INTERLEUKIN-6 UNDERGOES TRANSITION FROM PARACRINE GROWTH INHIBITOR TO AUTOCRINE STIMULATOR DURING HUMAN-MELANOMA PROGRESSION
INTERLEUKIN-6 UNDERGOES TRANSITION FROM PARACRINE GROWTH INHIBITOR TO AUTOCRINE STIMULATOR DURING HUMAN-MELANOMA PROGRESSION
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DOI：
10.1083/jcb.120.5.1281
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发表时间：
1993-03-01
影响因子：
7.8
通讯作者：
KERBEL, RS
中科院分区：
文献类型：
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作者：
LU, C;KERBEL, RS
穿透真皮基底膜并随后在下面的间充质中增殖的能力是人类黑色素瘤恶性进展的关键步骤之一。我们之前进行的研究旨在评估正常真皮成纤维细胞（间质的主要细胞成分之一）如何影响人类黑色素瘤细胞的生长并促进恶性亚群的过度生长（Cornil, I., D. Theodorescu, S. Man, M. Herlyn, J. Jambrosic, and R. S. Kerbel. 1991. Proc. Natl. Acad. Sci. USA。 88:6028-6032）。我们发现，来自早期（无转移能力）病变的黑色素瘤细胞系生长受到抑制，而来自晚期（有转移能力）病变的黑色素瘤细胞系在相同条件下通过与成纤维细胞共培养而受到刺激；来自此类细胞的条件培养基给出了相同的结果。随后使用生化纯化和中和抗体的研究表明其抑制活性与白细胞介素 6 (IL-6) 相同。我们现在报道，添加纯化的重组人 IL-6 会导致早期黑色素瘤细胞在体外 G1/G0 期停滞，但不会导致晚期黑色素瘤细胞的生长受到抑制。尽管反应发生了这种变化，但不同恶性肿瘤的黑色素瘤细胞系在编码 IL-6 受体或 gp130（IL-6 信号转导器）的基因表达方面没有显着差异。 Scatchard 分析还揭示了 IL-6 敏感组和耐药组中相似的 [I-125]IL-6 结合活性。然而，IL-6 产生的研究表明，已知对外源性 IL-6 介导的生长抑制具有抗性的 8 个 IL-6 黑色素瘤细胞系中，有 5 个持续表达 IL-6 mRNA；它们还将具有生物活性的 IL-6 分泌到培养基中。为了评估这种内源性 IL-6 在黑色素瘤细胞生长中的可能作用，将 IL-6 基因的反义寡核苷酸添加到黑色素瘤细胞的培养物中。这仅在产生内源性 IL-6 的细胞系中产生显着的生长抑制。相反，IL-6 的中和抗体不能有效引起这种生长抑制。这表明内源性 IL-6 可能通过细胞内（“私人”）自分泌机制发挥生长刺激剂的作用。因此，在恶性肿瘤进展过程中，单一细胞因子IL-6可以在同一细胞谱系中从旁分泌生长抑制剂转变为自分泌生长刺激剂。这种转换可能有助于原发或远处器官部位具有转移能力的黑色素瘤细胞的生长优势，从而促进疾病的进展。
The ability to penetrate the dermal basement membrane and subsequently proliferate in the underlying mesenchyme is one of the key steps in malignant progression of human melanomas. We previously undertook studies aimed at assessing how normal dermal fibroblasts (one of the main cellular components of mesenchyme) may affect the growth of human melanoma cells and facilitate the overgrowth of malignant subpopulations (Cornil, I., D. Theodorescu, S. Man, M. Herlyn, J. Jambrosic, and R. S. Kerbel. 1991. Proc. Natl. Acad. Sci. USA. 88:6028-6032). We found that melanoma cell lines from early-stage (metastatically incompetent) lesions were growth inhibited whereas those from advanced-stage (metastatically competent) lesions were stimulated under the same conditions by co-culture with fibroblasts; conditioned medium from such cells gave the same result. Subsequent studies using biochemical purification and neutralizing antibodies revealed the inhibitory activity to be identical to interleukin-6 (IL-6). We now report that addition of purified recombinant human IL-6 resulted in a growth inhibition in vitro by G1/G0 arrest of early, but not advanced stage melanoma cells. Despite this alteration in response there was no significant difference in melanoma cell lines of varying malignancy in respect to their expression of genes encoding the IL-6 receptor, or gp130, the IL-6 signal transducer. Scatchard analysis also revealed similar [I-125]IL-6 binding activities in both IL-6 sensitive and resistant groups. However, studies of IL-6 production indicated that five out of eight IL-6 melanoma cell lines known to be resistant to exogenous IL-6-mediated growth inhibition constitutively expressed mRNA for IL-6; they also secreted bioactive IL-6 into culture medium. To assess the possible role of this endogenous IL-6 in melanoma cell growth, antisense oligonucleotides to the IL-6 gene were added to cultures of melanoma cells. This resulted in a significant growth inhibition only in cell lines that produced endogenous IL-6. In contrast, neutralizing antibodies to IL-6 were ineffective in causing such growth inhibition. This indicates that endogenous IL-6 may behave as a growth stimulator by an intracellular (''private'') autocrine mechanism. Thus, a single cytokine, IL-6, can switch from behaving as a paracrine growth inhibitor to an autocrine growth stimulator within the same cell lineage during malignant tumor progression. Such a switch may contribute to the growth advantage of metastatically competent melanoma cells at the primary or distant organ sites and thereby facilitate progression of disease.