Skip to main content
SpringerLink
Log in

Identification of three gene candidates for multicellular resistance in colon carcinoma

  • Published:
Cytotechnology Aims and scope Submit manuscript

Abstract

Solid tumours display elevated resistance to chemo- and radiotherapies compared to individual tumour derived cells. This so-called multicellular resistance (MCR) phenomenon can only be partly explained by reduced diffusion and altered cell cycle status; even fast growing cells on the surface of solid tumours display MCR. Multicellular spheroids (MCS) recapture this phenomenon ex vivo and here we compare gene expression in exponentially growing MCS with gene expression in monolayer culture. Using an 18,664 gene microarray, we identified 42 differentially expressed genes and three of these genes can be linked to potential mechanisms of MCR. A group of interferon response genes were also up-regulated in MCS, as were a number of genes that that are indicative of greater differentiation in three-dimensional cultures.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

3D:

Three-dimensional

5FU:

5-Fluorouracil

MCR:

Multicellular resistance

MCS:

Multicellular spheroid

References

  • I. Arany S.H. Chen J.K. Megyesi K. Adler-Storthz Z. Chen S. Rajaraman I.A. Ember S.K. Tyring M.M. Brysk (2003) ArticleTitleDifferentiation-dependent expression of signal transducers and activators of transcription (STATs) might modify responses to growth factors in the cancers of the head and neck Cancer Lett. 199 IssueID1 83–89 Occurrence Handle10.1016/S0304-3835(03)00345-8 Occurrence Handle12963127

    Article  PubMed  Google Scholar 

  • A.S. Baldwin (2001) ArticleTitleControl of oncogenesis and cancer therapy resistance by the transcription factor NF-kappa B J. Clin. Invest. 107 IssueID3 241–246 Occurrence Handle11160144

    PubMed  Google Scholar 

  • D. Courilleau E. Chastre M. Sabbah G. Redeuilh A. Atfi J. Mester (2000) ArticleTitleB-ind1, a novel mediator of Rac1 signaling cloned from sodium butyrate-treated fibroblasts J. Biol. Chem. 275 IssueID23 17344–17348 Occurrence Handle10.1074/jbc.M000887200 Occurrence Handle10747961

    Article  PubMed  Google Scholar 

  • K.M. Debatin (2004) ArticleTitleApoptosis pathways in cancer and cancer therapy Cancer Immunol. Immunother 53 IssueID3 153–159 Occurrence Handle10.1007/s00262-003-0474-8 Occurrence Handle14749900

    Article  PubMed  Google Scholar 

  • B. Desoize J. Jardillier (2000) ArticleTitleMulticellular resistance: a paradigm for clinical resistance? Crit. Rev. Oncol. Hematol. 36 IssueID2-3 193–207 Occurrence Handle11033306

    PubMed  Google Scholar 

  • C. Dubessy J.M. Merlin C. Marchal F. Guillemin (2000) ArticleTitleSpheroids in radiobiology and photodynamic therapy Crit. Rev. Oncol. Hematol. 36 IssueID2-3 179–192 Occurrence Handle11033305

    PubMed  Google Scholar 

  • K. Flatmark K. Pedersen J. Nesland H. Rasmussen G. Aamodt S. Mikalsen K. Bjornland O. Fodstad G. Maelandsmo (2003) ArticleTitleNuclear localization of the metastasis-related protein s100a4 correlates with tumour stage in colorectal cancer J. Pathol. 200 IssueID5 589–595 Occurrence Handle10.1002/path.1381 Occurrence Handle12898594

    Article  PubMed  Google Scholar 

  • G. Fracasso M. Colombatti (2000) ArticleTitleEffect of therapeutic macromolecules in spheroids Crit. Rev. Oncol. Hematol. 36 IssueID2-3 159–178 Occurrence Handle11033304

    PubMed  Google Scholar 

  • G. Hamilton (1998) ArticleTitleMulticellular spheroids as an in vitro tumor model Cancer Lett. 131 29–34 Occurrence Handle10.1016/S0304-3835(98)00198-0 Occurrence Handle9839617

