Escape from breast tumor dormancy: The convergence of obesity and menopause.
Escape from breast tumor dormancy: The convergence of obesity and menopause.
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DOI：
10.1073/pnas.2204758119
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发表时间：
2022-10-11
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
绝经后 (PM) 肥胖与乳腺癌 (BC) 风险增加和预后不良相关；然而，目前尚不存在与肥胖相关的 PM BC 的临床相关治疗策略。我们报告说，PM 肥胖通过早期获得向血管表型 (SVP) 的转变，促进肿瘤休眠的逃脱，并通过增加新血管形成启动肿瘤的侵袭性生长。最后，我们发现，通过多激酶血管生成抑制剂靶向新生血管形成，可以延迟肥胖介导的 SVP、延长肿瘤潜伏期、降低肿瘤频率并增加肥胖 PM 小鼠的无肿瘤生存期。肥胖与绝经后 (PM) 乳腺癌 (BC) 的风险增加和预后不良相关。我们的目标是确定饮食诱导的肥胖 (DIO) 是否会促进 1) 缩短肿瘤潜伏期，2) 逃离肿瘤休眠，以及 3) 加速肿瘤生长，并阐明其潜在机制。我们开发了体外测定和 PM 乳腺肿瘤模型，并辅以无创成像系统来检测休眠肿瘤的血管侵袭，并利用它们来确定肥胖是否通过促进 PM BC 中血管表型 (SVP) 的转变来促进乳腺肿瘤休眠和肿瘤生长的逃脱。与瘦小鼠相比，肥胖小鼠的肿瘤发生率明显更高，肿瘤体积更大，总体存活率更低。我们证明，DIO 通过早期获取 SVP 加剧乳腺增生和肿瘤，减少肿瘤潜伏期并增加肿瘤发生率。 DIO 通过上调脂质运载蛋白-2 (LCN2)、血管内皮生长因子 (VEGF) 和碱性成纤维细胞生长因子 (bFGF) 建立局部和全身促血管生成和炎症环境，从而促进肿瘤休眠和肿瘤进展的逃脱。此外，我们发现通过多靶点受体酪氨酸激酶抑制剂舒尼替尼靶向新生血管形成可以延迟SVP的获得，从而延长肿瘤潜伏期、降低肿瘤频率并增加无瘤生存期，这表明靶向新生血管形成可能是肥胖相关PM BC进展的潜在治疗策略。这项研究确立了肥胖与 PM BC 之间的联系，并且据我们所知，首次将肥胖导致的功能失调的新血管形成与肿瘤发展的最早阶段联系起来。
Postmenopausal (PM) obesity is associated with an increased risk of, and a poor prognosis for, breast cancer (BC); however, clinically relevant therapeutic strategies for obesity-associated PM BC are currently nonexistent. We report that PM obesity promotes the escape from tumor dormancy via the early acquisition of the switch to the vascular phenotype (SVP) and initiates aggressive tumor growth via increased neovascularization. Finally, we show that targeting neovascularization via a multikinase angiogenesis inhibitor delayed the obesity-mediated SVP, prolonged tumor latency, reduced tumor frequency, and increased tumor-free survival in obese PM mice. Obesity is associated with an increased risk of, and a poor prognosis for, postmenopausal (PM) breast cancer (BC). Our goal was to determine whether diet-induced obesity (DIO) promotes 1) shorter tumor latency, 2) an escape from tumor dormancy, and 3) an acceleration of tumor growth and to elucidate the underlying mechanism(s). We have developed in vitro assays and PM breast tumor models complemented by a noninvasive imaging system to detect vascular invasion of dormant tumors and have used them to determine whether obesity promotes the escape from breast tumor dormancy and tumor growth by facilitating the switch to the vascular phenotype (SVP) in PM BC. Obese mice had significantly higher tumor frequency, higher tumor volume, and lower overall survival compared with lean mice. We demonstrate that DIO exacerbates mammary gland hyperplasia and neoplasia, reduces tumor latency, and increases tumor frequency via an earlier acquisition of the SVP. DIO establishes a local and systemic proangiogenic and inflammatory environment via the up-regulation of lipocalin-2 (LCN2), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) that may promote the escape from tumor dormancy and tumor progression. In addition, we show that targeting neovascularization via a multitargeted receptor tyrosine kinase inhibitor, sunitinib, can delay the acquisition of the SVP, thereby prolonging tumor latency, reducing tumor frequency, and increasing tumor-free survival, suggesting that targeting neovascularization may be a potential therapeutic strategy in obesity-associated PM BC progression. This study establishes the link between obesity and PM BC and, for the first time to our knowledge, bridges the dysfunctional neovascularization of obesity with the earliest stages of tumor development.
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影响因子：
4.8
作者：
Gunther, EJ;Belka, GK;Chodosh, LA
通讯作者：
Chodosh, LA
DOI：
10.1111/micc.12270
发表时间：
2016-04
期刊：
Microcirculation (New York, N.Y. : 1994)
影响因子：
--
作者：
Fukumura D;Incio J;Shankaraiah RC;Jain RK
通讯作者：
Jain RK
影响因子：
2.8
作者：
Favaro, Elena;Amadori, Alberto;Indraccolo, Stefano
通讯作者：
Indraccolo, Stefano
影响因子：
--
作者：
Campbell NE;Kellenberger L;Greenaway J;Moorehead RA;Linnerth-Petrik NM;Petrik J
通讯作者：
Petrik J
DOI：
10.1073/pnas.97.8.3884
发表时间：
2000-04-11
影响因子：
11.1
作者：
Fang, JM;Shing, Y;Moses, MA
通讯作者：
Moses, MA