Multicellular gastric cancer spheroids recapitulate growth pattern and differentiation phenotype of human gastric carcinomas

Background & Aims: Advanced gastric cancer has a poor prognosis and is larg ely unresponsive to currently available chemotherapeutic drugs. The develop ment of more effective therapies would be aided by better preclinical model s. Methods: An in vitro multicellular gastric cancer spheroid model was est ablished using the liquid overlay technique and compared with the correspon ding xenografts in immunodeficient mice. Results: Twelve of 17 (71%) gastri c cancer cell lines reflected growth characteristics of their parental gast ric carcinomas in three-dimensional culture. Thus, cell lines derived from peritoneal and pleural carcinomatosis grew as single cells (HSC-39, KATO-II , KATO-III) and cell aggregates (SNU-5, SNU-16). Cell lines representing ad enosquamous (MKN-1) and tubular differentiation (MKN-28, MKN-74, N87) forme d partly compact multicellular spheroids recapitulating the tumor architect ure of the respective original tumor. The differentiated phenotype was lost after subcutaneous implantation of the in vitro spheroids in mice. The deg ree of morphologic differentiation was reflected by the levels of mucin and constitutive E-cadherin expression. Heterogeneous changes of other adhesio n molecules (EpCAM, alpha (2)beta (1), CD44s, Le(x), sLe(x)) were observed. In contrast, cell lines derived from poorly differentiated gastric carcino mas (Hs-746T, RF-1, RF-48) formed fully compact spheroids mimicking the poo rly differentiated phenotype, were E-cadherin negative, and showed only CD4 4s up-regulation. Conclusions: Recapitulating some complexity of their in v ivo counterparts, multicellular gastric cancer spheroids may represent a ph ysiologically valid model for studying the biology of this cancer, and test ing new therapeutic strategies.