Cell-extrinsic consequences of epithelial stress: activation of protumorigenic tissue phenotypes.
Cell-extrinsic consequences of epithelial stress: activation of protumorigenic tissue phenotypes.
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DOI：
10.1186/bcr3368
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发表时间：
2012-12-07
期刊：
影响因子：
--
通讯作者：
Tlsty TD
中科院分区：
文献类型：
--
作者：
Fordyce CA;Patten KT;Fessenden TB;DeFilippis R;Hwang ES;Zhao J;Tlsty TD
肿瘤的特征在于上皮和基质区室的改变，这两者都有助于肿瘤的促进。然而，肿瘤间质在何处、何时以及如何发展仍然知之甚少。我们之前证明，DNA损伤或端粒功能障碍会诱导激活素A依赖性上皮应激反应，从而激活致命的、非致瘤性的人乳腺上皮细胞（HMEC和vHMEC）中的细胞内在和细胞外在后果。在这里，我们表明，这种上皮应激反应也诱导protumorigenic表型在相邻的原代成纤维细胞，概括了许多与肿瘤间质（例如，结缔组织增生）的形成相关的特征。在与端粒功能障碍的vHMEC（TRF 2-vHMEC）共培养的原代人乳腺成纤维细胞（HMF）或直接用DNA损伤剂处理的HMF中，分别研究了外源性和内源性DNA损伤对促结缔组织增生表型获得的贡献。通过定量聚合酶链反应、酶联免疫吸附试验和免疫细胞化学监测所选促肿瘤分子水平的增加来评估成纤维细胞重编程。通过添加外源性激活素A或激活素A沉默来评估诱导的表型对激活素A的依赖性。体外研究结果在体内进行了验证，在浸润前导管原位癌（DCIS）病变，使用免疫组化和端粒特异性荧光原位杂交。与TRF 2-vHMEC共培养或直接暴露于外源性激活素A或PGE 2的HMF显示细胞因子和生长因子的表达增加、细胞外基质（ECM）蛋白沉积以及向有氧糖酵解的转变。反过来，这些“活化的”成纤维细胞分泌促进上皮细胞运动的因子。有趣的是，HMF中的细胞内源性DNA损伤诱导了一些但不是全部的作为细胞外源性DNA损伤的结果而诱导的分子。在体外表征的对细胞外源性DNA损伤的反应在体内DCIS病变中重现，其表现出端粒丢失、DNA损伤反应增强以及激活素A和环氧合酶-2表达增加。这些病变被基质包围，其特征是α平滑肌肌动蛋白表达增加以及内皮细胞和免疫细胞浸润。因此，基质和上皮之间的相互作用，即使在癌变的起始阶段，似乎是必要的收购恶性肿瘤，并提供了新的见解，在哪里，何时，以及如何肿瘤间质的发展，允许新的治疗策略。
Tumors are characterized by alterations in the epithelial and stromal compartments, which both contribute to tumor promotion. However, where, when, and how the tumor stroma develops is still poorly understood. We previously demonstrated that DNA damage or telomere malfunction induces an activin A-dependent epithelial stress response that activates cell-intrinsic and cell-extrinsic consequences in mortal, nontumorigenic human mammary epithelial cells (HMECs and vHMECs). Here we show that this epithelial stress response also induces protumorigenic phenotypes in neighboring primary fibroblasts, recapitulating many of the characteristics associated with formation of the tumor stroma (for example, desmoplasia). The contribution of extrinsic and intrinsic DNA damage to acquisition of desmoplastic phenotypes was investigated in primary human mammary fibroblasts (HMFs) co-cultured with vHMECs with telomere malfunction (TRF2-vHMEC) or in HMFs directly treated with DNA-damaging agents, respectively. Fibroblast reprogramming was assessed by monitoring increases in levels of selected protumorigenic molecules with quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and immunocytochemistry. Dependence of the induced phenotypes on activin A was evaluated by addition of exogenous activin A or activin A silencing. In vitro findings were validated in vivo, in preinvasive ductal carcinoma in situ (DCIS) lesions by using immunohistochemistry and telomere-specific fluorescent in situ hybridization. HMFs either cocultured with TRF2-vHMEC or directly exposed to exogenous activin A or PGE2 show increased expression of cytokines and growth factors, deposition of extracellular matrix (ECM) proteins, and a shift toward aerobic glycolysis. In turn, these "activated" fibroblasts secrete factors that promote epithelial cell motility. Interestingly, cell-intrinsic DNA damage in HMFs induces some, but not all, of the molecules induced as a consequence of cell-extrinsic DNA damage. The response to cell-extrinsic DNA damage characterized in vitro is recapitulated in vivo in DCIS lesions, which exhibit telomere loss, heightened DNA damage response, and increased activin A and cyclooxygenase-2 expression. These lesions are surrounded by a stroma characterized by increased expression of α smooth muscle actin and endothelial and immune cell infiltration. Thus, synergy between stromal and epithelial interactions, even at the initiating stages of carcinogenesis, appears necessary for the acquisition of malignancy and provides novel insights into where, when, and how the tumor stroma develops, allowing new therapeutic strategies.
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影响因子：
50.3
作者：
Crawford, YG;Gauthier, ML;Tlsty, TD
通讯作者：
Tlsty, TD
影响因子：
64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
DOI：
10.1158/1940-6207.capr-09-0229
发表时间：
2010-02
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Fordyce C;Fessenden T;Pickering C;Jung J;Singla V;Berman H;Tlsty T
通讯作者：
Tlsty T
影响因子：
6.2
作者：
Kang, Hong-Yo;Huang, Hsuan-Ying;Huang, Ko-En
通讯作者：
Huang, Ko-En
影响因子：
4.3
作者：
Guido, Carmela;Whitaker-Menezes, Diana;Lisanti, Michael P.
通讯作者：
Lisanti, Michael P.