    Article  PubMed  Google Scholar 

  • J. Huang L. Teng T. Liu L. Li D. Chen F. Li L.G. Xu Z. Zhai H.B. Shu (2003) ArticleTitleIdentification of a novel serine/threonine kinase that inhibits TNF-induced NF-kappaB activation and p53-induced transcription Biochem. Biophys. Res. Commun. 309 IssueID4 774–778 Occurrence Handle10.1016/j.bbrc.2003.08.069 Occurrence Handle13679039

    Article  PubMed  Google Scholar 

  • B.J. Hwang J.M. Ford P.C. Hanawalt G. Chu (1999) ArticleTitleExpression of the p48 xeroderma pigmentosum gene is p53-dependent and is involved in global genomic repair Proc. Natl. Acad. Sci. USA 96 IssueID2 424–428 Occurrence Handle10.1073/pnas.96.2.424 Occurrence Handle9892649

    Article  PubMed  Google Scholar 

  • J.M. Kelm N.E. Timmins C.J. Brown M. Fussenegger L.K. Nielsen (2003) ArticleTitleMethod for generation of homogeneous multicellular tumor spheroids applicable to a wide variety of cell types Biotechnol. Bioeng. 83 IssueID2 173–180 Occurrence Handle10.1002/bit.10655 Occurrence Handle12768623

    Article  PubMed  Google Scholar 

  • H.J. Knowles R.M. Phillips (2001) ArticleTitleIdentification of differentially expressed genes in experimental models of the tumor microenvironment using differential display Anticancer Res. 21 IssueID4A 2305–2311 Occurrence Handle11724287

    PubMed  Google Scholar 

  • L. Kunz-Schughart W. Mueller-Klieser (2000) Three-dimensional culture J. Masters (Eds) Animal Cell Culture: A Practical Approach. EditionNumber3 Oxford University Press New York 123–184

    Google Scholar 

  • L.A. Kunz-Schughart M. Kreutz R. Knuechel (1998) ArticleTitleMulticellular spheroids: a three-dimensional in vitro culture system to study tumour biology Int. J. Exp. Pathol. 79 IssueID1 1–23 Occurrence Handle10.1046/j.1365-2613.1998.00051.x Occurrence Handle9614346

    Article  PubMed  Google Scholar 

  • J.A. Lazareff R. Suwinski R. De Rosa C.E. Olmstead (1999) ArticleTitleTumor volume and growth kinetics in hypothalamic-chiasmatic pediatric low grade gliomas Pediatr. Neurosurg. 30 IssueID6 312–319 Occurrence Handle10.1159/000028817 Occurrence Handle10494058

    Article  PubMed  Google Scholar 

  • K. Luker C. Pica R. Schreiber D. Piwnica-Worms (2001) ArticleTitleOverexpression of irf9 confers resistance to antimicrotubule agents in breast cancer cells Cancer Res. 61 IssueID17 6540–6547 Occurrence Handle11522652

    PubMed  Google Scholar 

  • M. Marusic Z. Bajzer Vuk-Pavlovic J. Freyer (1994) ArticleTitleTumour growth in vivoas multicellular spheroids compared by mathematical models Bull. Math. Biol. 56 617–631 Occurrence Handle10.1016/S0092-8240(05)80306-4 Occurrence Handle8054889

    Article  PubMed  Google Scholar 

  • M.W. Mayo A.S. Baldwin (2000) ArticleTitleThe transcription factor NF-kappaB: control of oncogenesis and cancer therapy resistance Biochim. Biophys. Acta 1470 IssueID2 M55–62 Occurrence Handle10722927

    PubMed  Google Scholar 

  • M. Moriyama-Kita Y. Endo Y. Yonemura C. Heizmann B. Schafer T. Sasaki E. Yamamoto (2004) ArticleTitleCorrelation of s100a4 expression with invasion and metastasis in oral squamous cell carcinoma Oral Oncol. 40 IssueID5 496–500 Occurrence Handle10.1016/j.oraloncology.2003.10.003 Occurrence Handle15006621

