Ju W D, Velu T J, Vass W C, Papageorge A G, Lowy D R
Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
New Biol. 1991 Apr;3(4):380-8.
A variety of cancer cells overexpress transforming growth factor alpha (TGF alpha), a mitogenic peptide. A cDNA sequence coding for the full-length human TGF alpha precursor protein was subcloned into a retroviral expression vector and introduced into clone 7 NIH 3T3 cells, which have low numbers of endogenous epidermal growth factor receptors (EGFRs). The autocrine synthesis of TGF alpha by these cells resulted in their focal transformation. In contrast, control NIH 3T3 cells treated in a paracrine manner with exogenous, saturating concentrations of the mature form of TGF alpha, though stimulated to divide, remained morphologically untransformed. The addition of saturating quantities of soluble, mature TGF alpha to NIH 3T3 cells expressing the transferred TGF alpha gene actually suppressed their growth and focal transformation. The transformation induced by the TGF alpha gene remained an EGFR-dependent process, since the degree of transformation was correlated with EGFR expression in NIH 3T3 cells and since NR6 cells, which are Swiss 3T3 cells devoid of endogenous EGFRs, were transformed by the TGF alpha vector only when exogenous EGFR genes were also introduced. When inoculated into nude mice, the TGF alpha-expressing cells rapidly gave rise to tumors that grew progressively, whereas control cells did not form tumors. We conclude that in certain circumstances autocrine TGF alpha can be more oncogenic than paracrine and that paracrine TGF alpha can suppress this effect.
多种癌细胞会过度表达转化生长因子α（TGFα），这是一种促有丝分裂肽。编码全长人TGFα前体蛋白的cDNA序列被亚克隆到逆转录病毒表达载体中，并导入克隆7 NIH 3T3细胞，这些细胞内源性表皮生长因子受体（EGFR）数量较少。这些细胞自分泌TGFα导致了它们的灶性转化。相比之下，用饱和浓度的外源性成熟形式的TGFα以旁分泌方式处理的对照NIH 3T3细胞，虽然被刺激分裂，但形态上未发生转化。向表达转移的TGFα基因的NIH 3T3细胞中添加饱和量的可溶性成熟TGFα实际上抑制了它们的生长和灶性转化。TGFα基因诱导的转化仍然是一个依赖EGFR的过程，因为转化程度与NIH 3T3细胞中的EGFR表达相关，并且由于NR6细胞（缺乏内源性EGFR的瑞士3T3细胞）仅在也导入外源性EGFR基因时才被TGFα载体转化。当接种到裸鼠体内时，表达TGFα的细胞迅速产生逐渐生长的肿瘤，而对照细胞未形成肿瘤。我们得出结论，在某些情况下，自分泌TGFα可能比旁分泌更具致癌性，并且旁分泌TGFα可以抑制这种效应。
