Hypoxia-driven metabolic reprogramming of adipocytes fuels cancer cell proliferation.
Hypoxia-driven metabolic reprogramming of adipocytes fuels cancer cell proliferation.
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DOI：
10.3389/fendo.2022.989523
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发表时间：
2022
影响因子：
5.2
通讯作者：
中科院分区：
文献类型：
--
作者：
肥胖会增加某些癌症的风险，特别是靠近脂肪组织的肿瘤（网膜中的乳腺癌和卵巢癌转移）。致肥胖和肿瘤微环境具有共同的致病特征，即缺氧。在这里，我们测试缺氧如何改变脂肪细胞的代谢组来帮助癌细胞生长。将人和小鼠乳腺癌和卵巢癌细胞系分别与人和小鼠脂肪细胞在常氧或缺氧条件下共培养。通过商业测定测量癌细胞中的增殖和脂质摄取。在正常氧或缺氧条件下的代谢物的变化进行了测量，在人类脂肪细胞的媒体有针对性的LC/MS。低氧癌条件培养基增加了人和小鼠脂肪细胞的脂解。这导致脂质向癌细胞的转移增加，从而导致缺氧下增殖增加。这些效应依赖于脂肪细胞中HIF 1 α的表达，因为缺乏HIF 1 α的小鼠脂肪细胞在缺氧条件下表现出迟钝的反应。人GBS脂肪细胞培养基的靶向代谢组学显示，用来自非恶性乳腺上皮细胞（MCF 10A）的缺氧条件培养基培养可以改变脂肪细胞代谢组并驱动非恶性细胞的增殖。在这里，我们表明脂肪肿瘤微环境中的缺氧是乳腺癌和卵巢癌细胞脂质摄入的驱动力。缺氧可以改变脂肪细胞的代谢组，加速脂肪分解，葡萄糖剥夺和减少酮症。脂肪细胞中的这些代谢变化可以帮助乳腺上皮细胞和癌细胞绕过缺氧对增殖的抑制作用并茁壮成长。
Obesity increases the risk of certain cancers, especially tumours that reside close to adipose tissue (breast and ovarian metastasis in the omentum). The obesogenic and tumour micro-environment share a common pathogenic feature, oxygen deprivation (hypoxia). Here we test how hypoxia changes the metabolome of adipocytes to assist cancer cell growth. Human and mouse breast and ovarian cancer cell lines were co-cultured with human and mouse adipocytes respectively under normoxia or hypoxia. Proliferation and lipid uptake in cancer cells were measured by commercial assays. Metabolite changes under normoxia or hypoxia were measured in the media of human adipocytes by targeted LC/MS. Hypoxic cancer-conditioned media increased lipolysis in both human and mouse adipocytes. This led to increased transfer of lipids to cancer cells and consequent increased proliferation under hypoxia. These effects were dependent on HIF1α expression in adipocytes, as mouse adipocytes lacking HIF1α showed blunted responses under hypoxic conditions. Targeted metabolomics of the human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes media revealed that culture with hypoxic-conditioned media from non-malignant mammary epithelial cells (MCF10A) can alter the adipocyte metabolome and drive proliferation of the non-malignant cells. Here, we show that hypoxia in the adipose-tumour microenvironment is the driving force of the lipid uptake in both mammary and ovarian cancer cells. Hypoxia can modify the adipocyte metabolome towards accelerated lipolysis, glucose deprivation and reduced ketosis. These metabolic shifts in adipocytes could assist both mammary epithelial and cancer cells to bypass the inhibitory effects of hypoxia on proliferation and thrive.
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影响因子：
82.9
作者：
通讯作者：
--
影响因子：
5.9
作者：
Balaban S;Shearer RF;Lee LS;van Geldermalsen M;Schreuder M;Shtein HC;Cairns R;Thomas KC;Fazakerley DJ;Grewal T;Holst J;Saunders DN;Hoy AJ
通讯作者：
Hoy AJ
影响因子：
--
作者：
Danielsson F;Fasterius E;Sullivan D;Hases L;Sanli K;Zhang C;Mardinoglu A;Al-Khalili C;Huss M;Uhlén M;Williams C;Lundberg E
通讯作者：
Lundberg E
影响因子：
15.9
作者：
Chaturvedi, Pallavi;Gilkes, Daniele M.;Semenza, Gregg L.
通讯作者：
Semenza, Gregg L.
DOI：
10.1073/pnas.1307237110
发表时间：
2013-05-28
影响因子：
11.1
作者：
Kamphorst, Jurre J.;Cross, Justin R.;Rabinowitz, Joshua D.
通讯作者：
Rabinowitz, Joshua D.