Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06520-8040, USA.
Cancer Res. 2009 Dec 15;69(24):9271-80. doi: 10.1158/0008-5472.CAN-09-1605.
Reduced oxygenation, or hypoxia, inhibits differentiation and facilitates stem cell maintenance. Hypoxia commonly occurs in solid tumors and promotes malignant progression. Hypoxic tumors are aggressive and exhibit stem cell-like characteristics. It remains unclear, however, whether and how hypoxia regulates cancer cell differentiation and maintains cancer cell stemness. Here, we show that hypoxia increases the expression of the stem cell gene DLK1, or delta-like 1 homologue (Drosophila), in neuronal tumor cells. Inhibition of DLK1 enhances spontaneous differentiation, decreases clonogenicity, and reduces in vivo tumor growth. Overexpression of DLK1 inhibits differentiation and enhances tumorigenic potentials. We further show that the DLK1 cytoplasmic domain, especially Tyrosine339 and Serine355, is required for maintaining both clonogenicity and tumorigenicity. Because elevated DLK1 expression is found in many tumor types, our observations suggest that hypoxia and DLK1 may constitute an important stem cell pathway for the regulation of cancer stem cell-like functionality and tumorigenicity.
低氧，或缺氧，会抑制分化，促进干细胞维持。缺氧通常发生在实体肿瘤中，并促进恶性进展。缺氧肿瘤具有侵袭性，并表现出干细胞样特征。然而，目前尚不清楚缺氧是否以及如何调节癌细胞分化并维持癌细胞干性。在这里，我们表明缺氧会增加神经元肿瘤细胞中干细胞基因 DLK1 或 delta-like 1 同源物（果蝇）的表达。DLK1 的抑制增强了自发分化，降低了集落形成能力，并减少了体内肿瘤生长。DLK1 的过表达抑制分化并增强了致瘤潜能。我们进一步表明，DLK1 的细胞质结构域，特别是酪氨酸 339 和丝氨酸 355，对于维持集落形成能力和致瘤性都是必需的。由于在许多肿瘤类型中发现升高的 DLK1 表达，我们的观察结果表明，缺氧和 DLK1 可能构成调节癌症干细胞样功能和致瘤性的重要干细胞途径。
