CXCL12 促进 CCR7 配体介导的乳腺癌细胞侵袭和向淋巴管迁移,Cancer Science

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CXCL12 促进 CCR7 配体介导的乳腺癌细胞侵袭和向淋巴管迁移
Cancer Science ( IF 4.5 ) Pub Date : 2022-02-08 , DOI: 10.1111/cas.15293
Haruko Hayasaka ₁ , Junichi Yoshida ₂ , Yasutaka Kuroda ₂ , Akihiro Nishiguchi ₃ , Michiya Matsusaki ₃ , Kei Kishimoto ₁ , Hitoshi Nishimura ₁ , Mari Okada ₂ , Yuki Shimomura ₂ , Daichi Kobayashi ₄ , Yoshihito Shimazu ₅ , Yuji Taya ₆ , Mitsuru Akashi ₃ , Masayuki Miyasaka _{2,

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Affiliation

趋化因子是介导白细胞运输并参与肿瘤细胞迁移、生长和进展的细胞因子家族。尽管有新的证据表明多种趋化因子在肿瘤组织中表达并且每种趋化因子都诱导受体介导的信号传导，但它们在调节肿瘤侵袭和淋巴结转移方面的协同作用尚未完全阐明。在这项研究中，我们检测了 CXCL12 对 MDA-MB-231 人乳腺癌细胞中 CCR7 依赖性信号传导的影响，以确定 CXCL12 和 CCR7 配体趋化因子在乳腺癌淋巴结转移中的作用。CXCL12 在 CCL21 的次优浓度下增强了 CCR7 依赖性体外趋化性和细胞侵入胶原凝胶的能力。CXCL12 促进 CCR7 同源二聚体形成、配体结合、CCR7 积累成膜皱褶，和较低浓度 CCL19 下的细胞反应。MDA-MB-231 衍生的异种移植肿瘤的免疫组织化学显示 CXCL12 主要位于肿瘤细胞周围的细胞外基质中，而 CCR7 配体 CCL21 主要与 LYVE-1 结合⁺瘤内和瘤周淋巴管。在具有淋巴网络的三维肿瘤侵袭模型中，CXCL12 刺激促进乳腺癌细胞迁移到 CCL21 重组的淋巴网络。这些结果表明，CXCL12/CXCR4 信号促进乳腺癌细胞向表达 CCR7 配体的肿瘤内淋巴管迁移和侵袭，并支持与淋巴结转移相关的 CCR7 信号。

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CXCL12 promotes CCR7 ligand–mediated breast cancer cell invasion and migration toward lymphatic vessels

Chemokines are a family of cytokines that mediate leukocyte trafficking and are involved in tumor cell migration, growth, and progression. Although there is emerging evidence that multiple chemokines are expressed in tumor tissues and that each chemokine induces receptor-mediated signaling, their collaboration to regulate tumor invasion and lymph node metastasis has not been fully elucidated. In this study, we examined the effect of CXCL12 on the CCR7-dependent signaling in MDA-MB-231 human breast cancer cells to determine the role of CXCL12 and CCR7 ligand chemokines in breast cancer metastasis to lymph nodes. CXCL12 enhanced the CCR7-dependent in vitro chemotaxis and cell invasion into collagen gels at suboptimal concentrations of CCL21. CXCL12 promoted CCR7 homodimer formation, ligand binding, CCR7 accumulation into membrane ruffles, and cell response at lower concentrations of CCL19. Immunohistochemistry of MDA-MB-231–derived xenograft tumors revealed that CXCL12 is primarily located in the pericellular matrix surrounding tumor cells, whereas the CCR7 ligand, CCL21, mainly associates with LYVE-1⁺ intratumoral and peritumoral lymphatic vessels. In the three-dimensional tumor invasion model with lymph networks, CXCL12 stimulation facilitates breast cancer cell migration to CCL21-reconstituted lymphatic networks. These results indicate that CXCL12/CXCR4 signaling promotes breast cancer cell migration and invasion toward CCR7 ligand–expressing intratumoral lymphatic vessels and supports CCR7 signaling associated with lymph node metastasis.

更新日期：2022-02-08

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