Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
PLoS One. 2011;6(10):e26858. doi: 10.1371/journal.pone.0026858. Epub 2011 Oct 27.
Expression of the α2β1 integrin, a receptor for collagens and laminin, is altered during tumor progression. Recent studies have linked polymorphisms in the α2 integrin gene with oral, squamous cell carcinoma (SCC). To determine the α2β1 integrin's role in SCC progression, we crossed α2-null mice with K14-HPV16 transgenic animals. Pathological progression to invasive carcinoma was evaluated in HPV-positive, α2-null (HPV/KO) and HPV-positive, wild-type (HPV/WT) animals. α2β1 integrin expression stimulated progression from hyperplasia and papillomatosis to dysplasia with concomitant dermal mast cell infiltration. Moreover, lymph node metastasis was decreased by 31.3% in HPV/KO, compared to HPV/WT, animals. To evaluate the integrin-specific impact on the malignant epithelium versus the microenvironment, we developed primary tumor cell lines. Although transition from dysplasia to carcinoma was unaltered during spontaneous tumor development, isolated primary HPV/KO SCC cell lines demonstrated decreased migration and invasion, compared to HPV/WT cells. When HPV/WT and HPV/KO SCC cells were orthotopically injected into WT or KO hosts, tumor α2β1 integrin expression resulted in decreased tumor latency, regardless of host integrin status. HPV/WT SCC lines failed to demonstrate a proliferative advantage in vitro, however, the HPV/WT tumors demonstrated increased growth compared to HPV/KO SCC lines in vivo. Although contributions of the integrin to the microenvironment cannot be excluded, our studies indicate that α2β1 integrin expression by HPV-transformed keratinocytes modulates SCC growth and progression.
α2β1 整合素是一种细胞外基质受体，可与胶原和层粘连蛋白结合，其表达在肿瘤进展过程中发生改变。最近的研究将 α2 整合素基因多态性与口腔鳞状细胞癌（SCC）联系起来。为了确定 α2β1 整合素在 SCC 进展中的作用，我们将 α2 缺失小鼠与 K14-HPV16 转基因动物杂交。在 HPV 阳性、α2 缺失（HPV/KO）和 HPV 阳性、野生型（HPV/WT）动物中评估了 HPV 阳性、α2 缺失（HPV/KO）和 HPV 阳性、野生型（HPV/WT）动物的病理性侵袭性癌进展。α2β1 整合素表达刺激了从增生和乳头瘤形成到异型增生的进展，同时伴有真皮肥大细胞浸润。此外，与 HPV/WT 动物相比，HPV/KO 动物的淋巴结转移减少了 31.3%。为了评估整合素对恶性上皮细胞与微环境的特异性影响，我们建立了原发性肿瘤细胞系。虽然在自发性肿瘤发展过程中，从异型增生到癌的转变没有改变，但与 HPV/WT 细胞相比，分离的原发性 HPV/KO SCC 细胞系显示出迁移和侵袭能力降低。当将 HPV/WT 和 HPV/KO SCC 细胞原位注射到 WT 或 KO 宿主中时，肿瘤 α2β1 整合素表达导致肿瘤潜伏期缩短，而与宿主整合素状态无关。尽管 HPV/WT SCC 系在体外没有表现出增殖优势，但 HPV/WT 肿瘤在体内的生长速度比 HPV/KO SCC 系更快。尽管整合素对微环境的贡献不能排除，但我们的研究表明，HPV 转化的角质形成细胞中 α2β1 整合素的表达调节 SCC 的生长和进展。
