Ronald O. Perlman Department of Dermatology, New York University Langone Medical Center, New York, NY, United States of America.
Department of Pharmacology, Weill Cornell Medicine, New York, NY, United States of America.
PLoS One. 2020 Nov 23;15(11):e0241551. doi: 10.1371/journal.pone.0241551. eCollection 2020.
Perineural invasion is a pathologic process of neoplastic dissemination along and invading into the nerves. Perineural invasion is associated with aggressive disease and a greater likelihood of poor outcomes. In this study, 3 of 9 patients with cutaneous squamous cell carcinoma and perineural invasion exhibited poor clinical outcomes. Tumors from these patients expressed high levels of MAGE-A3, a cancer testis antigen that may contribute to key processes of tumor development. In addition to perineural invasion, the tumors exhibited poor differentiation and deep invasion and were subsequently classified as Brigham and Women's Hospital tumor stage 3. Cyclin E, A and B mRNA levels were increased in these tumors compared with normal skin tissues (102.93±15.03 vs. 27.15±4.59, 36.83±19.41 vs. 11.59±5.83, 343.77±86.49 vs. 95.65±29.25, respectively; p<0.05). A431 cutaneous squamous cell carcinoma cells pretreated with MAGE-A3 antibody exhibited a decreased percentage S-phase cells (14.13±2.8% vs. 33.97±1.1%; p<0.05) and reduced closure in scratch assays (43.88±5.49% vs. 61.17±3.97%; p = 0.0058). In a syngeneic animal model of squamous cell carcinoma, immunoblots revealed overexpression of MAGE-A3 and cyclin E, A, and B protein in tumors at 6 weeks. However, knockout of MAGE-A3 expression caused a reduction in tumor growth (mean tumor volume 155.3 mm3 vs. 3.2 mm3) compared with parental cells. These results suggest that MAGE-A3 is a key mediator in cancer progression. Moreover, elevated collagen XI and matrix metalloproteases 3, 10, 11, and 13 mRNA levels were observed in poorly differentiated cutaneous squamous cell carcinoma with perineural invasion compared with normal skin tissue (1132.56±882.7 vs. 107.62±183.62, 1118.15±1109.49 vs. 9.5±5, 2603.87±2385.26 vs. 5.29±3, 957.95±627.14 vs. 400.42±967.66, 1149.13±832.18 vs. 19.41±35.62, respectively; p<0.05). In summary, this study highlights the potential prognostic value of MAGE-A3 in clinical outcomes of cutaneous squamous cell carcinoma patients.
神经周围侵犯是肿瘤沿神经扩散和侵犯的病理过程。神经周围侵犯与侵袭性疾病和不良预后的可能性增加相关。在这项研究中，9 例皮肤鳞状细胞癌伴神经周围侵犯的患者中有 3 例出现不良临床结局。这些患者的肿瘤表达高水平的 MAGE-A3，这是一种癌症睾丸抗原，可能有助于肿瘤发展的关键过程。除了神经周围侵犯外，这些肿瘤还表现出低分化和深部侵犯，随后被归类为 Brigham and Women's Hospital 肿瘤分期 3。与正常皮肤组织相比，这些肿瘤中的细胞周期蛋白 E、A 和 B mRNA 水平升高（102.93±15.03 与 27.15±4.59、36.83±19.41 与 11.59±5.83、343.77±86.49 与 95.65±29.25；p<0.05）。用 MAGE-A3 抗体预处理的 A431 皮肤鳞状细胞癌细胞显示 S 期细胞的百分比降低（14.13±2.8%与 33.97±1.1%；p<0.05），划痕试验中的闭合减少（43.88±5.49%与 61.17±3.97%；p = 0.0058）。在鳞状细胞癌的同种异体动物模型中，免疫印迹显示 6 周时肿瘤中 MAGE-A3 和细胞周期蛋白 E、A 和 B 蛋白过度表达。然而，与亲本细胞相比，MAGE-A3 表达的敲除导致肿瘤生长减少（平均肿瘤体积 155.3 mm3 与 3.2 mm3）。这些结果表明 MAGE-A3 是癌症进展的关键介质。此外，与正常皮肤组织相比，分化不良的伴神经周围侵犯的皮肤鳞状细胞癌中胶原 XI 和基质金属蛋白酶 3、10、11 和 13 mRNA 水平升高（1132.56±882.7 与 107.62±183.62、1118.15±1109.49 与 9.5±5、2603.87±2385.26 与 5.29±3、957.95±627.14 与 400.42±967.66、1149.13±832.18 与 19.41±35.62；p<0.05）。总之，这项研究强调了 MAGE-A3 在皮肤鳞状细胞癌患者临床结局中的潜在预后价值。
