesity-related breast cancer and improving the prognosis of patients with breast cancer in the future. This article reviews the literature reports on FABP4 and obesity-related breast cancer, and discusses the application prospect of FABP4 in the early diagnosis and treatment of breast cancer, predicting prognosis and treatment.

Keywords:Obesity, Breast Cancer, Fatty Acid Binding Proteins (FABP), FABP4

Copyright © 2023 by author(s) and beplay安卓登录

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

 1. 肥胖与乳腺癌的发生发展存在潜在联系

随着社会的发展和进步，现代人的生活方式正逐渐向着便捷、省力发展，随着生活方式及饮食结构的改变，肥胖及超重在人群中占比也逐年增高，也带来一系列针对健康问题的挑战，如心血管疾病、2型糖尿病、多种类型的癌症等 [ 1 ] [ 2 ]。肥胖是绝经后妇女患乳腺癌的主要危险因素。较为直观又简便的评价肥胖程度的方法如BMI测量值高及腰围 [ 3 ] [ 4 ]。许多研究表明，较高的BMI会增加患乳腺癌的风险 [ 5 ] [ 6 ] [ 7 ] [ 8 ]。有相关研究证明，肥胖与乳腺癌在亚洲女性中存在不同的关联，如导致绝经前乳腺癌的风险增加 [ 9 ] [ 10 ] [ 11 ]。另外，与BMI正常范围患者相比，肥胖乳腺癌患者总体呈现更差的TNM分期及预后，且根据Hillers-Ziemer等人长期随访发现肥胖患者乳腺癌远端复发时限短于正常范围BMI患者。不仅如此，肥胖乳癌患者更容易对内分泌治疗产生耐药，以及与乳腺癌化疗疗效降低有关 [ 12 ]，导致患者在治疗后整体预后较差。肥胖及超重人群往往伴有较高的体脂率，即体内有更多的脂肪组织，脂肪组织作为一种内分泌器官，产生多种调节因子(如脂肪因子、细胞因子、趋化因子、激素等)来维持代谢平衡。如瘦素增加、脂联素减少和炎性细胞因子分泌增加，以及肥胖的激发效应，导致高胰岛素血症和高脂血症，导致癌症发病率增加 [ 13 ]。除内分泌功能，脂肪组织，特别是瘤周脂肪组织床上富集各种类型的免疫细胞，包括巨噬细胞及调节性细胞，产生多种细胞因子影响周围组织 [ 14 ]。脂肪组织作为代谢器官，包括从脂肪生成后储存甘油三酯到通过脂解产生二甘油三酯、单甘油三酯和游离脂肪酸的能量调动。乳腺癌细胞和脂肪细胞之间的代谢相互作用，如“反向Warburg效应”促进乳腺癌的发展 [ 15 ]。参与乳腺癌进展的脂肪细胞被称为癌症相关脂肪细胞(CAAs)。CAAs最重要的特征是其更小的体积和减少的脂滴 [ 16 ] [ 17 ]，这可以解释为脂肪细胞通过脂肪分解产生的脂肪酸转移到乳腺癌细胞。脂肪酸可作为新合成的膜磷脂的底物，有助于癌细胞的增殖 [ 18 ]。

 2. FABP4与肥胖相关乳腺癌

FABPs在多种组织中表达，溶解不溶于水的长链脂肪酸(FAs)，促进FAs的吸收和利用，并协调它们在细胞内的运输和反应。根据其高表达的组织命名FABPs家族不同蛋白，如FABP5高表达于内皮组织，不同蛋白在其独特环境中表现出独特的生物学功能，共同参与机体内外环境稳定的调节 [ 19 ]。FABP4，又称脂肪细胞脂肪酸结合蛋白，在肿瘤周围组织相关细胞(在脂肪细胞、内皮细胞和免疫细胞)上均有高表达，与其他细胞因子、炎症介质、肿瘤组织等一起构成“肿瘤微环境(Tumor Micro Environment, TME)”的概念 [ 20 ]。在巨噬细胞中，FABP4通过激活核因子κB (NF-κB)和c-Jun n-末端激酶(JNK)途径调节炎性反应。在脂肪细胞中，FABP4通过与激素敏感脂肪酶(Hormone-Sensitive Lipase, HSL)和过氧化物酶体增殖物激活受体γ (PPARγ)的相互作用促进脂肪分解并抑制脂肪生成 [ 21 ]。KIM等人通过实验发现瘤周脂肪细胞和乳腺癌细胞之间存在代谢相互作用。乳腺癌细胞增加脂肪细胞的脂肪分解，产生脂肪酸和脂肪酸进入癌细胞。脂肪细胞利用脂肪细胞中的脂肪酸促进–氧化的生存和生长。这一过程的关键分子是FABP4，它与FFA结合，支持向癌细胞的迁移 [ 22 ]。根据Li等人的研究表明：与BMI正常或低于正常范围的患者相比，肥胖或超重患者血清中可检测到更高水平的FABP4，与体重指数呈正相关，且与乳腺癌患者肿瘤分期、分型及预后密切相关，此项研究结果将血清中游离FABP4水平与肥胖及乳腺癌的诊疗联系在一起 [ 23 ]。今天我们将通过此篇综述来进一步总结和探索FABP4之于乳腺癌，尤其是肥胖相关乳腺癌发生发展过程中扮演的重要角色。

