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首页> 外文期刊>Oncoimmunology. >Tumor-associated macrophages in human breast cancer produce new monocyte attracting and pro-angiogenic factor YKL-39 indicative for increased metastasis after neoadjuvant chemotherapy
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Tumor-associated macrophages in human breast cancer produce new monocyte attracting and pro-angiogenic factor YKL-39 indicative for increased metastasis after neoadjuvant chemotherapy

机译：人类乳腺癌中的肿瘤相关巨噬细胞产生新的单核细胞吸引和促血管生成因子YKL-39指示新辅助化疗后的转移增加

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In breast cancer, the tumor microenvironment plays a critical role in the tumor progression and responses to therapy. Tumor-associated macrophages (TAMs) are major innate immune cells in tumor microenvironment that regulate intratumoral immunity and angiogenesis by secretion of cytokines, growth factors as well as chitinase-like proteins (CLPs), that combine properties of cytokines and growth factors. YKL-39 is achitinase-like protein found in human and absent in rodents, and its expression in TAMs and role in breast cancer progression was not studied to date. Here for the first time we demonstrate that YKL-39 is expressed on TAMs, predominantly positive for stabilin-1, but not by malignant cells or other stromal cells in human breast cancer. TGF-beta in combination with IL-4, but not IL-4 alone was responsible of the stimulation of the production of YKL-39 in human primary macrophages. Mechanistically, stabilin-1 directly interacted with YKL-39 and acted as sorting receptor for targeting YKL-39 into the secretory pathway. Functionally, purified YKL-39 acted as a strong chemotactic factor for primary human monocytes, and induced angiogenesis in vitro. Elevated levels of YKL-39 expression in tumors after neoadjuvant chemotherapy (NAC) were predictive for increased risk of distant metastasis and for poor response to NAC in patients with nonspecific invasive breast carcinoma. Our findings suggest YKL-39 as a novel therapeutic target, and blocking of its activity can be combined with NAC in order to reduce the risk of metastasis in breast cancer patients.
机译：在乳腺癌中，肿瘤微环境在肿瘤进展和对治疗的反应中起着关键作用。肿瘤相关的巨噬细胞（TAMS）是肿瘤微环境中的主要先天免疫细胞，其通过分泌细胞因子，生长因子以及几丁质酶样蛋白（CLP）来调节肿瘤内免疫和血管生成，其结合细胞因子和生长因子的性能。 YKL-39是在人类中发现的achitinase样蛋白，在啮齿动物中缺席，并未研究其在TAMS中的表达和在乳腺癌进展中的作用迄今为止。在这里首次证明YKL-39在TAMS上表达，主要用于稳定蛋白-1，但不是由人乳腺癌中的恶性细胞或其他基质细胞。 TGF-β结合IL-4，但单独的IL-4也负责刺激人的原发性巨噬细胞的YKL-39的刺激。机械上，稳定素-1直接与YKL-39相互作用，并用作靶向YKL-39进入分泌途径的分选受体。在功能上，纯化的YKL-39充当原发性人单核细胞的强趋化因子，并在体外诱导血管生成。 Neoadjuvant化疗（NAC）后肿瘤中的YKL-39表达的升高预测是对不特异性侵袭性乳腺癌患者的远处转移的风险增加以及对NAC的差的影响。我们的研究结果表明YKL-39作为一种新的治疗靶标，并阻断其活性可以与NAC结合，以降低乳腺癌患者转移的风险。

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