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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment
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Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment

机译：Mac-1（CD11b / CD18）的抑制作用通过减少骨髓细胞募集来增强肿瘤对放射的反应

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摘要

Despite recent advances in radiotherapy, loco-regional failures are still the leading cause of death in many cancer patients. We have previously reported that bone marrow-derived CD11 b~+ myeloid cells are recruited to tumors grown in irradiated tissues, thereby restoring the vasculature and tumor growth. In this study, we examined whether neutralizing CD11b monoclonal antibodies could inhibit the recruitment of myeloid cells into irradiated tumors and inhibit their regrowth. We observed a significant enhancement of antitu-mor response to radiation in squamous cell carcinoma xenografts in mice when CD11b antibodies are administered systemically. His-tological examination of tumors revealed that CD11 b antibodies reduced infiltration of myeloid cells expressing S100A8 and matrix metalloproteinase-9. CD11b antibodies further inhibited bone marrow-derived cell adhesion and transmigration to C166 endothe-lial cell monolayers and chemotactic stimuli, respectively, to levels comparable to those from CD11b knockout or CD18 hypomorphic mice. Given the clinical availability of humanized CD18 antibodies, we tested two murine tumor models in CD18 hypomorphic or CD11 b knockout mice and found that tumors were more sensitive to irradiation when grown in CD 18 hypomorphic mice but not in CD11b knockout mice. When CD18 hypomorphism was partially rescued by reconstitution with the wild-type bone marrow, the resistance of the tumors to irradiation was restored. Our study thus supports the rationale of using clinically available Mac-1 (CD11b/CD18) antibodies as an adjuvant therapy to radiotherapy.
机译：尽管放射疗法最近取得了进展，但局部区域衰竭仍然是许多癌症患者死亡的主要原因。我们先前曾报道过，骨髓来源的CD11 b +骨髓细胞被募集到受辐照组织中生长的肿瘤上，从而恢复了脉管系统和肿瘤的生长。在这项研究中，我们检查了中和的CD11b单克隆抗体是否可以抑制髓样细胞募集进入照射的肿瘤并抑制其再生。当全身施用CD11b抗体时，我们观察到小鼠鳞状细胞癌异种移植物中对放射的抗肿瘤应答显着增强。肿瘤的组织学检查显示，CD11b抗体减少了表达S100A8和基质金属蛋白酶9的髓样细胞的浸润。 CD11b抗体进一步抑制了骨髓来源的细胞粘附和分别迁移至C166内皮细胞单层和趋化性刺激，其水平与CD11b敲除或CD18亚型小鼠的水平相当。考虑到人源化CD18抗体的临床可用性，我们在CD18亚型或CD11b基因敲除小鼠中测试了两种鼠类肿瘤模型，发现当在CD 18亚型小鼠中生长但对CD11b基因敲除小鼠中的肿瘤对辐射更敏感。当通过用野生型骨髓重建而部分挽救了CD18亚型时，肿瘤对放射线的抵抗力得以恢复。因此，我们的研究支持使用临床上可用的Mac-1（CD11b / CD18）抗体作为放疗辅助疗法的基本原理。

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    G-One Ahn; Diane Tseng; Cho-Hwa Liao; Mary Jo Dorie; Agnieszka Czechowicz; J. Martin Brown;

  • 作者单位

    Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305;

    rnDivision of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305 Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305;

    rnDivision of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305;

    rnDivision of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305;

    rnInstitute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305;

    rnDivision of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    S100A8; vasculogenesis; radiosensitivity;

    机译：S100A8;血管生成;放射敏感性;

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