 3. FABP4影响乳腺癌发展的潜在机制 3.1. 组织内的FABP4

FABP4在不同分型乳腺癌组织中表达水平不同，根据KIM等人的调查显示，FABP4在三阴性乳腺癌中表达最高，其次是HER-2阳性乳腺，Luminal型乳腺组织中FABP4表达水平较低，其中LuminalB型中表达最低 [ 24 ]。而乳腺癌组织不同部位FABP4蛋白表达量也不同，其中在癌旁脂肪组织中表达最高，其次是癌伴脂肪细胞和中央癌伴成纤维细胞区 [ 22 ]。瘤周脂肪组织或肿瘤周围的脂肪细胞与肿瘤组织有活跃的相互作用。瘤周脂肪组织不仅对脂肪细胞有影响，对免疫细胞、巨噬细胞和内皮细胞也有影响。此外，因肥胖时脂肪组织内部平衡被打破，脂肪组织与肿瘤之间的相互作用可能会增加 [ 25 ]。从这个意义上说，许多类型的肿瘤，如胃癌、乳腺癌、结肠癌、肾癌、卵巢癌等，生长与脂肪组织密切相关。在乳腺癌中，恶性乳腺肿瘤旁脂肪组织中FABP4及其他脂肪生成相关基因表达发生改变，如HOXC9和激素敏感脂肪酶(HSL)表达下调，炎性细胞因子如TNFα和MCP-1表达上调。瘤周组织与肿瘤组织相互作用，促进瘤周脂肪细胞和巨噬细胞释放FABP4，以旁分泌的方式影响乳腺癌组织代谢。孤核受体Nur77诱导SWI/SNF复合物和HDAC1抑制CD36和FABP4的转录，阻碍乳腺癌细胞吸收外源性FAs，从而抑制细胞增殖 [ 26 ]。FABP4还作用于激素敏感脂肪酶(HSL)，催化脂肪组织分解释放游离脂肪酸，且通过介导JNK/IKK和胰岛素功能调节脂肪细胞内的炎症反应 [ 27 ]。FABP4在一小部分肿瘤相关巨噬细胞(TAMs)中高度表达。FABP4阳性TAM亚群在晚期乳腺癌组织周围积累，促进肿瘤的发展。具体机制为乳腺癌细胞内的FABP4通过也可激活(NF-κB)通路，进而负调控miR-29b的表达，减少miR-29b与IL-6’UTR的结合导致巨噬细胞中IL-6原体信号转导，进而促进巨噬细胞功能 [ 21 ]。FABP4还介导CD8+驻留性记忆T细胞群(Trm)的维持和功能。Trm细胞利用FABP4运输的外源性游离脂肪酸维持其氧化代谢以维护获得性免疫 [ 28 ]。另有研究表明，在卵巢癌中，瘤周巨噬细胞产生IL-17A通过介导p-STAT3影响FABP4的表达，进而影响卵巢癌的进展 [ 29 ]。受肿瘤细胞影响，瘤周组织代谢产生相应变化，这些改变将不可避免地影响邻近肿瘤细胞对化疗药物的反应。有研究发现：脂肪细胞来源的条件培养基可以减少化疗对乳腺癌细胞的细胞毒性作用。另有研究表明，FABP4特异性抑制剂BMS309403不仅在同源原位小鼠模型中显著降低了肿瘤负担，而且还增加了癌细胞对卡铂的敏感性 [ 30 ] [ 31 ]。因此，不管是通过基因消融还是化学抑制剂降低FABP4的表达均可以抑制乳腺肿瘤的生长。

