Expression of C5aR1 in Cutaneous Squamous Cell Carcinoma is Associated with Invasion, Metastasis and Poor Prognosis

Lauri Heiskanen, Liisa Nissinen, Elina Siljamaki, Jaakko Knuutila, Teijo Pellinen, Markku Kallajoki, Jyrki Heino, Pilvi Riihila, Veli-Matti Kahari
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Abstract

Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer, and the metastatic disease is associated with poor prognosis. We have examined the role of complement C5a receptor, C5aR1, in the progression and metastasis of cSCC. C5aR1 expression was increased in cSCC cells in 3D spheroid coculture model in the presence of fibroblasts, and that treatment with recombinant C5a enhanced the invasion of cSCC cells. Staining for C5aR1 was detected on the surface of tumor cells at the invasive edge of human cSCC xenografts in vivo. Staining of metastatic and nonmetastatic primary human cSCCs, premalignant and benign epidermal lesions and normal skin for C5aR1 with multiplex immunofluorescence and chromogenic immunohistochemistry revealed increased expression of C5aR1 on the surface of tumor cells and fibroblasts in invasive cSCCs and recessive dystrophic epidermolysis bullosa associated cSCCs compared to cSCC in situ, actinic keratoses, seborrheic keratoses and normal skin. Increased expression of C5aR1 on the tumor cell surface and in fibroblasts was associated with metastatic risk and poor disease specific survival of patients with primary cSCC. These findings reveal the role of C5aR1 in cSCC invasion and identify C5aR1 as a novel biomarker for metastasis risk and poor prognosis in patients with cSCC. The results also suggest that C5aR1 could be a novel therapeutic target for treatment of locally advanced and metastatic cSCC.
皮肤鳞状细胞癌中 C5aR1 的表达与侵袭、转移和预后不良有关
皮肤鳞状细胞癌(cSCC)是最常见的转移性皮肤癌,转移性疾病与预后不良有关。我们研究了补体C5a受体C5aR1在cSCC进展和转移中的作用。在有成纤维细胞存在的三维球形细胞培养模型中,cSCC细胞的C5aR1表达增加,用重组C5a处理可增强cSCC细胞的侵袭。在体内人cSCC异种移植物侵袭边缘的肿瘤细胞表面检测到了C5aR1染色。对转移性和非转移性原发性人类 cSCC 进行染色、用多重免疫荧光和色原免疫组织化学方法对转移性和非转移性原发性人类cSCC、癌前病变和良性表皮病变以及正常皮肤进行C5aR1染色,结果显示,与原位cSCC、光化性角化病、脂溢性角化病和正常皮肤相比,浸润性cSCC和隐性萎缩性表皮松解症相关cSCC的肿瘤细胞和成纤维细胞表面的C5aR1表达量增加。肿瘤细胞表面和成纤维细胞中 C5aR1 表达的增加与原发性 cSCC 患者的转移风险和疾病特异性存活率低有关。这些发现揭示了 C5aR1 在 cSCC 侵袭中的作用,并确定 C5aR1 是 cSCC 患者转移风险和预后不良的新型生物标记物。研究结果还表明,C5aR1 可能是治疗局部晚期和转移性 cSCC 的新型治疗靶点。
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