Fibroblast-derived 3D matrix differentially regulates the growth and drug-responsiveness of human cancer cells.
Recent studies have emphasized the importance of cellular microenvironment in modulating cell growth and signaling. In vitro, collagen matrices, Matrigel, and other synthetic support systems have been used to simulate in vivo microenvironments, and epithelial cells grown in these matrices manifest significant differences in proliferation, differentiation, response to drugs, and other parameters. However, these substrates do not closely resemble the mesenchymal microenvironment that is typically associated with advanced carcinomas in vivo, which is produced to a large extent by fibroblasts. In this study, we have evaluated the ability of a fibroblast-derived three-dimensional matrix to regulate the growth of a panel of 11 human tumor epithelial cell lines. Although proliferative and morphological responses to three-dimensional cues segregated independently, general responsiveness to the matrix correlated with the ability of matrix to influence drug responses. Fibroblast-derived three-dimensional matrix increased beta1-integrin-dependent survival of a subset of human cancer cell lines during taxol treatment, while it sensitized or minimally influenced survival of other cells. beta1-integrin-dependent changes in cell resistance to taxol did not correlate with the degree of modulation of FAK and Akt, implying that additional signaling factors are involved. Based on these results, we propose that these matrices potentially have value as in vitro drug screening platforms.
Serebriiskii
Ilya
I
Division of Basic Science/Tumor Cell Biology, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111.
Castelló-Cros
Remedios
R
Division of Basic Science/Tumor Cell Biology, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111.
Lamb
Acacia
A
Division of Basic Science/Tumor Cell Biology, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111.
Golemis
Erica A
EA
Division of Basic Science/Tumor Cell Biology, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111.
Cukierman
Edna
E
Division of Basic Science/Tumor Cell Biology, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018929:Cell Culture Techniques; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000166:cytology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D008422:Materials Testing; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D041681:NIH 3T3 Cells; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D054457:Tissue Scaffolds; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000502:physiology
D000970:Antineoplastic Agents; D019012:Integrin beta1; D016328:NF-kappa B; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt