Laboratory of Biomedical Engineering for Cancer, Graduate School of Biomedical Engineering, Tohoku University, 4-1 Seiryo, Aoba, Sendai, Miyagi, 980-8575, Japan.
Department of Anatomy, Basic Medical Science College, Harbin Medical University, Harbin, 150081, China.
BMC Cancer. 2018 May 30;18(1):608. doi: 10.1186/s12885-018-4538-8.
Surgical removal of primary tumors can promote the incidence of tumor metastasis. However, molecular mechanisms underlying this process remain unclear.
We inoculated tumor cells expressing luciferase gene into subiliac lymph node (SiLN) of the MXH10/Mo-lpr/lpr mice. The tumor-bearing SiLNs were surgically removed at a certain period of time after inoculation.
In vivo bioluminescence imaging system and histological staining revealed metastasis in lung, proper axillary lymph node (PALN) and liver. The lung metastasis rate in SiLN removal groups was significantly higher than in the control group using Fisher exact test. Mann-Whitney U-test indicated that the luciferase-positive tumor cells in the lung and liver were significantly higher than in the control groups. The lung samples in SiLN removal groups had strong expression of lysine oxidase (LOX). Moreover, the number of CD11b cells in the lung and liver in the SiLN removal groups was significantly increased, which was positively correlated with LOX expression level. In addition, the condition of LOX and CD11b in liver was similar to lung. In the SiLN surgical removal groups, the matrix metalloproteinase (MMP)-2 and VEGFA expression in the lung tissues was significantly higher than in the control groups; the collagen fibers per area around the pulmonary vessels was quite significantly lower and negatively correlated with the expression of MMP-2 by Spearman's analysis. Our data indicated that the reticular fibers were deposited and disordered in the tumor tissues of the lungs in the removal groups, and the reticular fibers per area was higher than in the control groups. The tumor cells in the PALN of control groups were significantly higher than in the SiLN removal groups, and CD169 and CD11c cells were also higher than in the SiLN removal groups.
Altogether, surgical removal of the tumor-bearing lymph node promoted tumor metastasis through changing the niche in lung and liver. Treatment targeting the metastatic niche might be an effective strategy to prevent tumor metastasis, thereby possibly increasing the survival and reducing the incidence of metastasis in cancer patients.
手术切除原发肿瘤会促进肿瘤转移的发生。然而，这一过程的分子机制尚不清楚。
我们将表达荧光素酶基因的肿瘤细胞接种到 MXH10/Mo-lpr/lpr 小鼠的髂下淋巴结（SiLN）中。在接种后的一定时间内，手术切除携带肿瘤的 SiLN。
体内生物发光成像系统和组织学染色显示肿瘤转移到肺、腋窝淋巴结（PALN）和肝脏。Fisher 确切检验显示 SiLN 切除组的肺转移率明显高于对照组。Mann-Whitney U 检验表明，肺和肝中的荧光素酶阳性肿瘤细胞明显高于对照组。SiLN 切除组的肺组织中赖氨酸氧化酶（LOX）表达较强。此外，SiLN 切除组的肺和肝中 CD11b 细胞数量明显增加，与 LOX 表达水平呈正相关。此外，肝中 LOX 和 CD11b 的情况与肺相似。在 SiLN 手术切除组中，肺组织中基质金属蛋白酶（MMP）-2 和血管内皮生长因子 A（VEGFA）的表达明显高于对照组；肺血管周围区域的胶原纤维面积明显减少，与 MMP-2 的表达呈负相关，Spearman 分析。我们的数据表明，在切除组的肺肿瘤组织中，网状纤维沉积且紊乱，每单位面积的网状纤维高于对照组。对照组 PALN 中的肿瘤细胞明显高于 SiLN 切除组，CD169 和 CD11c 细胞也高于 SiLN 切除组。
总之，肿瘤负荷淋巴结的手术切除通过改变肺和肝中的小生境促进肿瘤转移。针对转移小生境的治疗可能是预防肿瘤转移的有效策略，从而可能增加癌症患者的生存机会并降低转移发生率。
