Chemokine CXCL14/BRAK transgenic mice suppress growth of carcinoma cell xenografts
- 262 Downloads
We reported previously that the forced expression of the chemokine BRAK, also called CXCL14 in head and neck squamous cell carcinoma (HNSCC) cells decreased the rate of tumor formation and size of tumor xenografts compared with mock-vector treated cells in athymic nude mice or in severe combined immunodeficiency mice. This suppression occurred even though the growth rates of these cells were the same under in vitro culture conditions, suggesting that a high expression level of the gene in tumor cells is important for the suppression of tumor establishment in vivo. The aim of this study was to determine whether CXCL14/BRAK transgenic mice show resistance to tumor cell xenografts or not. CXCL14/BRAK cDNA was introduced into male C57BL/6 J pronuclei, and 10 founder transgenic mice (Tg) were obtained. Two lines of mice expressed over 10 times higher CXCL14/BRAK protein levels (14 and 11 ng/ml plasma, respectively) than normal blood level (0.9 ng/ml plasma), without apparent abnormality. The sizes of Lewis lung carcinoma and B16 melanoma cell xenografts in Tg mice were significantly smaller than those in control wild-type mice, indicating that CXCL14/BRAK, first found as a suppressor of tumor progression of HNSCC, also suppresses the progression of a carcinoma of other tissue origin. Immunohistochemical studies showed that invasion of blood vessels into tumors was suppressed in tumor xenografts of CXCL14/BRAK Tg mice. These results indicate that CXCL14/BRAK suppressed tumor cell xenografts by functioning paracrine or endocrine fashion and that CXCL14/BRAK is a very promising molecular target for tumor suppression without side effects.
KeywordsChemokine CXCL14/BRAK Tumor suppression Lewis lung carcinoma cells Transgenic mouse Tumor therapy
We appreciate Ms. Etsuko Shimada for preparation of reference list. This work was supported in part by a Grant-in Aid from the High-Tech Research Center Project of the Ministry of Education, Culture, Sports, Science and Technology of Japan and by a Grant-in Aid for Scientific Research from Japan Society for Promotion of Science.
- Augsten M, Hagglof C, Olsson E, Stolz C, Tsagozis P, Levchenko T, Frederick MJ, Borg A, Micke P, Egevad L, Ostman A (2009) CXCL14 is an autocrine growth factor for fibroblasts and acts as a multi-modal stimulator of prostate tumor growth. Proc Natl Acad Sci USA 106:3414–3419CrossRefPubMedGoogle Scholar
- Izukuri K, Ito S, Nozaki N, Yajima N, Iwamiya M, Kawahara S, Suzuki K, Kubota E, Hata R (2010) Determination of serum BRAK/CXCL14 level in healthy volunteers. LabMedicine (in press)Google Scholar
- Ozawa S, Kato Y, Ito S, Komori R, Shiiki N, Tsukinoki K, Ozono S, Maehata Y, Taguchi T, Imagawa-Ishiguro Y, Tsukuda M, Kubota E, Hata RI (2009a) Restoration of BRAK/CXCL14 gene expression by gefitinib is associated with antitumor efficacy of the drug in head and neck squamous cell carcinoma. Cancer Sci 100:2202–2209CrossRefPubMedGoogle Scholar
- Sato K, Ozawa S, Izukuri K, Kato Y, Hata R (2010) Expression of tumor-suppressing chemokine BRAK/CXCL14 reduces cell migration rate of HSC-3 tongue carcinoma cells and stimulates attachment to collagen and formation of elongated focal adhesions in vitro. Cell Biol Int (in press).Google Scholar
- Shellenberger TD, Wang M, Gujrati M, Jayakumar A, Strieter RM, Burdick MD, Ioannides CG, Efferson CL, El-Naggar AK, Roberts D, Clayman GL, Frederick MJ (2004) CXCL14/BRAK is a potent inhibitor of angiogenesis and a chemotactic factor for immature dendritic cells. Cancer Res 64:8262–8270CrossRefPubMedGoogle Scholar