Spaks Artjoms
Department of Thoracic Surgery, Pauls Stradins Clinical University Hospital, Riga, Latvia.
J Thorac Dis. 2017 Apr;9(Suppl 3):S164-S171. doi: 10.21037/jtd.2017.03.61.
Clinical and translational research on lung cancer patients undergoing surgical treatment can provide valuable scientific data and unique opportunity to study tumor microenvironment. CXC chemokines, which are members of a big family of cytokines, are undoubtedly involved in tumor growth regulation and metastasizing pathways. For better understanding of CXC chemokine involvement in the process of carcinogenesis we have studied the cohort of early stage non-small cell lung cancer patients undergoing surgery with curative intent. Our aim was to assess CXC chemokine ligand (CXCL) levels in patient blood samples representing systemic circulation and tumor microenvironment; assess CXC chemokine receptor (CXCR) expression in tumor tissue; and measure tumor infiltrating immune cell subpopulations.
A total of 54 patients with NSCLC had radical lung resection were enrolled in a single center prospective study and were followed-up annually for up to six years. During surgical procedure peripheral and tumor draining blood samples were taken. CXCL1, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL11 and CXCL12 levels were determined by ELISA, and chemokine concentration gradient was calculated. Tumor infiltrating immune cells (T helper cells, T cytotoxic cells, macrophages, B cells, plasma cells) and expression of CXCR1, CXCR2, CXCR3 and CXCR4 in tumor tissue were assessed by immunohistochemistry.
Statistically significant decrease in chemokine concentration was found for CXCL4 (P=0.002) and CXCL5 (P=0.011), and statistically significant concentration increase was found for CXCL7 (P=0.001) in total cohort. We have found statistically significant CXC chemokine concentration change for majority of chemokines-CXCL1 (P=0.002), CXCL4 (P=0.001), CXCL5 (P=0.013), CXCL7 (P=0.036), CXCL8 (P=0.026), CXCL9 (P=0.034) and CXCL10 (P=0.032) in a group of patients who had good clinical result after surgery with no evidence of relapse, on the other hand patients with cancer recurrence including local and systemic cancer spread did not show any change of chemokine concentration in blood except for CXCL1 (P=0.041). We have also found that chemokine levels and gradients correlate with CXC receptor expression and number of tumor infiltrating immune cell subpopulations.
Assessment of tumor microcirculation is useful for evaluation of different types of circulating biomarkers and application of our method can be very wide, integrating thoracic surgeons into translational cancer research.
对接受手术治疗的肺癌患者进行临床和转化研究，可为研究肿瘤微环境提供有价值的科学数据和独特机会。CXC趋化因子是一大类细胞因子家族的成员，无疑参与肿瘤生长调节和转移途径。为了更好地理解CXC趋化因子在致癌过程中的作用，我们研究了一组接受根治性手术的早期非小细胞肺癌患者。我们的目的是评估代表体循环和肿瘤微环境的患者血液样本中CXC趋化因子配体（CXCL）水平；评估肿瘤组织中CXC趋化因子受体（CXCR）的表达；并测量肿瘤浸润免疫细胞亚群。
共有54例接受根治性肺切除术的非小细胞肺癌患者纳入一项单中心前瞻性研究，并每年随访长达6年。在手术过程中采集外周血和肿瘤引流血样本。通过酶联免疫吸附测定法测定CXCL1、CXCL4、CXCL5、CXCL6、CXCL7、CXCL8、CXCL9、CXCL10、CXCL11和CXCL12水平，并计算趋化因子浓度梯度。通过免疫组织化学评估肿瘤浸润免疫细胞（辅助性T细胞、细胞毒性T细胞、巨噬细胞、B细胞、浆细胞）以及肿瘤组织中CXCR1、CXCR2、CXCR3和CXCR4的表达。
在整个队列中，发现CXCL4（P = 0.002）和CXCL5（P = 0.011）的趋化因子浓度有统计学意义的降低，CXCL7（P = 0.001）有统计学意义的浓度升高。我们发现，在术后临床效果良好且无复发迹象的一组患者中，大多数趋化因子——CXCL1（P = 0.002）、CXCL4（P = 0.001）、CXCL5（P = 0.013）、CXCL7（P = 0.036）、CXCL8（P = 0.026）、CXCL9（P = 0.034）和CXCL10（P = 0.032）的CXC趋化因子浓度有统计学意义的变化，另一方面，包括局部和全身癌症扩散在内的癌症复发患者，除CXCL1（P = 0.041）外，血液中趋化因子浓度未显示任何变化。我们还发现趋化因子水平和梯度与CXC受体表达以及肿瘤浸润免疫细胞亚群数量相关。
评估肿瘤微循环有助于评估不同类型的循环生物标志物，我们方法的应用范围可能非常广泛，可将胸外科医生纳入转化癌症研究。
