Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 Jun 22;13:274.
doi: 10.1186/1471-2164-13-274.

Defining New Criteria for Selection of Cell-Based Intestinal Models Using Publicly Available Databases

Affiliations
Free PMC article

Defining New Criteria for Selection of Cell-Based Intestinal Models Using Publicly Available Databases

Jon Christensen et al. BMC Genomics. .
Free PMC article

Abstract

Background: The criteria for choosing relevant cell lines among a vast panel of available intestinal-derived lines exhibiting a wide range of functional properties are still ill-defined. The objective of this study was, therefore, to establish objective criteria for choosing relevant cell lines to assess their appropriateness as tumor models as well as for drug absorption studies.

Results: We made use of publicly available expression signatures and cell based functional assays to delineate differences between various intestinal colon carcinoma cell lines and normal intestinal epithelium. We have compared a panel of intestinal cell lines with patient-derived normal and tumor epithelium and classified them according to traits relating to oncogenic pathway activity, epithelial-mesenchymal transition (EMT) and stemness, migratory properties, proliferative activity, transporter expression profiles and chemosensitivity. For example, SW480 represent an EMT-high, migratory phenotype and scored highest in terms of signatures associated to worse overall survival and higher risk of recurrence based on patient derived databases. On the other hand, differentiated HT29 and T84 cells showed gene expression patterns closest to tumor bulk derived cells. Regarding drug absorption, we confirmed that differentiated Caco-2 cells are the model of choice for active uptake studies in the small intestine. Regarding chemosensitivity we were unable to confirm a recently proposed association of chemo-resistance with EMT traits. However, a novel signature was identified through mining of NCI60 GI50 values that allowed to rank the panel of intestinal cell lines according to their drug responsiveness to commonly used chemotherapeutics.

Conclusions: This study presents a straightforward strategy to exploit publicly available gene expression data to guide the choice of cell-based models. While this approach does not overcome the major limitations of such models, introducing a rank order of selected features may allow selecting model cell lines that are more adapted and pertinent to the addressed biological question.

Figures

Figure 1
Figure 1
Most dominant gene expression differences between normal epithelium and all tumor-derived cell lines, and cells with epithelial versus mesenchymal properties. Principal component analysis (PCA) of genomic expression data from human colon carcinoma cell lines (black); laser-dissected tissues (red) of normal human colonocytes (LI), tumor cells (T) and small-intestinal enterocytes (SI); primary cell cultures (green, CAFs); breast cancer cell lines (grey). For each sample 2–3 three replicates were measured.
Figure 2
Figure 2
Signatures predictive for survival. Kaplan-Meier representation of overall survival and recurrence-free survival (EMT_RFS) probability over time for patients bearing colon cancers with average high (i.e. relative average expression > 0, green) or low expression (i.e. relative average expression < 0, red) of a selection of gene sets (details see Table 1).
Figure 3
Figure 3
Gain of malignant traits and loss of differentiation signature are associated with migratory properties. Migratory properties of intestinal cell lines across membrane in the absence (motility) or presence (chemotaxis) of a FCS gradient (details see “Material and Methods” section). Cell lines are ordered in dependence of rank orders of EMT and SLC_SI3 signatures as shown in Table 1.
Figure 4
Figure 4
Caco-2 cells most similar to small intestinal enterocytes with respect to expression of solute carriers. Principal component analysis (PCA) as shown in Figure 1, but carried out on data set filtered using probe sets representing solute carriers.
Figure 5
Figure 5
Drug transporter profiles of small intestinal enterocytes most similar to Caco-2 cells. Heatmap of the relative expression levels of transporters known to be relevant for oral drug absorption (Trans_BC). Tumor = laser dissected tumor cells, Normal = laser dissected colonocytes, JE, IL = laser dissected enterocytes of the jejunum or ileum, respectively, D = differentiated, U = undifferentiated, Fi = grown on filters, Fl = grown in flasks. Detailed description of samples in Additional file 5: Table S1.
Figure 6
Figure 6
Expression of EMT and HuISC gene sets do not correlate with GI50 values, but with a signature defined by mining NCI databases. Boxplots of the median correlation coefficients between –log (GI50) values and (A) expression of various gene sets in the NCI60 cell line panel or (B) rank orders according to Table 1 of the six intestinal cell lines represented in the NCI60 panel (i.e. SW620, HCT116, HCT15, COLO205, KM12, HT29). Gene sets as described in Table 1.

Similar articles

See all similar articles

Cited by 18 articles

See all "Cited by" articles

References

    1. Markowitz SD, Bertagnolli MM. Molecular origins of cancer: Molecular basis of colorectal cancer. N Engl J Med. 2009;361(25):2449–2460. doi: 10.1056/NEJMra0804588. - DOI - PMC - PubMed
    1. Gayet J, Zhou XP, Duval A, Rolland S, Hoang JM, Cottu P, Hamelin R. Extensive characterization of genetic alterations in a series of human colorectal cancer cell lines. Oncogene. 2001;20(36):5025–5032. doi: 10.1038/sj.onc.1204611. - DOI - PubMed
    1. Oliveira C, Pinto M, Duval A, Brennetot C, Domingo E, Espin E, Armengol M, Yamamoto H, Hamelin R, Seruca R. et al. BRAF mutations characterize colon but not gastric cancer with mismatch repair deficiency. Oncogene. 2003;22(57):9192–9196. doi: 10.1038/sj.onc.1207061. - DOI - PubMed
    1. Rosin-Arbesfeld R, Cliffe A, Brabletz T, Bienz M. Nuclear export of the APC tumour suppressor controls beta-catenin function in transcription. EMBO J. 2003;22(5):1101–1113. doi: 10.1093/emboj/cdg105. - DOI - PMC - PubMed
    1. van Erk MJ, Krul CA, Caldenhoven E, Stierum RH, Peters WH, Woutersen RA, van Ommen B. Expression profiling of colon cancer cell lines and colon biopsies: towards a screening system for potential cancer-preventive compounds. Eur J Cancer Prev. 2005;14(5):439–457. doi: 10.1097/01.cej.0000174781.51883.21. - DOI - PubMed

Publication types

Substances

Feedback