Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital, P.O.B 12000, Jerusalem 91120, Israel.
Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital, P.O.B 12000, Jerusalem 91120, Israel.
Cytokine. 2018 Sep;109:11-16. doi: 10.1016/j.cyto.2018.02.020.
The chemokine receptor CXCR4 and its ligand stromal cell-derived factor-1 (SDF-1/CXCL12) are important players in the cross-talk among lymphoma, myeloma and leukemia cells and their microenvironments. In hematological malignancies and solid tumors, the overexpression of CXCR4 on the cell surface has been shown to be responsible for disease progression, increasing tumor cell survival and chemoresistance and metastasis to organs with high CXCL12 levels (e.g., lymph nodes and bone marrow (BM)). Furthermore, the overexpression of CXCR4 has been found to have prognostic significance for disease progression in many type of tumors including lymphoma, leukemia, glioma, and prostate, breast, colorectal, renal, and hepatocellular carcinomas. In leukemia, CXCR4 expression granted leukemic blasts a higher capacity to seed into BM niches, thereby protecting leukemic cells from chemotherapy-induced apoptosis, and was correlated with shorter disease-free survival. In contrast, neutralizing the interaction of CXCL12/CXCR4 with a variety of antagonists induced apoptosis and differentiation and increased the chemosensitivity of lymphoma, myeloma, and leukemia cells. The role of CXCL12 and CXCR4 in the pathogenesis of hematological malignancies and the clinical therapeutic potential of CXCR4 antagonists in these diseases is discussed.
趋化因子受体 CXCR4 及其配体基质细胞衍生因子-1（SDF-1/CXCL12）是淋巴瘤、骨髓瘤和白血病细胞及其微环境之间相互作用的重要参与者。在血液恶性肿瘤和实体肿瘤中，细胞表面 CXCR4 的过度表达被证明与疾病进展、增加肿瘤细胞存活以及向 CXCL12 水平高的器官（如淋巴结和骨髓（BM））转移有关。此外，CXCR4 的过度表达已被发现对许多类型的肿瘤（包括淋巴瘤、白血病、神经胶质瘤和前列腺癌、乳腺癌、结直肠癌、肾癌和肝癌）的疾病进展具有预后意义。在白血病中，CXCR4 的表达使白血病细胞具有更高的能力在 BM 龛中播种，从而保护白血病细胞免受化疗诱导的细胞凋亡，并与无病生存期缩短相关。相比之下，用各种拮抗剂中和 CXCL12/CXCR4 的相互作用会诱导细胞凋亡和分化，并增加淋巴瘤、骨髓瘤和白血病细胞的化疗敏感性。本文讨论了 CXCL12 和 CXCR4 在血液恶性肿瘤发病机制中的作用以及 CXCR4 拮抗剂在这些疾病中的临床治疗潜力。
