Integrin α3β1 regulates tumor cell responses to stromal cells and can function to suppress prostate cancer metastatic colonization.
Integrin α3β1 regulates tumor cell responses to stromal cells and can function to suppress prostate cancer metastatic colonization.
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DOI：
10.1007/s10585-012-9558-1
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发表时间：
2013-04
影响因子：
4
通讯作者：
Stipp, Christopher S.
中科院分区：
文献类型：
--
作者：
Varzavand, Afshin;Drake, Justin M.;Svensson, Robert U.;Herndon, Mary E.;Zhou, Bo;Henry, Michael D.;Stipp, Christopher S.
整合素α3β1促进肿瘤细胞在层粘连蛋白亚型上的粘附、迁移和侵袭，并且一些临床研究已经表明肿瘤α3β1整合素表达增加与肿瘤进展、转移和不良患者结局之间的相关性。然而，其他一些临床和实验研究表明，α3β1在某些情况下可以具有抗转移活性。为了帮助确定α3β1在体内肿瘤细胞中的功能范围，我们使用RNAi来沉默PC-3前列腺癌细胞的侵袭性体内传代亚系中的α3整联蛋白亚基。α3整联蛋白的缺失损害了体外α3β1整联蛋白配体层粘连蛋白-332上的粘附和增殖。尽管在体外存在这些缺陷，但α3沉默细胞在体内肺定植模型中的侵袭性显著更强，肿瘤生长速率显著增加，显著降低了生存率。相反，沉默相关的α6整合素亚基延迟体内转移生长。在与肺成纤维细胞或前成骨细胞样细胞的3D胶原共培养物中重现了体内α3沉默肿瘤细胞的定植增加，其中α3沉默细胞显示出显著增强的生长。α3沉默的肿瘤细胞对共培养基质细胞的反应增加可以通过成纤维细胞条件培养基再现，该条件培养基含有一种或多种选择性有利于α3沉默细胞生长的肝素结合因子。我们的新数据表明，α3β1在转移性肿瘤微环境中调节肿瘤-宿主相互作用以限制生长，这提供了一些第一个直接证据，表明肿瘤细胞中α3功能的特异性丧失可能在体内产生促转移后果。
Integrin α3β1 promotes tumor cell adhesion, migration, and invasion on laminin isoforms, and several clinical studies have indicated a correlation between increased tumoral α3β1 integrin expression and tumor progression, metastasis, and poor patient outcomes. However, several other clinical and experimental studies have suggested that α3β1 can possess anti-metastatic activity in certain settings. To help define the range of α3β1 functions in tumor cells in vivo, we used RNAi to silence the α3 integrin subunit in an aggressive, in vivo-passaged subline of PC-3 prostate carcinoma cells. Loss of α3 integrin impaired adhesion and proliferation on the α3β1 integrin ligand, laminin-332 in vitro. Despite these deficits in vitro, the α3-silenced cells were significantly more aggressive in a lung colonization model in vivo, with a substantially increased rate of tumor growth that significantly reduced survival. In contrast, silencing the related α6 integrin subunit delayed metastatic growth in vivo. The increased colonization of α3-silenced tumor cells in vivo was recapitulated in 3D collagen co-cultures with lung fibroblasts or pre-osteoblast-like cells, where α3-silenced cells showed dramatically enhanced growth. The increased response of α3-silenced tumor cells to stromal cells in co-culture could be reproduced by fibroblast-conditioned medium, which contains one or more heparin binding factors that selectively favor the growth of α3-silenced cells. Our new data suggest a scenario in which α3β1 regulates tumor-host interactions within the metastatic tumor microenvironment to limit growth, providing some of the first direct evidence that specific loss of α3 function in tumor cells can have pro-metastatic consequences in vivo.
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影响因子：
11.2
作者：
Mitchell K;Svenson KB;Longmate WM;Gkirtzimanaki K;Sadej R;Wang X;Zhao J;Eliopoulos AG;Berditchevski F;Dipersio CM
通讯作者：
Dipersio CM
影响因子：
4.2
作者：
Nagle RB;Cress AE
通讯作者：
Cress AE
影响因子：
4
作者：
Demetriou, MC;Cress, AE
通讯作者：
Cress, AE
影响因子：
3.3
作者：
Drake, Justin M.;Strohbehn, Garth;Henry, Michael D.
通讯作者：
Henry, Michael D.
影响因子：
6
作者：
Hao, JS;Jackson, L;Nagle, RB
通讯作者：
Nagle, RB