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

Abstract

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 poly-HEMA 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.

Evaluation of Three-Dimensional Porous Iron-Cross-Linked Alginate as a Scaffold for Cell Culture

“…On surfaces unsuitable for cell adhesion, cells aggregate into spheroids because they show only minimal adhesion to the substratum surface [16][17][18]. However, under such conditions, cells are unable to show anchorage-dependent growth [17,18]. Therefore, when a nonadhesive culture substratum is used, the size of multicellular spheroids is dependent on the number of seeded cells [18].…”

“…Two types of surface properties of the culture substratum are known to affect the development of cell spheroids, one being unfavorable and the other partially favorable for cell adhesion. On surfaces unsuitable for cell adhesion, cells aggregate into spheroids because they show only minimal adhesion to the substratum surface [16][17][18]. However, under such conditions, cells are unable to show anchorage-dependent growth [17,18].…”

Chemoresistance of Lung Cancer Cells: 2D and 3D In Vitro Models for Anticancer Drug Screening

“…So, an effective and improved drug development, drug delivery and drug testing programme are the need of hour to make significant inroads in a fight against cancer. It is important to mention that Steadman et al raised concerns about the possibility that the chemoresistance mechanisms found in spheroids may differ from the resistance found in intractable solid tumors in patients [61]. If this is the case, drugs selected by this system will be ineffective in primary tumors.…”

Multicellular Spheroid Culture Models: Applications in prostate Cancer Research and Therapeutics

“…These findings suggest that MCS formation may be dependent on tumor cell adhesion molecules and culture conditions. In addition, different MCS formation techniques may lead to different MCS phenotypes with different gene expression patterns [44]. Thus, it is essential to carefully select the most appropriate method.…”