TY - JOUR
T1 - PolyHEMA spheroids are an inadequate model for the drug resistance of the intractable solid tumors
AU - Steadman, Kenneth
AU - Stein, Wilfred D.
AU - Litman, Thomas
AU - Yang, Sherry X.
AU - Abu-Asab, Mones
AU - Dutcher, Sarah K.
AU - Bates, Susan
PY - 2008
Y1 - 2008
N2 - Cancers arising in pancreas, lung, liver and stomach are difficult to treat successfully. Wanting to understand the basis for such intractability, we previously performed comparative analyses of publicly available gene expression data from tumor biopsies. Expression of many cell adhesion genes correlated significantly with intractability of cancers, our surrogate of intractability being the SEER five-year survivals of patients with disseminated tumors. To model resistance mediated by cell adhesion, we evaluated HCT 116 cells grown in two modes differing in cell adhesion status: (i)as monolayers attached to plastic culture dishes, (ii) cells attached to one another in spheroids. We determined gene expression profiles of cells grown in these two modes, for three or six days, using the human genome U133A microarray (Affymetrix, Inc.). There was a striking overlap between (a) the genes expressed differentially between early monolayers and early spheroids and (b) those expressed differentially between early and confluent monolayers. However, there was no similarity between these overlaps and the genes that were differentially expressed in intractable, as opposed to more tractable, tumors. We hypothesize that the cytotoxicity resistance for polyHEMA spheroids and for confluent cells have a similar basis, one that differs from the resistance found in intractable solid tumors in patients. Cytotoxicity, cell cycle and immunohistochemistry assays on early and on confluent monolayers, and on spheroids, showed similarities between these latter two conditions. We conclude that while spheroids (and confluent monolayer cells) show drug resistance, the mechanisms underlying this resistance diverge from those conferring resistance to intractable cancers.
AB - Cancers arising in pancreas, lung, liver and stomach are difficult to treat successfully. Wanting to understand the basis for such intractability, we previously performed comparative analyses of publicly available gene expression data from tumor biopsies. Expression of many cell adhesion genes correlated significantly with intractability of cancers, our surrogate of intractability being the SEER five-year survivals of patients with disseminated tumors. To model resistance mediated by cell adhesion, we evaluated HCT 116 cells grown in two modes differing in cell adhesion status: (i)as monolayers attached to plastic culture dishes, (ii) cells attached to one another in spheroids. We determined gene expression profiles of cells grown in these two modes, for three or six days, using the human genome U133A microarray (Affymetrix, Inc.). There was a striking overlap between (a) the genes expressed differentially between early monolayers and early spheroids and (b) those expressed differentially between early and confluent monolayers. However, there was no similarity between these overlaps and the genes that were differentially expressed in intractable, as opposed to more tractable, tumors. We hypothesize that the cytotoxicity resistance for polyHEMA spheroids and for confluent cells have a similar basis, one that differs from the resistance found in intractable solid tumors in patients. Cytotoxicity, cell cycle and immunohistochemistry assays on early and on confluent monolayers, and on spheroids, showed similarities between these latter two conditions. We conclude that while spheroids (and confluent monolayer cells) show drug resistance, the mechanisms underlying this resistance diverge from those conferring resistance to intractable cancers.
KW - Antineoplastic Agents
KW - Cell Adhesion
KW - Cell Line, Tumor
KW - Drug Resistance, Neoplasm
KW - Gene Expression Profiling
KW - Gene Expression Regulation, Neoplastic
KW - Humans
KW - Immunoblotting
KW - Immunohistochemistry
KW - In Situ Nick-End Labeling
KW - Microscopy, Electron, Transmission
KW - Neoplasms
KW - Oligonucleotide Array Sequence Analysis
KW - Polyhydroxyethyl Methacrylate
KW - Spheroids, Cellular
KW - Tumor Cells, Cultured
U2 - 10.4161/cc.7.6.5597
DO - 10.4161/cc.7.6.5597
M3 - Journal article
C2 - 18239467
SN - 1538-4101
VL - 7
SP - 818
EP - 829
JO - Cell Cycle
JF - Cell Cycle
IS - 6
ER -
