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

Kenneth Steadman, Wilfred D. Stein, Thomas Litman, Sherry X. Yang, Mones Abu-Asab, Sarah K. Dutcher and Susan Bates

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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.

Authors

Kenneth Steadman

National Cancer Institute; Bethesda, MD

Wilfred D. Stein

National Cancer Institute; Bethesda, MD

Thomas Litman

Exiqon; Vedbaek, Denmark

Sherry X. Yang

National Cancer Institute; Bethesda, MD

Mones Abu-Asab

National Cancer Institute; Bethesda, MD

Sarah K. Dutcher

National Cancer Institute; Bethesda, MD

Susan Bates

National Cancer Institute; Bethesda, MD

Purchase article for $19

Subscribe to this journal for $129/year