Fibroblast growth factor receptor promotes progression of cutaneous squamous cell carcinoma.
Fibroblast growth factor receptor promotes progression of cutaneous squamous cell carcinoma.
复制标题
成纤维细胞生长因子受体促进皮肤鳞状细胞癌的进展。
DOI：
10.1002/mc.23012
复制
发表时间：
2019
影响因子：
4.6
通讯作者：
Nathan,Cherie-AnnO
中科院分区：
文献类型：
--
作者：
Khandelwal,AlokR;Kent,Burton;Hillary,Savage;Alam,MdMaksudul;Ma,Xiaohua;Gu,Xin;DiGiovanni,John;Nathan,Cherie-AnnO
皮肤鳞状细胞癌是一种皮肤角质形成细胞来源的侵袭性和转移性肿瘤。它是第二种最常见的皮肤癌，每年有20万 ，000美国人患病。此外，在器官移植患者中，与普通人群相比，CSCC的发病率增加了65到100倍。切除头颈部鳞状细胞癌会导致严重的面部毁容。因此，增加对CSCC发病机制的了解可以找到预防、抑制和逆转这一过程的方法。在我们以前的研究中，抑制成纤维细胞生长因子受体(FGFR)显著减少了紫外线B诱导的SKH-1小鼠的表皮增生和过度增殖，表明FGFR信号在皮肤癌的发生发展中起着重要作用。然而，FGFR信号在宫颈鳞癌发生发展中的作用尚不清楚。FGFR在CSCC细胞和正常表皮角质形成细胞中的表达分析显示，与正常角质形成细胞相比，CSCC细胞中FGFR2蛋白过度表达和FGFR2活性增强。此外，在人鳞状细胞癌中检测到肿瘤细胞特异性的FGFR2过表达，而在癌前病变和正常皮肤中FGFR2的表达很低。用PAN-FGFR抑制剂预处理后，AZD4547显著降低CSCC细胞周期的穿越、增殖、迁移和运动能力。有趣的是，AZD4547还显著下调哺乳动物雷帕霉素复合体1和AKT在CSCC细胞中的激活，表明这些信号通路在FGFR介导的效应中发挥了重要作用。为了进一步支持体外研究，用AZD4547(15 mg/kg/bw，每周两次灌胃)治疗SCC12A肿瘤移植瘤的NOD.Cg-Prkdccid Il2rgtm1Wjl/SzJ小鼠显示出与单纯赋形剂治疗组相比肿瘤体积显著减少。目前的研究为FGFR和选择性的FGFR2在CSCC早期进展中的作用提供了机制证据，并确定FGFR是皮肤癌治疗的假定治疗靶点。
Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte‐derived invasive and metastatic tumor of the skin. It is the second‐most commonly diagnosed form of skin cancer striking 200 000 Americans annually. Further, in organ transplant patients, there is a 65‐ to 100‐fold increased incidence of cSCC compared to the general population. Excision of cSCC of the head and neck results in significant facial disfigurement. Therefore, increased understanding of the mechanisms involved in the pathogeneses of cSCC could identify means to prevent, inhibit, and reverse this process. In our previous studies, inhibition of fibroblast growth factor receptor (FGFR) significantly decreased ultraviolet B‐induced epidermal hyperplasia and hyperproliferation in SKH‐1 mice, suggesting an important role for FGFR signaling in skin cancer development. However, the role of FGFR signaling in the progression of cSCC is not yet elucidated. Analysis of the expression of FGFR in cSCC cells and normal epidermal keratinocytes revealed protein overexpression and increased FGFR2 activation in cSCC cells compared to normal keratinocytes. Further, tumor cell‐specific overexpression of FGFR2 was detected in human cSCCs, whereas the expression of FGFR2 was low in premalignant lesions and normal skin. Pretreatment with the pan‐FGFR inhibitor; AZD4547 significantly decreased cSCC cell‐cycle traverse, proliferation, migration, and motility. Interestingly, AZD4547 also significantly downregulated mammalian target of rapamycin complex 1 and AKT activation in cSCC cells, suggesting an important role of these signaling pathways in FGFR‐mediated effects. To further bolster thein vitrostudies, NOD.Cg‐Prkdcscid Il2rgtm1Wjl/SzJ mice with SCC12A tumor xenografts treated with AZD4547 (15 mg/kg/bw, twice weekly oral gavage) exhibited significantly decreased tumor volume compared to the vehicle‐only treatment group. The current studies provide mechanistic evidence for the role of FGFR and selectively FGFR2 in the early progression of cSCC and identifies FGFR as a putative therapeutic target in the treatment of skin cancer.