Reduction of TGF-beta activity abrogates growth promoting tumor cell-cell interactions in vivo.
Reduction of TGF-beta activity abrogates growth promoting tumor cell-cell interactions in vivo.
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TGF-β活性的降低消除了体内促进肿瘤细胞-细胞相互作用的生长。
DOI：
10.1002/jcp.1041480308
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发表时间：
1991
影响因子：
5.6
通讯作者：
Kerbel,RS
中科院分区：
文献类型：
--
作者：
Theodorescu,D;Caltabiano,M;Greig,R;Rieman,D;Kerbel,RS
我们在先前的研究中已经表明，来自非转移性小鼠乳腺腺癌（SP1）的具有转移能力的变异亚群（B5，C1）在原发性肿瘤中具有明显的生长优势，优于其非转移性肿瘤细胞对应物。结果，原发性肿瘤可以被具有在身体中扩散到其他地方的能力的细胞逐渐过度生长。尽管有任何证据表明转移性细胞作为分离群体生长时具有内在的体内生长速率优势，但仍发生了这种情况。这表明转移性和非转移性肿瘤群体之间的细胞-细胞相互作用可能参与转移性细胞生长优势过程。因此，寻找SP1细胞释放的生长因子的证据，这些生长因子可以优先刺激B5或C1变体，从而介导这种细胞间相互作用过程。我们发现，共培养的SP1和C1或B5细胞与辐射C1，B5，或SP1的“饲养”细胞显示出显着的刺激C1和B5的SP1的“饲养”细胞。对EGF、TGF-α、TGF-β1、bFGF、PDGF、NGF、IGF-1或IGF-2的细胞生长刺激表明，只有TGF-β1可以复制这种作用。因此，在存在特异性中和抗TGF-β抗体的情况下重复进行共培养实验，发现这显著降低了辐照SP1细胞对C1或B5细胞的刺激。对来自SP1和C1细胞系的条件培养基的TGF-β活性进行定量，其含量分别为4.5 ng/ml和2.0 ng/ml。然而，发现SP1细胞释放的大多数TGF-β是自发活性的，而C1细胞释放的TGF-β中有70%是潜伏形式。Scatchard分析显示，与SP1细胞相比，C1细胞上存在的TGF-β受体数量约为SP1细胞的4倍，其类型和亲和力相似。体外结果支持由SP1细胞释放的活性TGF-β可能以旁分泌样方式刺激转移性变体细胞增殖的假设。通过显示共注射经辐照的SP1细胞可以选择性地刺激活C1细胞的肿瘤生长，并且通过神经化多克隆抗TGF-β抗体显著减弱这种作用，获得了体内证据。总之，结果表明TGF-β在恶性肿瘤生长的克隆进化中具有新的作用，并作为肿瘤细胞-肿瘤细胞相互作用的分子介质参与促进肿瘤进展。
We have shown in previous studies that metastatically‐competent variant subpopulations (B5, C1) derived from a non‐metastatic murine mammary adenocarcinoma (SP1) have a pronounced growth advantage over their non‐metastatic tumor cell counterparts in primary tumors. As a result, primary tumors can be progressively overgrown by cells having the competence to spread elsewhere in the body. This occurs despite any evidence to indicate an intrinsic in vivo growth rate advantage of the metastatic cells when grown as isolated populations. This suggested that cell‐cell interactions between metastatic and non‐metastatic tumor populations may be involved in the metastatic cell growth dominance process. Evidence was therefore sought for growth factors released by SP1 cells which could preferentially stimulate the B5 or C1 variants and thereby mediate this cell‐cell interaction process. We found that cocultures of SP1 and C1 or B5 cells with irradiated C1, B5, or SP1 “feeder” cells showed significant stimulation of C1 and B5 by SP1 “feeder” cells. Cell growth stimulation in response to EGF, TGF‐α, TGF‐β1, bFGF, PDGF, NGF, IGF‐1, or IGF‐2 demonstrated that only TGF‐β1 could duplicate this effect. A repeat of the coculture experiment in the presence of specific neutralizing anti‐TGF‐β antibodies was therefore undertaken and this was found to markedly reduce the stimulation of C1 or B5 cells by irradiated SP1 cells. Conditioned media from the SP1 and C1 cell lines was quantitated for TGF‐β activity and contained 4.5 ng/ml and 2.0 ng/ml, respectively. However, the majority of the TGF‐β released by SP1 cells was found to be spontaneously active, whereas 70% of the TGF‐β released by C1 cells was in its latent form. Scatchard analysis revealed approximately four times the number of TGF‐β receptors, of similar type and affinity, present on C1 as compared with SP1 cells. The in vitro results support the hypothesis that active TGF‐β released by SP1 cells may stimulate the proliferation of metastatic variant cells in a paracrine like fashion. In vivo evidence for this was obtained by showing that coinjection of irradiated SP1 cells could selectively stimulate tumor growth of viable C1 cells and this effect was markedly diminished by neurtralizing polyclonal anti‐TGF‐β antibodies. Taken together, the results suggest a novel role for TGF‐β in clonal evolution of malignant tumor growth and as a molecular mediator of tumor cell‐tumor cell interactions involved in facilitating tumor progression.