肿瘤相关中性粒细胞分泌TIMP-1诱导乳腺癌发生EMT的机制研究

The role of neutrophils in metastasis is enigmatic in previous animal studies, indicating a pressing need to evaluate their function in a more patient-relevant scenario. Moreover, the different prognostic values of tumor-infiltrating neutrophils in different tissue compartments are unknown. Here, we evaluated CD66+ neutrophils in primary tumors of 446 breast cancer patients enrolled from 2 independent centers. We observed neutrophils in tumor parenchyma, rather than the ones in stroma, was an independent poor prognostic factor of patients. By isolating primary tumor-infiltrating neutrophils from clinical samples and cytokine microarray screening, we found that neutrophils induced breast cancer epithelial-mesenchymal transition (EMT) via TIMP-1. However, the mechanism still remains unclear.Thus, we will explore how Tumor-associated neutrophils promote the epithelial–mesenchymal transition of breast cancer via the secretion of TIMP-1. Our study will shed light onthe role of TANs participating in EMT of breast cancer and will help to provide novel molecular targets for therapies against tumor inflammatory microenvironment.

既往动物实验表明中性粒细胞在乳腺癌转移中的作用具有争议，TANs在乳腺癌患者肿瘤组织中浸润的临床意义尚未阐明，且不同部位组织浸润TANs 对预后的影响价值更未可知。本课题组在来自2个独立中心的446例乳腺癌患者临床样本中应用免疫组化的方法检测CD66b+ TANs，预实验结果显示：不同组织浸润的TANs对预后影响亦不同；癌巢高表达TANs是患者预后不良的独立危险因素，尤其三阴性乳腺癌更为显著；但是间质TANs的浸润密度与患者预后无关联性。体外实验发现TANs通过分泌TIMP-1促进乳腺癌上皮细胞向间质细胞的转变（EMT）及转移，然而其具体机制尚不明确。因此，本课题组将进一步阐明TANs如何通过TIMP-1促进乳腺癌细胞EMT的分子机理。本研究有助阐明TANs激活促进乳腺癌EMT的分子机制，为靶向非可控性炎症肿瘤微环境治疗乳腺癌转移提供新的分子靶点。

90%以上的恶性肿瘤患者死亡的原因是肿瘤发生远处转移。随着筛查的普及和筛查技术的提高，早期乳腺癌的发现率明显提高，但仍有5～10%的患者在初诊时即发现远处转移，这类患者的5年生存率不超过20%。此外大约30%的早期乳腺癌患者在接受规范治疗后仍然出现远处转移。我们发现了乳腺癌转移的新机制，并发现其中可能的治疗靶点。