Simon C, Hicks M J, Nemechek A J, Mehta R, O'Malley B W, Goepfert H, Flaitz C M, Boyd D
Department of Head and Neck Surgery, The University of Texas, MD Anderson Cancer Center, Houston 77030, USA.
Br J Cancer. 1999 Jul;80(9):1412-9. doi: 10.1038/sj.bjc.6690537.
Increased mortality of patients with oral cancer largely reflects the local and regional spread of the disease. The invasiveness of these tumours requires hydrolases which are regulated through AP-1-dependent transcriptional mechanisms. Since the amount/activity of transcription factors bound to the AP-1 motif are regulated partly through the extracellular signal-regulated kinases (ERK1/ERK2), we determined the effect of PD 098059, an inhibitor of ERK1/ERK2 activation, on the in vivo invasiveness of a human squamous cell carcinoma cell line (UM-SCC-1) derived from the oral cavity. We utilized the floor of mouth musculature consisting of the mylohyoid, geniohyoid and genioglossus muscle (which are sequentially arranged), as a natural barrier to assess tumour spread in vivo in the nude mouse. Mice were inoculated with tumour cells superficial to the mylohyoid muscle. After 18 days, tumours were injected with either empty liposomes (control) or liposomes containing 5 microM PD 098059 and, after an additional 22 days, the jaws of mice examined histologically. Highly infiltrative tumours, which had penetrated the genioglossus muscle, were evident in 10/12 control mice. In contrast, in 9/12 mice in which the tumours were injected with PD 098059, tumours did not extend beyond the mylohyoid or geniohyoid muscles. Tumours penetrated bone nutrient canals in 7/12 control mice but in only 3/12 PD 098059-treated mice. Neurotropism, characteristic of aggressive oral squamous cell carcinoma, was evident in 6/12 control mice but was completely abolished (0/12 mice) in the PD 098059-treated mice. Using a staging system based on the muscle layer involved, neurotropism, as well as bone involvement, we found the inhibition of invasion to be statistically significant (P < 0.01). The reduced invasiveness of the PD 098059-liposome-treated oral cancers was associated with diminished 92-kDa type IV collagenase and ERK1/ERK2 activities but was not a consequence of a slower tumour growth rate. This is the first study to demonstrate reduced in vivo invasiveness of a malignancy brought about by an inhibitor of ERK1/ERK2 activation. These results raise the exciting possibility that second generation PD 098059 congeners may reduce the spread of the disease in patients afflicted with oral cancers.
口腔癌患者死亡率的增加很大程度上反映了该疾病的局部和区域扩散。这些肿瘤的侵袭性需要通过AP-1依赖的转录机制进行调节的水解酶。由于与AP-1基序结合的转录因子的数量/活性部分通过细胞外信号调节激酶（ERK1/ERK2）进行调节，我们确定了ERK1/ERK2激活抑制剂PD 098059对源自口腔的人鳞状细胞癌细胞系（UM-SCC-1）体内侵袭性的影响。我们利用由下颌舌骨肌、颏舌骨肌和颏舌肌（依次排列）组成的口底肌肉组织，作为评估裸鼠体内肿瘤扩散的天然屏障。将肿瘤细胞接种于下颌舌骨肌表面的小鼠。18天后，给肿瘤注射空脂质体（对照）或含有5 microM PD 098059的脂质体，再过22天后，对小鼠的颌骨进行组织学检查。在12只对照小鼠中有10只出现了穿透颏舌肌的高度浸润性肿瘤。相比之下，在12只注射了PD 098059的小鼠中有9只，肿瘤未超出下颌舌骨肌或颏舌骨肌。在12只对照小鼠中有7只肿瘤穿透了骨滋养管，但在仅接受PD 098059治疗的12只小鼠中只有3只。侵袭性口腔鳞状细胞癌的特征性嗜神经性在12只对照小鼠中有6只明显，但在接受PD 098059治疗的小鼠中完全消失（12只小鼠中有0只）。使用基于所累及肌肉层、嗜神经性以及骨受累情况的分期系统，我们发现侵袭的抑制具有统计学意义（P < 0.01）。PD 098059脂质体治疗的口腔癌侵袭性降低与92-kDa IV型胶原酶和ERK1/ERK2活性降低有关，但不是肿瘤生长速度减慢的结果。这是第一项证明ERK1/ERK2激活抑制剂可降低恶性肿瘤体内侵袭性的研究。这些结果提出了一个令人兴奋的可能性，即第二代PD 098059同系物可能会减少口腔癌患者疾病的扩散。