 3.2. 游离FABP4

高水平的血清FABP4作为一种新的预后因子，已被证实与肥胖、乳腺癌分期、预后等有关。流行病学调查表明，乳腺癌患者血清中FABP4 (A-FABP4)水平明显高于健康组，且肥胖患者血清循环FABP4水平明显高于非肥胖患者和健康对照组。另外，它与乳腺癌癌肿大小、周围组织蔓延、淋巴结侵犯呈正相关 [ 32 ]。在Luminal型乳腺癌病例中，A-FABP4水平明显升高，BMI ≥ 25 kg/m2的绝经后乳腺癌患者血清中发现FABP4显著增高，且与乳腺癌合并糖尿病呈显著相关性。因此，我们可以将A-FABP4视为乳腺癌发展的生物标志物，其特定的代谢脂质途径可能会根据肿瘤ER和HER-2受体的状态而加速或减缓 [ 33 ]。FABP4由脂肪细胞和巨噬细胞释放，并可通过旁分泌或外分泌的方式发挥其代谢作用。FABP4的分泌增强脂肪组织诱导分解信号的敏感度，增强脂肪分解释放游离脂肪酸 [ 34 ]。根据Hao等人的实验结果：A-FABP4通过影响IL-6/STAT3/ALDH1通路促进肥胖相关乳腺癌的肿瘤细胞干性，促进肿瘤的发生、发展 [ 35 ]。外源性FABP4还可以通过激活PI3K/AKT和MAPK/ERK通路诱导乳腺癌细胞增殖。此外，在MCF-7细胞中，A-FABP4激活促癌基因FOXM1和脂肪酸转运蛋白CD36和FABP5的表达 [ 36 ]。另有研究表明：环氧二十碳三烯酸(EET)相关的FABP4核易位显著增强了TNBC细胞迁移转化和远端转移 [ 37 ]。循环的FABP4还可以通过促进FA的分泌运输促进肿瘤的进展。通常认为，血清白蛋白是循环游离FA (FFA)的主要载体。肥胖时，脂肪细胞死亡或脂肪分解可引起FFA的病理性升高 [ 22 ]。

此外，FABP4已被证明通过其他机制促进肿瘤进展。例如，FABP4通过增强髓系白血病细胞中异常的DNA甲基化来抑制肿瘤抑制基因，将肥胖与表观遗传改变和白血病肿瘤进展 [ 15 ] 联系起来。FABP4还能促进肿瘤间质中新血管的形成。综合这些发现，FABP4加强了肿瘤间质巨噬细胞、脂肪细胞和肿瘤细胞之间的相互作用，并将肥胖相关的脂肪因子与肿瘤促进信号连接起来，从而代表了肥胖促进肥胖相关癌症发展和进展的机制 [ 22 ]。

 4. 靶向抑制FABP4与临床治疗

FABP4在肿瘤发生发展中起重要作用，FABP4有望在未来成为肿瘤治疗的新靶点。目前已有多种靶向FABP4的抑制剂：小分子抑制剂、si-RNA等。目前，尚无抑制剂应用于临床。BMS309403作为一种FABP4抑制剂，最先被确定可以用于治疗代谢综合征，它也可以通过靶向肿瘤及基质细胞进而有效地抑制小鼠模型中肿瘤的生长和转移 [ 31 ]。

 5. 讨论

根据全球癌症观察，乳腺癌(BC)目前是全球最常见恶性肿瘤，是导致女性癌症相关死亡的主要原因。患者被诊断时分期的早晚将直接影响患者的预后。肥胖乳腺癌患者与BMI正常或低于正常患者相比，预后更差，生存率降低，转移率增加，且与乳腺癌患者内分泌及化疗治疗反应降低有关。因此进一步探讨影响肥胖相关乳腺癌发展的相关潜在机制至关重要。FABP4在癌组织及癌旁组织中表达，加强肿瘤间质巨噬细胞、脂肪细胞和肿瘤细胞之间的相互作用，加重肿瘤周围炎症反应，促进肿瘤的发展及周围侵犯。因此，靶向FABP4可作为辅助治疗肥胖相关恶性肿瘤的新思路，包括乳腺癌、卵巢癌等。FABP4通过介导IL-6/STAT3/ALDH1、JNK/IKK等多条通路及影响不同炎症因子分泌影响炎症反应，从机制上探究肿瘤治疗的新方向。A-FABP4又称循环FABP4，乳腺癌患者血清中可检测到较高水平的A-FABP4，肥胖患者循环FABP4水平高于非肥胖患者，这将肥胖与乳腺癌联系在一起。另外，血清A-FABP4在不同分型乳腺癌中的水平不同，并且与乳腺癌分期(肿瘤大小，脉管侵犯，远处转移)相关，提示对细胞内和循环中FABP4水平的动态监测在未来可以作为临床评估乳腺癌进展的一个新的生物标志物。外源性游离FABP4靶向多条通路，影响肿瘤微环境中巨噬细胞及脂肪细胞的代谢和炎症反应，进而影响乳腺癌的进展。针对FABP4的靶向治疗方法多种多样，包括小分子抑制剂、RNA治疗。目前市面上还没有成熟的FABP4靶向抑制剂应用于肿瘤临床治疗。因此，加大对FABP4的相关研究及药物开发和相关临床试验，为治疗癌症患者临床实践提供依据和新的选择，改善乳腺癌患者的预后，延长患者生存期至关重要。

 文章引用

郇喻淇,孔 滨. FABP4：肥胖相关乳腺癌诊疗新方向FABP4: A New Direction for the Diagnosis and Treatment of Obesity-Related Breast Cancer[J]. 临床医学进展, 2023, 13(01): 1118-1123. https://doi.org/10.12677/ACM.2023.131154

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