Modulation of CXCR3 ligand secretion by prostaglandin E2 and cyclooxygenase inhibitors in human breast cancer.
Modulation of CXCR3 ligand secretion by prostaglandin E2 and cyclooxygenase inhibitors in human breast cancer.
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DOI：
10.1186/bcr3115
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发表时间：
2012-02-14
期刊：
影响因子：
--
通讯作者：
Schmitt M
中科院分区：
文献类型：
--
作者：
Bronger H;Kraeft S;Schwarz-Boeger U;Cerny C;Stöckel A;Avril S;Kiechle M;Schmitt M
在小鼠乳腺癌模型中，两种干扰素-γ诱导的趋化因子和CXC-趋化因子受体3的受体配体、γ-干扰素诱导的单核因子和干扰素-γ诱导的蛋白-10通过自然杀伤细胞和肿瘤抑制T淋巴细胞的募集来抑制肿瘤的生长和转移。在人类乳腺癌中，CXCL9mRNA的过度表达与肿瘤浸润性淋巴细胞的数量相关，并预测对不同化疗方案的反应。因此，提高肿瘤内CXCR3配体浓度是加强乳腺癌免疫干预的一种可能方式。然而，人们对这些趋化因子在人类乳腺癌中的表达水平和调控知之甚少。由于环氧合酶(COX)的抑制已被证明以淋巴细胞和干扰素-γ依赖的方式减少肿瘤生长和转移，我们认为COX同工酶是增加乳腺癌中CXCR3配体浓度的药理靶点。免疫组织化学方法检测CXCL9在乳腺癌组织中的表达，ELISA法检测CXCL9的表达水平，Western blotting检测环氧合酶的表达水平。在调控研究中，密歇根癌症基金会-7(MCF7)和M.D.安德森转移性乳腺癌细胞(MDAM231)用干扰素-γ加或不加前列腺素E2(PGE_2)或COX抑制剂(消炎痛、乙酰水杨酸、塞来昔布)刺激。用ELISA法测定细胞释放CXCR3配体。在肿瘤微环境中，癌细胞是CXCL9的主要来源。前列腺素E_2抑制干扰素-γ介导的CXCL9和CXCL10的释放，吲哚美辛或阿司匹林抑制内源性环氧合酶相应地增加这种分泌。此外，高浓度的环氧合酶-2(COX-2)特异性拮抗剂塞来昔布具有相反的作用，并损害CXCL9和CXCL10的释放。在人类乳腺癌组织标本中，COX-2的过度表达与CXCL9浓度呈负相关，这表明体外观察的效应在体内也是重要的。通过抑制环氧合酶抑制内源性PGE2的合成增加了CXCL9和CXCL10从乳腺癌细胞中的释放，因此是增强肿瘤内免疫渗透的候选药物。然而，为了达到这一目的，非选择性COX抑制剂ASA和消炎痛似乎比塞来昔布更可取，后者在较高浓度时减少CXCR3配体的释放，很可能是由于COX非依赖机制。
In murine breast cancer models, the two interferon-gamma (IFN-γ) inducible chemokines and CXC-chemokine receptor 3 (CXCR3) receptor ligands, monokine induced by γ-interferon (CXCL9) and interferon-γ-inducible protein-10 (CXCL10) impair tumor growth and metastasis formation through recruitment of natural killer (NK) cells and tumor-suppressive T lymphocytes. In human breast cancer, CXCL9 mRNA overexpression correlates with the number of tumor infiltrating lymphocytes and predicts response to different chemotherapeutic regimens. Raising the intratumoral CXCR3 ligand concentration is therefore a possible way to enhance immune intervention in breast cancer. Little is known, however, about expression levels and regulation of these chemokines in human breast cancer. Since the inhibition of cyclooxygenases (COX) has been shown to reduce tumor growth and incidence of metastases in a lymphocytic and IFN-γ dependent manner, we argued that COX isoenzymes are a pharmacologic target to increase intratumoral CXCR3 ligand concentration in human breast cancer. CXCL9 was visualized in breast cancer specimens by immunohistochemistry, expression levels of CXCL9 and cyclooxygenases were determined by ELISA and western blotting, respectively. For regulation studies, Michigan Cancer Foundation-7 (MCF-7) and M.D. Anderson - Metastatic Breast 231 (MDA-MB 231) breast cancer cells were stimulated with IFN-γ with or without prostaglandin E2 (PGE2) or COX inhibitors (indomethacin, acetylsalicylic acid (ASA), celecoxib). CXCR3 ligand release from cells was measured by ELISA. Within the tumor microenvironment, cancer cells are the major source of CXCL9. PGE2 impairs IFN-γ mediated CXCL9 and CXCL10 release from MCF-7 and MDA-MB 231 cells, and inhibition of endogenous cyclooxygenases by indomethacin or ASA correspondingly increases this secretion. Otherwise, high concentrations of the Cyclooxygenase-2 (COX-2) specific antagonist celecoxib have opposite effects and impair CXCL9 and CXCL10 release. In human breast cancer tissue specimens there is an inverse correlation between COX-2 overexpression and CXCL9 concentration, suggesting that the observed in vitro effects are of importance in vivo as well. Suppressing endogenous PGE2 synthesis by cyclooxygenase inhibition increases CXCL9 and CXCL10 release from breast cancer cells and is therefore a pharmacologic candidate to enhance intratumoral immune infiltration. Yet, to this end the unselective COX inhibitors ASA and indomethacin seem preferable to celecoxib that at higher concentrations reduces CXCR3 ligand release most probably due to COX independent mechanisms.
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IFN-GAMMA及其受体在人类乳腺癌中的影响。
影响因子：
3.8
作者：
García-Tuñón I;Ricote M;Ruiz A A;Fraile B;Paniagua R;Royuela M
通讯作者：
Royuela M
影响因子：
20.3
作者：
Kryczek, Ilona;Banerjee, Mousumi;Zou, Weiping
通讯作者：
Zou, Weiping
DOI：
10.1186/bcr2089
发表时间：
2008
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Gierach GL;Lacey JV Jr;Schatzkin A;Leitzmann MF;Richesson D;Hollenbeck AR;Brinton LA
通讯作者：
Brinton LA
影响因子：
3
作者：
de Heer, Pieter;Sandel, Maro H.;Guertens, Gunther;de Boeck, Gert;Koudijs, Margaretha M.;Nagelkerke, J. Fred;Junggeburt, Jan M. C.;de Bruijn, Ernst A.;van de Velde, Cornelis J. H.;Kuppen, Peter J. K.
通讯作者：
Kuppen, Peter J. K.
影响因子：
4.4
作者：
Gorbachev, Anton V.;Kobayashi, Hirobito;Fairchild, Robert L.
通讯作者：
Fairchild, Robert L.