Wu Lingyun, Saxena Sugandha, Goel Paran, Prajapati Dipakkumar R, Wang Cheng, Singh Rakesh K
Department of Pathology and Microbiology, University of Nebraska Medical Center, 985900 UNMC, Omaha, NE 68198-5900, USA.
Vascular Biology and Therapeutics Program and Department of Pharmacology, Yale University, Yale School of Medicine, New Haven, CT 06520-8089, USA.
Cancers (Basel). 2020 Oct 8;12(10):2884. doi: 10.3390/cancers12102884.
Breast cancer remains the most prevalent cancer in women with limited treatment options for patients suffering from therapy-resistance and metastatic disease. Neutrophils play an important role in breast cancer progression and metastasis. We examined the pro-tumorigenic nature of the breast cancer cell-neutrophil interactions and delineated the differences in neutrophil properties between the chemotherapy-resistant and the parent tumor microenvironment. Our data demonstrated that high neutrophil infiltration is associated with disease aggressiveness and therapy resistance. In the human breast cancer dataset, expression of neutrophil-related signature gene expression was higher in tumors from therapy-resistant patients than therapy-sensitive patients. We observed that breast cancer-derived factors significantly enhanced neutrophil survival, polarization, and pro-inflammatory cytokine expression. Breast cancer cell-derived supernatant treated neutrophils significantly expressed high levels of interleukin-1β (IL-1β), CC-chemokine ligand-2-4 (CCL2, CCL3, CCL4), inducible nitric oxide synthase (iNOS), and matrix metallopeptidase-9 (MMP9), and formed extracellular traps (NETs). Moreover, neutrophils showed increased secretion of MMP9 when cultured with the supernatant of chemotherapy-resistant Cl66-Doxorubicin (Cl66-Dox) and Cl66-Paclitaxel (Cl66-Pac) cells in comparison with the supernatant of Cl66-parent cells. Together, these data suggest an important role of breast cancer cell-neutrophil interactions in regulating pro-tumor characteristics in neutrophils and its modulation by therapy resistance.
乳腺癌仍然是女性中最常见的癌症，对于患有治疗抵抗性和转移性疾病的患者而言，治疗选择有限。中性粒细胞在乳腺癌进展和转移中起重要作用。我们研究了乳腺癌细胞与中性粒细胞相互作用的促肿瘤发生性质，并阐述了化疗耐药性肿瘤微环境与亲本肿瘤微环境中中性粒细胞特性的差异。我们的数据表明，高中性粒细胞浸润与疾病侵袭性和治疗耐药性相关。在人类乳腺癌数据集中，与治疗敏感患者的肿瘤相比，治疗耐药患者的肿瘤中中性粒细胞相关特征基因表达更高。我们观察到，乳腺癌衍生因子显著提高了中性粒细胞的存活率、极化和促炎细胞因子表达。乳腺癌细胞衍生的上清液处理后的中性粒细胞显著高表达白细胞介素-1β（IL-1β）、CC趋化因子配体2-4（CCL2、CCL3、CCL4）、诱导型一氧化氮合酶（iNOS）和基质金属蛋白酶-9（MMP9），并形成细胞外陷阱（NETs）。此外，与Cl66亲本细胞的上清液相比，中性粒细胞与化疗耐药的Cl66-阿霉素（Cl66-Dox）和Cl66-紫杉醇（Cl66-Pac）细胞的上清液一起培养时，MMP9的分泌增加。总之，这些数据表明乳腺癌细胞与中性粒细胞的相互作用在调节中性粒细胞的促肿瘤特征及其受治疗耐药性的调节中起重要作用。
