Van Trappen Philippe O, Steele Dawn, Lowe David G, Baithun Suhail, Beasley Nigel, Thiele Wilko, Weich Herbert, Krishnan Jaya, Shepherd John H, Pepper Michael S, Jackson David G, Sleeman Jonathan P, Jacobs Ian J
Department of Gynaecological Oncology, Cancer Research UK Translational Oncology Laboratory, St Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
J Pathol. 2003 Dec;201(4):544-54. doi: 10.1002/path.1467.
Cervical carcinogenesis has well-defined stages of disease progression including three grades of pre-invasive lesions--cervical intraepithelial neoplasia grades 1-3 (CIN 1-3)--and invasive cervical cancer. However, the biological properties of CIN lesions prone to develop invasive disease are not well defined. Recent observations suggest that early invasive disease spreads to regional lymph nodes in several tumour types and that growth factors (VEGF-C and VEGF-D) involved in new lymphatic vessel formation may play a crucial role in this process. The present study has assessed the expression of VEGF-C and VEGF-D, and their receptor VEGFR-3, in 152 cervical lesions (33 CIN 1, 33 CIN 2, 37 CIN 3, and 49 squamous cell carcinomas) to determine whether expression of lymphangiogenic factors occurs prior to invasion. The presence of lymphatic vessels was determined using LYVE-1 and podoplanin staining, as well as double immunostaining for LYVE-1/CD34 and podoplanin/CD34. In situ hybridization was performed to determine VEGFR-3 mRNA expression. A significant positive correlation was found between VEGF-C, VEGF-D, and VEGFR-3 expression through the different stages of cervical carcinogenesis. Significant differences in protein expression for VEGF-C, VEGF-D, and VEGFR-3 were found between CIN 1-2 and CIN 3 (p<0.001 for all), but not between CIN 3 and cervical cancer. More than 50% of the CIN 3 lesions showed moderate to strong staining for VEGF-C and VEGF-D, whereas most of the early pre-cancerous lesions (CIN 1 and 2) were negative. In cervical cancer, similar observations to those in CIN 3 were found. VEGFR-3 mRNA expression was found in the cytoplasm of epithelial neoplastic cells and VEGFR3 protein expression was found in more than 50% of CIN 3 lesions and cervical cancers, compared with 15% in CIN 1 and 2. These findings suggest an autocrine growth stimulation pattern via VEGFR-3. Adjacent CIN 3 was present in nine cervical cancers and displayed strong expression for VEGF-C, VEGF-D, and VEGFR-3. These results suggest that in cervical carcinogenesis a switch to the lymphangiogenic phenotype may occur at the stage of CIN 3.
宫颈癌发生具有明确的疾病进展阶段，包括三级癌前病变——宫颈上皮内瘤变1 - 3级（CIN 1 - 3）以及浸润性宫颈癌。然而，易于发展为浸润性疾病的CIN病变的生物学特性尚未明确界定。最近的观察结果表明，在几种肿瘤类型中，早期浸润性疾病会扩散至区域淋巴结，并且参与新淋巴管形成的生长因子（VEGF - C和VEGF - D）可能在此过程中起关键作用。本研究评估了152例宫颈病变（33例CIN 1、33例CIN 2、37例CIN 3和49例鳞状细胞癌）中VEGF - C、VEGF - D及其受体VEGFR - 3的表达情况，以确定淋巴管生成因子的表达是否在浸润之前出现。使用LYVE - 1和血小板内皮细胞黏附分子染色以及LYVE - 1/CD34和血小板内皮细胞黏附分子/CD34双重免疫染色来确定淋巴管的存在。进行原位杂交以确定VEGFR - 3 mRNA的表达。在宫颈癌发生的不同阶段，VEGF - C、VEGF - D和VEGFR - 3的表达之间存在显著的正相关。在CIN 1 - 2和CIN 3之间发现VEGF - C、VEGF - D和VEGFR - 3的蛋白表达存在显著差异（所有p均<0.001），但在CIN 3和宫颈癌之间未发现差异。超过50%的CIN 3病变对VEGF - C和VEGF - D呈中度至强染色，而大多数早期癌前病变（CIN 1和2）为阴性。在宫颈癌中，发现了与CIN 3中类似的观察结果。VEGFR - 3 mRNA表达见于上皮肿瘤细胞的细胞质中，并且在超过50%的CIN 3病变和宫颈癌中发现VEGFR3蛋白表达，相比之下，CIN 1和2中为15%。这些发现提示通过VEGFR - 3的自分泌生长刺激模式。9例宫颈癌中存在相邻的CIN 3，并对VEGF - C、VEGF - D和VEGFR - 3呈强表达。这些结果表明，在宫颈癌发生过程中，向淋巴管生成表型的转变可能发生在CIN 3阶段。
