Adhesion of human myeloma-derived cell lines to bone marrow stromal cells stimulates interleukin-6 secretion.
Adhesion of human myeloma-derived cell lines to bone marrow stromal cells stimulates interleukin-6 secretion.
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DOI：
10.1182/blood.v82.12.3712.bloodjournal82123712
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发表时间：
1993-12
期刊：
影响因子：
20.3
通讯作者：
H. Uchiyama;B. Barut;A. Mohrbacher;D. Chauhan;K. Anderson
中科院分区：
文献类型：
--
作者：
H. Uchiyama;B. Barut;A. Mohrbacher;D. Chauhan;K. Anderson
以往的研究表明，人骨髓瘤来源的细胞系通过很晚的抗原-4(VLA-4；α-4-β1整合素复合体)和RGD-肽机制与纤维连接蛋白(FN)特异性黏附，这可能有助于肿瘤细胞在骨髓中的定位。在这些研究中，我们研究了骨髓瘤来源的细胞系与正常和骨髓瘤骨髓基质细胞(BMSCs)的黏附以及黏附对DNA合成的影响。由于白细胞介素6(IL-6)在多发性骨髓瘤的发病机制中起重要作用，我们还检测了肿瘤细胞黏附对骨髓间充质干细胞分泌IL-6的影响。在51铬结合实验中，U266、ARH-77和IM-9细胞对正常BMSCs的特异性黏附率分别为52%+/-12%、55%+/-6%和47%+/-7%，对骨髓瘤BMSCs的特异性黏附率分别为74%+/-4%、60%+/-3%和61%+/-6%。相比之下，HS-Sultan细胞与BMSCs的特异性结合仅为12%~13%。抗β1单抗、抗β2整合素单抗和过量RGD多肽可部分阻断骨髓瘤细胞与骨髓间充质干细胞的结合，提示骨髓瘤细胞与骨髓间充质干细胞的黏附存在多种机制。细胞与FN或骨髓瘤BMSCs的结合不影响细胞的增殖，但骨髓瘤细胞与正常BMSCs的黏附降低了DNA合成，即贴壁的非IL-6依赖的U266、ARH-77、HS-Sultan和IM-9细胞的刺激指数分别为0.1+/-0.04、0.2+/-0.1、0.2+/-0.07和0.1+/-0.06(n=5，P或=12小时)。骨髓间充质干细胞贴壁前的多聚甲醛固定可完全抑制IL-6的分泌，提示IL-6的分泌是在骨髓间充质干细胞而不是细胞系中触发的。用抗β1整合素和抗β2整合素抗体和RGD多肽部分阻断细胞与BMSCs的黏附，也部分阻断了BMSCs分泌IL-6的触发。当细胞系被放置在Transwell插入物中，然后与正常或骨髓瘤BMSCs培养，允许骨髓瘤细胞系和BMSCs之间没有细胞对细胞接触的并置，没有观察到IL-6的分泌增加。
Previous studies show that human myeloma-derived cell lines specifically adhere to fibronectin (FN) through very late antigen-4 (VLA-4; alpha 4 beta 1 integrin complex) and RGD-peptide mechanisms, which may contribute to the localization of tumor cells in bone marrow (BM). In these studies, we characterized the adhesion of myeloma-derived cell lines to both normal and myeloma BM stromal cells (BMSCs) and the effect of adhesion on DNA synthesis. Because interleukin-6 (IL-6) plays an important role in the pathogenesis of multiple myeloma, we also examined the effects of tumor cell adhesion on IL-6 secretion by BMSCs. In 51chromium binding assays, the U266, ARH-77, and IM-9 cell lines showed 52% +/- 12%, 55% +/- 6%, and 47% +/- 7% specific adherence, respectively, to normal BMSCs and 74% +/- 4%, 60% +/- 3%, and 61% +/- 6% specific adherence, respectively, to myeloma BMSCs. In contrast, only 12% to 13% specific binding of HS-Sultan cells to BMSCs was noted. The binding of myeloma cells to BMSCs was partially blocked with anti-beta 1 monoclonal antibody (MoAb), anti-beta 2 integrin MoAb, and excess RGD peptide, suggesting multiple mechanisms for the adhesion of myeloma cell lines to BMSCs. Binding of cell lines to FN or myeloma BMSCs did not affect cell line proliferation; however, adhesion of myeloma cell lines to normal BMSCs decreased DNA synthesis, ie, stimulation indices are 0.1 +/- 0.04, 0.2 +/- 0.1, 0.2 +/- 0.07, and 0.1 +/- 0.06 for the adherent non-IL-6-dependent U266, ARH-77, HS-Sultan, and IM-9 cells, respectively (n = 5, P or = 12 hours) normal and myeloma BMSC cultures. Paraformaldehyde fixation of BMSCs before adhesion completely abrogated IL-6 secretion, suggesting that IL-6 secretion was triggered in BMSCs rather than in cell lines. Partial blocking of cell line adhesion to BMSCs, using anti-beta 1 integrin and anti-beta 2 integrin MoAbs and RGD peptide, also partially blocked the triggering of IL-6 secretion by BMSCs. When cell lines were placed in Transwell inserts and then cultured with either normal or myeloma BMSCs, permitting juxtaposition without cell to cell contact between myeloma cell lines and BMSCs, no increase in IL-6 secretion was observed.(ABSTRACT TRUNCATED AT 400 WORDS)