Young M R, Aquino S, Young M E
Research Services, Hines V.A. Hospital, IL 60141.
J Leukoc Biol. 1989 Mar;45(3):262-73. doi: 10.1002/jlb.45.3.262.
Mice bearing large (greater than or equal to 3 g) metastatic and nonmetastatic Lewis lung carcinoma (LLC) tumors were studied to determine if the tumor variants differentially induced bone marrow versus splenic hematopoiesis and the appearance of hematopoiesis-associated immune suppressor cells. The metastatic LLC-C3 and nonmetastatic LLC-C8 tumors were equal in their stimulatory effects in vivo on both the number of bone marrow myeloid progenitor cells (CFU) and the appearance of bone marrow immune suppressor cells. In contrast, the tumor variants differed in their effects on the spleen, with the metastatic tumors causing a more pronounced increase in the number of nucleated cells and CFU, a reduced blastogenic responsiveness to concanavalin (Con-A), and an increased suppressor cell activity than nonmetastatic LLC-C8 tumors. The splenic suppressor cells of mice bearing large LLC-C3 tumors resembled the bone marrow suppressor cells which we previously described (Young et al.: Cancer Res. 47, 100, 1987) in that they were nonadherent to nylon wool, sensitive to treatment with L-leucine methyl ester, insensitive to treatment with complement and Thy-1.2, MG-1.2, asialo-GM1, or anti-IgM antibodies, and mediated their suppression through a mechanism which was only partially indomethacin sensitive. The stimulatory effects on hematopoiesis and suppressor cells by the LLC variant tumors may have been mediated by the tumor-derived colony stimulating factor (CSF) activities. Bone marrow cell proliferation and colony formation were stimulated in vitro by culture supernatants of metastatic LLC-C3 cells and, to a lesser degree, of nonmetastatic LLC-C8 cells. These colony-stimulating factor (CSF)-containing supernatants also induced normal bone marrow cells to become immune suppressive. In contrast, supernatants of only LLC-C3 cells, and not of LLC-C8 cells, stimulated in vitro growth of splenic CFU from LLC-C3-bearing mice; spleen cells from normal mice and from LLC-C8 bearers were unresponsive to supernatants of the LLC variants. These results suggest that CSF produced by either the metastatic LLC-C3 or the nonmetastatic LLC-C8 tumors could concurrently stimulate bone marrow hematopoiesis and the appearance of bone marrow suppressor cells. However, the metastatic LLC-C3 tumor cells, and not the nonmetastatic LLC-C8 cells, could also cause expansion of progenitor cells and hematopoiesis to the spleen and, consequently, induce the appearance in the spleen of hematopoiesis-associated immune suppressor cells.
对携带大尺寸（大于或等于3克）转移性和非转移性Lewis肺癌（LLC）肿瘤的小鼠进行了研究，以确定肿瘤变体是否差异诱导骨髓与脾脏造血以及造血相关免疫抑制细胞的出现。转移性LLC-C3和非转移性LLC-C8肿瘤在体内对骨髓髓系祖细胞（CFU）数量和骨髓免疫抑制细胞出现的刺激作用相同。相比之下，肿瘤变体对脾脏的影响不同，转移性肿瘤导致有核细胞和CFU数量增加更为明显，对刀豆球蛋白（Con-A）的增殖反应降低，并且与非转移性LLC-C8肿瘤相比，抑制细胞活性增加。携带大尺寸LLC-C3肿瘤的小鼠的脾脏抑制细胞类似于我们之前描述的（Young等人：《癌症研究》47, 100, 1987）骨髓抑制细胞，即它们不黏附于尼龙毛，对L-亮氨酸甲酯处理敏感，对补体和Thy-1.2、MG-1.2、去唾液酸GM1或抗IgM抗体处理不敏感，并且通过一种仅部分对吲哚美辛敏感的机制介导其抑制作用。LLC变体肿瘤对造血和抑制细胞的刺激作用可能是由肿瘤衍生集落刺激因子（CSF）活性介导的。转移性LLC-C3细胞的培养上清液在体外刺激骨髓细胞增殖和集落形成，非转移性LLC-C8细胞的培养上清液刺激程度较小。这些含集落刺激因子（CSF）的上清液还诱导正常骨髓细胞产生免疫抑制作用。相比之下，只有LLC-C3细胞的上清液，而不是LLC-C8细胞的上清液，刺激了携带LLC-C3小鼠脾脏CFU的体外生长；正常小鼠和携带LLC-C8小鼠脾脏细胞对LLC变体的上清液无反应。这些结果表明，转移性LLC-C3或非转移性LLC-C8肿瘤产生的CSF可同时刺激骨髓造血和骨髓抑制细胞的出现。然而，转移性LLC-C3肿瘤细胞，而非非转移性LLC-C8细胞，还可导致祖细胞扩增并在脾脏造血，从而诱导脾脏中出现造血相关免疫抑制细胞。
