Ross Robert A, Biedler June L, Spengler Barbara A
Laboratory of Neurobiology, Department of Biological Sciences, Fordham University, 441 E. Fordham Road, Bronx, NY 10458, USA.
Cancer Lett. 2003 Jul 18;197(1-2):35-9. doi: 10.1016/s0304-3835(03)00079-x.
Human neuroblastoma arises from the developing neural crest. Tumors are categorized clinically by their location, age at diagnosis, spread/metastasis, and degree of cellular maturation and heterogeneity. Our long-term studies have shown the presence in human neuroblastoma cell lines of three distinct cell types: I-type stem cells, N-type neuroblastic/neuroendocrine precursors, and S-type Schwannian/melanoblastic precursors. These distinct cell types can differentiate predictably along specific neural crest lineages in response to particular morphogens. As assessed by tumor formation in nude mice and anchorage-independent growth in soft agar, I-type stem cells are significantly more malignant than either N- or S-type cells. Recent research shows that three similar cell types are also present in human neuroblastoma tumors. Using immunocytochemical, laser-capture microdissection, or short-term culture methods to identify cell types in tumors of different stages and/or different outcomes, these studies have shown that (1) all tumors contain neuroblasts in various differentiation states; (2) presumptive I-type stem cells are present in tumors of all stages; and (3) stromal cells may be tumor-derived, i.e. S-type cells, as well as of normal origin. More importantly, there is a higher incidence of I-type cells in tumors that progress, consistent with the high malignant potential of this cell type in vitro. A better understanding of the cause and consequences of cellular heterogeneity of human neuroblastoma tumors is an important prerequisite to the development of more effective therapies for this often fatal disease.
人类神经母细胞瘤起源于发育中的神经嵴。肿瘤根据其位置、诊断时的年龄、扩散/转移情况以及细胞成熟度和异质性程度进行临床分类。我们的长期研究表明，人类神经母细胞瘤细胞系中存在三种不同的细胞类型：I型干细胞、N型神经母细胞/神经内分泌前体细胞和S型雪旺氏/成黑色素细胞前体细胞。这些不同的细胞类型可根据特定形态发生素的作用，沿着特定的神经嵴谱系进行可预测的分化。通过裸鼠体内肿瘤形成和软琼脂中不依赖贴壁生长的评估，I型干细胞的恶性程度明显高于N型或S型细胞。最近的研究表明，人类神经母细胞瘤肿瘤中也存在三种类似的细胞类型。利用免疫细胞化学、激光捕获显微切割或短期培养方法来识别不同阶段和/或不同预后肿瘤中的细胞类型，这些研究表明：（1）所有肿瘤都含有处于不同分化状态的神经母细胞；（2）假定的I型干细胞存在于所有阶段的肿瘤中；（3）基质细胞可能来源于肿瘤，即S型细胞，也可能来源于正常组织。更重要的是，进展性肿瘤中I型细胞的发生率更高，这与该细胞类型在体外的高恶性潜能一致。更好地理解人类神经母细胞瘤肿瘤细胞异质性的原因和后果，是开发针对这种常致命疾病更有效疗法的重要前提。
