BRAK/CXCL14 expression in oral carcinoma cells completely suppresses tumor cell xenografts in SCID mouse

Abstract

SCID mice are a model of human severe combined immunodeficiency disease and are deficient in B cell function in addition to T cell function. Tumors from other species are easily transplanted into SCID mice and will grow without being rejected. We previously reported that the chemokine BRAK/CXCL14 is expressed in normal cells but its expression is down regulated in an in vitro cancer progression model, suggesting that it has the potential for antitumor activity. Here we report that the growth of BRAK/CXCL14 expression vector-transfected oral cancer cells was completely (100%) suppressed in SCID mouse xenografts even though mock-vector introduced control tumor cells grew well with 100% of animals developing tumors. In addition, suppression of xenografts was much faster and the rate was much higher in SCID mice than in T cell functiondeficient nude mice. These data indicate the possibility that BRAK expression inhibits tumor cell establishment by regulating interactions between tumor stem cells and NK cells and/or suppressing formation of tumor microvessels.Tumors develop in multiple steps (6,19,25), and tumor progression is dependent on the balance of the expression between tumor progression-promoting and -suppressing genes being in favor of the former at each step (1, 2). In order to prevent tumor progression, many investigators have searched for molecules that are over-expressed during tumor progression as target molecules for therapeutic drugs and have tried to prevent tumor progression by inhibiting these tumor-promoting molecules. However, drugs for many of the target molecules were not successful for clinical applications owing to the serious side effects of these drugs, which is not surprising because these target molecules are also important for normal development and maintenance of tissues and for homeostasis of our body (16,22).On the other hand, activation of presumptive tumor suppressor(s) or inhibition of their down-regulation may be much more promising for the prevention of tumor progression without significant side effects, because these molecules are supposedly present abundantly in normal tissues. In the course of our study to find an endogenous tumor suppressor(s) for oral cancers (OC), we searched for molecules down-regulated in OC cells when the cells were treated with epidermal growth factor (EGF), whose receptor is frequently overactivated in OC. The expression of BRAK, which is also known as CXC chemokine ligand 14 (CXCL14), was down-regulated significantly by the treatment of OC cells with EGF as observed by cDNA microarray analysis followed by reverse-transcriptase polymerase chain reaction analysis. In order to investigate whether BRAK/CXCL14 have a tumor-suppressing effect in vivo, we prepared BRAK/CXCL14-expression vector-transfected tongue tumor-derived cells (HSC-3 BRAK) and cloned them. No difference in the growth rates of these cells was observed in vitro

Expression of a chemokine BRAK/CXCL14 in oral floor carcinoma cells reduces the settlement rate of the cells and suppresses their proliferation in vivo

“…Cells were lysed with Laemmli buffer consisting of 62.5 mM Tris-HCl (pH 6.8) containing 2% SDS, 8% glycerol, SCC and adenocarcinoma. We reported previously that the forced expression of BRAK/CXCL14 in tongue carcinoma cells decreased the rate of tumor formation and size of tumor xenografts in athymic nude mice (16) and SCID mice (17). In these experiments on cloned cells with an upregulated BRAK/CXCL14 protein expression, the growth of these cells under culture conditions was the same as that of control mock vector-transfected cells.…”

Cancer-Associated Fibroblasts Expressing CXCL14 Rely upon NOS1-Derived Nitric Oxide Signaling for Their Tumor-Supporting Properties

“…The functional roles of CXCL14 in tumor biology have been addressed in a number of studies and indicate context-dependent pro-or antitumoral effects (1). Some studies, analyzing effects of CXCL14 overexpression in cancer cells, have reported antitumoral and antiangiogenic effects (3)(4)(5)(6). Protumoral effects of CXCL14 have been suggested based on evidence for upregulation of CXCL14 in the tumor stroma and cancer-associated fibroblasts (CAF; refs.…”

Chemokine CXCL14/BRAK transgenic mice suppress growth of carcinoma cell xenografts

“…Thus in order to investigate whether CXCL14/ BRAK has a tumor-suppressing effect in vivo, we prepared CXCL14/BRAK-expression vector-transfected and mock vector-transfected tongue tumor derived cells and cloned them. The rate of tumor formation in vivo of the former in athymic nude mice or in severe combined immunodeficiency (SCID) mice was significantly lower than that of the latter, even though no difference in the growth rates of these cells was observed under in vitro culture conditions, indicating that CXCL14/BRAK expression in tumor cells suppresses the growth of the cells in vivo (Ozawa et al 2006(Ozawa et al , 2009b.…”