Loss of PPARγ activity characterizes early protumorigenic stromal reprogramming and dictates the therapeutic window of opportunity.
Loss of PPARγ activity characterizes early protumorigenic stromal reprogramming and dictates the therapeutic window of opportunity.
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DOI：
10.1073/pnas.2303774120
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发表时间：
2023-10-17
影响因子：
11.1
通讯作者：
Tlsty, Thea D.
中科院分区：
文献类型：
--
作者：
Caruso, Joseph A.;Wang, Xianhong;Murrow, Lyndsay M.;Rodriguez, Carlos Ivan;Chen-Tanyolac, Chira;Vu, Lisa;Chen, Yunn-Yi;Gascard, Philippe;Gartner, Zev J.;Kerlikowske, Karla;Tlsty, Thea D.
肿瘤进展过程中间质CD36的丢失反映了肿瘤衍生因子对PPARγ表达的损害。这种PPARγ的缺失不仅直接解放了EC的增殖，而且允许周细胞向促肿瘤的肌成纤维细胞表型转变，能够在体外和体内阐明促进血管生成和肿瘤细胞增殖的因素。在小鼠异种移植模型中，PPARγ的激活剂罗格列酮作为早期干预措施显示出抗肿瘤作用，但不作为治疗，肿瘤形成抑制PPARγ并使基质细胞对配体不敏感。因此，肿瘤细胞信号可以破坏健康组织中发现的某些基质细胞的PPARγ依赖的抗肿瘤状态。这项研究有助于理解PPARγ作为治疗干预的基质靶点。虽然CD36在无疾病(DF)的乳腺间质中强烈表达，但CD36在浸润性乳腺癌(IBCs)周围的间质中始终缺失。在这项研究中，我们主要观察了CD36在DF乳房内的脂肪细胞和小叶内毛细血管中的表达。集中在小叶间区的较大血管缺乏CD36，而以CD31的表达为标志。当对导管原位癌周围的毛细血管进行评估时，CD36丢失在与随后的IBC相关的病变中更为常见。过氧化物酶体增殖物激活受体γ(PPARγ)调控CD36及其相关分化、代谢、血管生成和炎症相关基因的表达。与CD36缺失一致的是，我们观察到PPARγ及其靶基因在毛细血管内皮细胞(ECs)和周细胞中显著抑制，这两种细胞通常包围并支持毛细血管内皮细胞的稳定性。恶性细胞条件培养液中存在的因子抑制了PPARγ及其靶基因，不仅在培养的内皮细胞和周细胞中，而且在脂肪细胞中也是如此，这需要PPARγ来进行适当的分化。此外，我们确定了PPARγ在反对周细胞向肿瘤支持的肌成纤维细胞表型转变中的作用。在小鼠异种移植模型中，早期使用PPARγ激动剂罗格列酮显示了显著的抗肿瘤作用；然而，随着可触及的肿瘤的发展，罗格列酮的抗肿瘤作用被小鼠间质中PPARγ的抑制所抵消。总之，健康组织中的PPARγ活性使几种基质细胞处于抗肿瘤状态，直接抑制EC的增殖，维持脂肪细胞的分化，并抑制周细胞向支持肿瘤的肌成纤维细胞的转变。
Stromal CD36 loss during tumor progression reflects impairment of PPARγ expression by tumor-derived factors. This PPARγ loss not only directly liberated EC proliferation but also permitted transition of pericytes towards pro-tumorigenic myofibroblast phenotypes capable of elaborating factors that enhanced both angiogenesis and tumor cell proliferation in vitro and in vivo. In mouse xenograft models, rosiglitazone, an activator of PPARγ, demonstrated anti-tumor effects as an early intervention, but not as a treatment, with tumor formation repressing PPARγ and rendering stromal cells insensitive to ligand. Thus, tumor cell signaling can impair the PPARγ-dependent, anti-tumorigenic state of certain stromal cells found in healthy tissues. This study contributes to the understanding of PPARγ as a stromal target for therapeutic intervention. Although robustly expressed in the disease-free (DF) breast stroma, CD36 is consistently absent from the stroma surrounding invasive breast cancers (IBCs). In this study, we primarily observed CD36 expression in adipocytes and intralobular capillaries within the DF breast. Larger vessels concentrated in interlobular regions lacked CD36 and were instead marked by the expression of CD31. When evaluated in perilesional capillaries surrounding ductal carcinoma in situ, a nonobligate IBC precursor, CD36 loss was more commonly observed in lesions associated with subsequent IBC. Peroxisome proliferator-activated receptor γ (PPARγ) governs the expression of CD36 and genes involved in differentiation, metabolism, angiogenesis, and inflammation. Coincident with CD36 loss, we observed a dramatic suppression of PPARγ and its target genes in capillary endothelial cells (ECs) and pericytes, which typically surround and support the stability of the capillary endothelium. Factors present in conditioned media from malignant cells repressed PPARγ and its target genes not only in cultured ECs and pericytes but also in adipocytes, which require PPARγ for proper differentiation. In addition, we identified a role for PPARγ in opposing the transition of pericytes toward a tumor-supportive myofibroblast phenotype. In mouse xenograft models, early intervention with rosiglitazone, a PPARγ agonist, demonstrated significant antitumor effects; however, following the development of a palpable tumor, the antitumor effects of rosiglitazone were negated by the repression of PPARγ in the mouse stroma. In summary, PPARγ activity in healthy tissues places several stromal cell types in an antitumorigenic state, directly inhibiting EC proliferation, maintaining adipocyte differentiation, and suppressing the transition of pericytes into tumor-supportive myofibroblasts.
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影响因子：
16.6
作者：
通讯作者：
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影响因子：
3.2
作者：
Pusztaszeri, MP;Seelentag, W;Bosman, FT
通讯作者：
Bosman, FT
影响因子：
82.9
作者：
Sarraf, P;Mueller, E;Spiegelman, BM
通讯作者：
Spiegelman, BM
影响因子：
8
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Hu, Chunyan;Keen, Henry L.;Sigmund, Curt D.
通讯作者：
Sigmund, Curt D.
影响因子：
16
作者：
Mueller, E;Sarraf, P;Spiegelman, BM
通讯作者：
Spiegelman, BM