Laboratory for Immunological and Molecular Cancer Research, Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Rheumatology and Infectiology, Paracelsus Medical University, Salzburg, Austria.
Cancer Res. 2013 Jan 15;73(2):561-70. doi: 10.1158/0008-5472.CAN-12-2749. Epub 2012 Nov 1.
Microenvironmental interactions are crucial for the survival and proliferation of chronic lymphocytic leukemia (CLL) cells. CD4+ T cells that express CD40 ligand (CD40L), along with other accessory immune and stromal cells within CLL lymph nodes, provide signals needed for activation and outgrowth of the tumor clone. Furthermore, correct positioning of CLL cells within lymphoid subcompartments is essential for the transmission of these supportive signals. Thereby, interstitial cell migration and adhesion events, influenced by activational stimuli, determine CLL cell localization. CD44 has been implicated in cell activation, migration, and tissue retention via binding to its extracellular matrix ligand hyaluronan (HA). In this study, we investigated the role of CD44-HA interactions for CLL positioning and interaction with supportive microenvironments in peripheral lymph nodes, focusing on its regulation via CD40L-dependent, T-cell-mediated activation of CLL cells. We found that hyaluronan triggered a robust CCL21-induced motility of resting CLL cells. However, CD40L stimulation promoted the firm, CD44-mediated adhesion of CLL cells to hyaluronan, antagonizing their motile behavior. N-linked glycosylations of CD44, particularly associated with the variant isoform CD44v6 after CD40L activation, seemed to facilitate hyaluronan recognition by CD44. We propose that the CD40L-CD40 signaling axis provides a stop signal to motile CLL cells within lymph node compartments by inducing high avidity CD44-HA adhesion. This might retain CLL cells close to T-cell stimuli and facilitate essential interactions with hyaluronan-bearing stromal cells, collectively promoting CLL cell proliferation and survival.
微环境相互作用对于慢性淋巴细胞白血病 (CLL) 细胞的存活和增殖至关重要。表达 CD40 配体 (CD40L) 的 CD4+T 细胞以及 CLL 淋巴结中的其他辅助免疫和基质细胞，为肿瘤克隆的激活和生长提供了所需的信号。此外，CLL 细胞在淋巴亚区室中的正确定位对于这些支持信号的传递至关重要。因此，受激活刺激影响的间质细胞迁移和黏附事件决定了 CLL 细胞的定位。CD44 通过与其细胞外基质配体透明质酸 (HA) 结合，参与细胞激活、迁移和组织保留。在这项研究中，我们研究了 CD44-HA 相互作用对于 CLL 定位和与外周淋巴结中支持性微环境相互作用的作用，重点关注其通过 CD40L 依赖性、T 细胞介导的 CLL 细胞激活的调节。我们发现透明质酸触发静止 CLL 细胞强烈的 CCL21 诱导迁移。然而，CD40L 刺激促进了 CLL 细胞与透明质酸的牢固、CD44 介导的黏附，拮抗了它们的迁移行为。CD44 的 N-连接糖基化，特别是在 CD40L 激活后与变体同工型 CD44v6 相关，似乎促进了 CD44 对透明质酸的识别。我们提出，CD40L-CD40 信号轴通过诱导高亲和力 CD44-HA 黏附，为淋巴结区室中迁移的 CLL 细胞提供停止信号。这可能使 CLL 细胞靠近 T 细胞刺激物，并促进与携带透明质酸的基质细胞的必要相互作用，共同促进 CLL 细胞的增殖和存活。
