Suppression of tumor progression and angiogenesis in two Lewis lung carcinoma mouse models by shRNA knockdown of fibroblast activation protein.

Abstract

e13592 Background: Fibroblast activation protein (FAP), a transmembrane serine peptidase, is expressed by tumor-associated fibroblasts. As an important factor in tumor microenvironment, it has been reported that FAP plays a dual role in tumor progression, both positive and negative. In a mouse model of breast cancer, FAP increasing microvessel densities had been experimentally demonstrated. The aim of the study was to determine the effect of FAP in tumor growth and tumor microenvironment in LLC mouse models, especially in lung metastasis model. Methods: Female C57 mice received i.v injection of LLC cells into tail vein or s.c into right flank to establish lung metastasis model or subcutaneous xenograft model. 21 mice were randomly divided into 3 groups (n=7, per group) and treated with 5% GS,control-shRNA or FAP-shRNA, respectively. Xenograft tumor size and weight, numbers of pulmonary metastatic nodules and lung weight were measured. FAP expression, microvessel density and collagen fiber were evaluated. Data were analyzed using one-way analysis of variance (ANOVA), and a value of P <0.05 was considered to be statistically significant. Results: FAP-shRNA decreased significantly in the number of metastases on the lung surface and average lung weight, compared with 5%GS and control-shRNA (P<0.05).The size of metastases in treatment group was large than those of the controls (P<0.05). Moreover, FAP-shRNA showed a significant reduction of 44% in tumor volume and tumor weight, relative to other groups (P<0.05). In both models, FAP expression and microvessel density were lower in treatment group compared to the controls. And FAP-shRNA indicated an increase in the accumulation of collagen fiber. Conclusions: The study suggests that shRNA targeting FAP inhabit tumor growth in LLC mouse models, especially in lung metastasis model. We hypothesize that the anti-tumor mechanism is related to angiogenesis reduction and alteration of collage fibro accumulation, which eventually change tumor microenvironment. These findings indicate the potential of FAP as a new therapeutic strategy for lung cancer.