Metastatic growth instructed by neutrophil-derived transferrin.
Metastatic growth instructed by neutrophil-derived transferrin.
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DOI：
10.1073/pnas.1811717115
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发表时间：
2018-10-23
影响因子：
11.1
通讯作者：
Ferrara N
中科院分区：
文献类型：
--
作者：
Liang W;Li Q;Ferrara N
目前的研究揭示了中性粒细胞和癌症转移之间的机制联系。转铁蛋白是一种铁转运蛋白，在小鼠和人中性粒细胞中以mRNA和蛋白质水平表达，主要负责嗜中性粒细胞分泌的对肿瘤细胞的促有丝分裂活性。GM-CSF是一种主要由转移性微环境中的肿瘤细胞产生的细胞因子，通过激活Jak/Stat 5 β途径选择性地作用于中性粒细胞以增强转铁蛋白基因表达。因此，删除肿瘤细胞中的转铁蛋白受体（Tfr 1）、阻断GM-CSF或抑制Jak激酶可抑制小鼠肿瘤肺转移。我们的研究结果提高了抑制GM-CSF或Jak/Stat 5 b通路可能有益于转移性疾病和高局部中性粒细胞浸润的患者的可能性。中性粒细胞的促肿瘤作用主要是通过诱导肿瘤血管生成或抑制肿瘤免疫来实现的。然而，嗜中性粒细胞对肿瘤细胞生长和转移的直接影响在很大程度上仍然是未知的。在这里，我们结合蛋白质组学方法与功能筛选来询问肿瘤相关中性粒细胞的分泌组。令人惊讶的是，铁转运蛋白转铁蛋白被确定为由中性粒细胞分泌的肿瘤细胞的主要促分裂原。中性粒细胞的耗竭抑制肺转移和转移微环境中转铁蛋白的产生。转铁蛋白受体的缺失抑制了肺部肿瘤细胞的生长。此外，从转移性乳腺癌患者分离的中性粒细胞条件培养基刺激人乳腺癌细胞的生长，运铁蛋白免疫耗竭在很大程度上消除了这种作用。我们鉴定了主要由肿瘤细胞产生的GM-CSF，作为中性粒细胞通过Jak/Stat 5 β途径重新合成转铁蛋白的选择性诱导剂。GM-CSF中和或抑制Jak激酶在体外和体内以及癌症转移中减少中性粒细胞转铁蛋白表达。因此，由于肿瘤浸润性嗜中性粒细胞响应GM-CSF刺激而局部递送这种生长促进蛋白的能力，转铁蛋白提供了嗜中性粒细胞和转移性生长之间的机械联系。我们的研究确定嗜铁细胞衍生的转铁蛋白作为转移性肿瘤细胞生长的关键调节因子和抗转移治疗的治疗靶点。
The current study uncovers a mechanistic link between neutrophils and cancer metastasis. Transferrin, an iron-transporting protein, is expressed at mRNA and protein levels in mouse and human neutrophils and is mainly responsible for neutrophil-secreted mitogenic activity on tumor cells. GM-CSF, a cytokine largely produced by tumor cells in the metastatic microenvironment, selectively acts on neutrophils to enhance transferrin gene expression, through activation of the Jak/Stat5β pathway. Accordingly, deletion of the transferrin receptor (Tfr1) in tumor cells, blockade of GM-CSF, or inhibition of Jak kinases inhibited mouse tumor lung metastasis. Our findings raise the possibility that inhibiting GM-CSF or the Jak/Stat5b pathway may benefit patients with metastatic diseases and high local neutrophil infiltration. The tumor-promoting functions of neutrophils have been mainly attributed to induction of tumor angiogenesis or suppression of anticancer immunity. However, a direct impact of neutrophils on tumor cell growth and metastasis remains largely uncharacterized. Here, we coupled a proteomic approach with a functional screen to interrogate the secretome of tumor-associated neutrophils. Surprisingly, the iron-transporting protein transferrin was identified as the major mitogen for tumor cells secreted by neutrophils. Depletion of neutrophils inhibited lung metastasis and transferrin production in the metastatic microenvironment. Deletion of transferrin receptor suppressed growth of lung-colonizing tumor cells. Also, media conditioned by neutrophils isolated from metastatic breast cancer patients stimulated growth of human breast cancer cells, an effect that was largely abolished by transferrin immunodepletion. We identified GM-CSF, which is produced primarily by tumor cells, as a selective inducer of de novo transferrin synthesis in neutrophils through the Jak/Stat5β pathway. GM-CSF neutralization or inhibition of Jak kinases curtailed neutrophil transferrin expression in vitro and in vivo as well as cancer metastasis. Thus, transferrin provides a mechanistic link between neutrophils and metastatic growth owing to the ability of tumor-infiltrating neutrophils to locally deliver this growth-promoting protein in response to GM-CSF stimulation. Our study identifies neutrophil-derived transferrin as a key regulator of metastatic tumor cell growth and a therapeutic target for antimetastatic treatment.
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影响因子：
50.3
作者：
Granot Z;Henke E;Comen EA;King TA;Norton L;Benezra R
通讯作者：
Benezra R
影响因子：
64.5
作者：
Acharyya S;Oskarsson T;Vanharanta S;Malladi S;Kim J;Morris PG;Manova-Todorova K;Leversha M;Hogg N;Seshan VE;Norton L;Brogi E;Massagué J
通讯作者：
Massagué J
影响因子：
7.3
作者：
Orditura M;Galizia G;Diana A;Saccone C;Cobellis L;Ventriglia J;Iovino F;Romano C;Morgillo F;Mosca L;Diadema MR;Lieto E;Procaccini E;De Vita F;Ciardiello F
通讯作者：
Ciardiello F
影响因子：
2.9
作者：
PAPACONSTANTINOU, J;HILL, RE;RAO, EY
通讯作者：
RAO, EY
影响因子：
4.8
作者：
Rhodes, DR;Yu, JJ;Chinnaiyan, AM
通讯作者：
Chinnaiyan, AM