Ishii E, Greaves A, Grunberger T, Freedman M H, Letarte M
Division of Immunology/Cancer Research, Hospital for Sick Children, Toronto, Canada.
Leukemia. 1995 Jan;9(1):175-84.
We have previously demonstrated the engraftment of human pre-B acute lymphoblastic leukemia (ALL) cells injected intravenously into irradiated scid mice. We now report on the ability of the reconstituted extracellular matrix, Matrigel, to promote the formation of subcutaneous tumors in non-irradiated scid mice by a CD10- pre-B ALL cell line termed G2. Lymphatic tumors infiltrating the dermis were seen in all eight mice sacrificed 10-13 weeks after the co-injection of G2 cells and Matrigel but in only 2/8 mice injected with leukemic cells alone. Infiltration of bone marrow, spleen, thymus, lung and liver was observed earlier and was more extensive in the Matrigel-treated group. The tumor cells derived from Matrigel-treated mice could be passaged in vitro and their colony-forming ability was higher than that of the original G2 line. When re-injected intravenously into non-irradiated scid mice, the tumor cells invaded the thymus earlier than did the G2 cells. The expression of CD10/neutral endopeptidase was induced at high levels in all tumors, in Matrigel or non Matrigel-treated animals. This up-regulation was transient as the tumor variants grown in vitro or in vivo lost expression of CD10. However, 6-8 weeks later, induction of CD10 was observed on both tumor variants and parental G2 cells growing in the thymus and at a lower level on cells in bone marrow and spleen. Culturing G2 cells in vitro at high density or in the presence of documented growth-promoting cytokines such as IL-3, IL-6, IL-7, and GM-CSF did not stimulate the expression of CD10 mRNA. The induction of this surface endopeptidase was thus associated with growth of leukemic cells in the specific microenvironments provided by the lymphoid tumors and the thymus in scid mice. The function of CD10 might be related to the hydrolysis of peptides which are critical in regulating interactions between adjacent pre-B cells, the stromal microenvironment and the transduction of growth and/or differentiation signals.
我们之前已经证明，将人前B细胞急性淋巴细胞白血病（ALL）细胞静脉注射到经辐照的严重联合免疫缺陷（scid）小鼠体内后，这些细胞能够实现植入。我们现在报告重组细胞外基质基质胶促进一种名为G2的CD10阴性前B ALL细胞系在未辐照的scid小鼠体内形成皮下肿瘤的能力。在共同注射G2细胞和基质胶后10 - 13周处死的所有8只小鼠中，均可见浸润真皮的淋巴瘤，但仅2/8只单独注射白血病细胞的小鼠出现这种情况。在基质胶处理组中，更早观察到骨髓、脾脏、胸腺、肺和肝脏的浸润，且浸润更广泛。来自基质胶处理小鼠的肿瘤细胞能够在体外传代，其集落形成能力高于原始的G2细胞系。当将这些肿瘤细胞静脉重新注射到未辐照的scid小鼠体内时，它们比G2细胞更早侵袭胸腺。在所有肿瘤中，无论是基质胶处理还是未处理的动物，CD10/中性内肽酶均高表达。这种上调是短暂的，因为在体外或体内生长的肿瘤变体失去了CD10的表达。然而，6 - 8周后，在胸腺中生长的肿瘤变体和亲本G2细胞上均观察到CD10的诱导，而在骨髓和脾脏中的细胞上诱导水平较低。在体外以高密度培养G2细胞或在存在如IL - 3、IL - 6、IL - 7和GM - CSF等已证实的生长促进细胞因子的情况下，并不会刺激CD10 mRNA的表达。因此，这种表面内肽酶的诱导与scid小鼠淋巴肿瘤和胸腺提供的特定微环境中白血病细胞的生长有关。CD10的功能可能与肽的水解有关，这些肽对于调节相邻前B细胞之间的相互作用、基质微环境以及生长和/或分化信号的转导至关重要。
