PolyHEMA spheroids are an inadequate model for the drug resistance of the intractable solid tumors

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 -