The impact of stress on tumor growth: peripheral CRF mediates tumor-promoting effects of stress.
The impact of stress on tumor growth: peripheral CRF mediates tumor-promoting effects of stress.
复制标题
DOI：
10.1186/1476-4598-9-261
复制
发表时间：
2010-09-27
期刊：
影响因子：
37.3
通讯作者：
Tsatsanis C
中科院分区：
文献类型：
--
作者：
Arranz A;Venihaki M;Mol B;Androulidaki A;Dermitzaki E;Rassouli O;Ripoll J;Stathopoulos EN;Gomariz RP;Margioris AN;Tsatsanis C
压力已被证明是一种肿瘤促进因素。临床和实验室研究都表明，慢性压力与几种类型癌症的肿瘤生长有关。促肾上腺皮质激素释放因子（CRF）是下丘脑应激的主要介质，但也在外周组织中表达。早期的研究表明，外周CRF影响乳腺癌细胞的增殖和运动。本研究的目的是评估外周CRF作为体内应激反应的介质对肿瘤生长的意义。为此，我们在细胞培养和体内使用4 T1乳腺癌细胞系。在培养中用CRF处理细胞，并进行基因特异性阵列以鉴定直接受CRF影响并参与乳腺癌细胞生长的基因。为了评估外周CRF作为肿瘤生长中的应激介质的影响，在Balb/c小鼠的乳腺脂肪垫中原位注射4 T1细胞以诱导乳腺肿瘤。将小鼠反复固定应激作为慢性应激模型。为了抑制CRF的作用，腹腔注射CRF拮抗剂antalarmin。对乳腺组织样本进行组织学分析并评估新生血管生成。阵列分析显示，在其他基因中，CRF诱导SMAD 2和β-catenin的表达，这些基因参与乳腺癌细胞增殖和与转移相关的细胞骨架变化。细胞转染和荧光素酶测定证实了CRF在WNT- β-catenin信号传导中的作用。CRF诱导4 T1细胞增殖并增强TGF-β对增殖的作用，证实其对TGFβ/SMAD 2信号传导的影响。此外，CRF还促进肌动蛋白重组和细胞迁移，这表明其具有直接的促肿瘤作用。慢性应激增强了4 T1乳腺肿瘤荷瘤小鼠的肿瘤生长，外周给予CRF拮抗剂antalarmin抑制了这种作用。此外，antalarmin在体内抑制4 T1肿瘤中的新血管生成。这是第一份证明外周CRF至少部分介导应激的促肿瘤作用并暗示CRF参与SMAD 2和β-catenin表达的报告。
Stress has been shown to be a tumor promoting factor. Both clinical and laboratory studies have shown that chronic stress is associated with tumor growth in several types of cancer. Corticotropin Releasing Factor (CRF) is the major hypothalamic mediator of stress, but is also expressed in peripheral tissues. Earlier studies have shown that peripheral CRF affects breast cancer cell proliferation and motility. The aim of the present study was to assess the significance of peripheral CRF on tumor growth as a mediator of the response to stress in vivo. For this purpose we used the 4T1 breast cancer cell line in cell culture and in vivo. Cells were treated with CRF in culture and gene specific arrays were performed to identify genes directly affected by CRF and involved in breast cancer cell growth. To assess the impact of peripheral CRF as a stress mediator in tumor growth, Balb/c mice were orthotopically injected with 4T1 cells in the mammary fat pad to induce breast tumors. Mice were subjected to repetitive immobilization stress as a model of chronic stress. To inhibit the action of CRF, the CRF antagonist antalarmin was injected intraperitoneally. Breast tissue samples were histologically analyzed and assessed for neoangiogenesis. Array analysis revealed among other genes that CRF induced the expression of SMAD2 and β-catenin, genes involved in breast cancer cell proliferation and cytoskeletal changes associated with metastasis. Cell transfection and luciferase assays confirmed the role of CRF in WNT- β-catenin signaling. CRF induced 4T1 cell proliferation and augmented the TGF-β action on proliferation confirming its impact on TGFβ/SMAD2 signaling. In addition, CRF promoted actin reorganization and cell migration, suggesting a direct tumor-promoting action. Chronic stress augmented tumor growth in 4T1 breast tumor bearing mice and peripheral administration of the CRF antagonist antalarmin suppressed this effect. Moreover, antalarmin suppressed neoangiogenesis in 4T1 tumors in vivo. This is the first report demonstrating that peripheral CRF, at least in part, mediates the tumor-promoting effects of stress and implicates CRF in SMAD2 and β-catenin expression.
登录
查看更多内容
DOI：
10.1111/j.1349-7006.2002.tb01313.x
发表时间：
2002-07
期刊：
Japanese journal of cancer research : Gann
影响因子：
--
作者：
Hasegawa H;Saiki I
通讯作者：
Saiki I
影响因子：
6.5
作者：
Arbiser, JL;Karalis, K;Majzoub, JA
通讯作者：
Majzoub, JA
影响因子：
4.8
作者：
Hirota, Morihisa;Watanabe, Kazuhide;Salomon, David S.
通讯作者：
Salomon, David S.
影响因子：
4
作者：
Gavert, Nancy;Ben-Ze'ev, Avri
通讯作者：
Ben-Ze'ev, Avri
影响因子：
4.1
作者：
Graziani, Grazia;Tentori, Lucio;Navarra, Pierluigi
通讯作者：
Navarra, Pierluigi