    Article  PubMed  Google Scholar 

  • W. Mueller-Klieser (1997) ArticleTitleThree-dimensional cell cultures: from molecular mechanisms to clinical applications Am. J. Physiol. 273 IssueID4 Pt 1 C1109–1123 Occurrence Handle9357753

    PubMed  Google Scholar 

  • T. Nederman P. Twentyman (1984) ArticleTitleSpheroids for studies of drug effects Recent Results Cancer Res. 95 84–102 Occurrence Handle6396762

    PubMed  Google Scholar 

  • P.L. Olive R.E. Durand (1994) ArticleTitleDrug and radiation resistance in spheroids: cell contact and kinetics Cancer Metastasis Rev. 13 IssueID2 121–138 Occurrence Handle10.1007/BF00689632 Occurrence Handle7923546

    Article  PubMed  Google Scholar 

  • P.L. Olive J.P. Banath H.H. Evans (1993) ArticleTitleCell killing and DNA damage by etoposide in Chinese hamster V79 monolayers and spheroids: influence of growth kinetics, growth environment and DNA packaging Br. J. Cancer 67 IssueID3 522–530 Occurrence Handle8382510

    PubMed  Google Scholar 

  • A. Oloumi S.H. MacPhail P.J. Johnston J.P. Banath P.L. Olive (2000) ArticleTitleChanges in subcellular distribution of topoisomerase IIalpha correlate with etoposide resistance in multicell spheroids and xenograft tumors Cancer Res. 60 IssueID20 5747–5753 Occurrence Handle11059769

    PubMed  Google Scholar 

  • A. Oloumi W. Lam J.P. Banath P.L. Olive (2002) ArticleTitleIdentification of genes differentially expressed in v79 cells grown as multicell spheroids Int. J. Radiation Biol. 78 IssueID6 483–492 Occurrence Handle10.1080/09553000210122299

    Article  Google Scholar 

  • C.M. Perou S.S. Jeffrey M. Rijn Particlevan de C.A. Rees M.B. Eisen D.T. Ross A. Pergamenschikov C.F. Williams S.X. Zhu J.C. Lee D. Lashkari D. Shalon P.O. Brown D. Botstein (1999) ArticleTitleDistinctive gene expression patterns in human mammary epithelial cells and breast cancers Proc. Natl. Acad. Sci. USA 96 IssueID16 9212–9217 Occurrence Handle10.1073/pnas.96.16.9212 Occurrence Handle10430922

    Article  PubMed  Google Scholar 

  • J. Poland P. Sinha A. Siegert M. Schnolzer U. Korf S. Hauptmann (2002) ArticleTitleComparison of protein expression profiles between monolayer and spheroid cell culture of ht-29 cells revealed fragmentation of ck18 in three-dimensional cell culture Electrophoresis 23 IssueID78 1174–1184 Occurrence Handle10.1002/1522-2683(200204)23:7/8<1174::AID-ELPS1174>3.0.CO;2-O Occurrence Handle11981867

    Article  PubMed  Google Scholar 

  • G. Rainaldi A. Calcabrini G. Arancia M.T. Santini (1999) ArticleTitleDifferential expression of adhesion molecules (CD44, ICAM-1 and LFA-3) in cancer cells grown in monolayer or as multicellular spheroids Anticancer Res. 19 IssueID3A 1769–1778 Occurrence Handle10470114

    PubMed  Google Scholar 

  • C. Ramakers J.M. Ruijter R.H. Deprez A.F. Moorman (2003) ArticleTitleAssumptionfree analysis of quantitative real-time polymerase chain reaction (PCR) data Neurosci. Lett. 339 IssueID1 62–66 Occurrence Handle10.1016/S0304-3940(02)01423-4 Occurrence Handle12618301

    Article  PubMed  Google Scholar 

  • C. Rosty T. Ueki P. Argani M. Jansen C. Yeo J. Cameron R. Hruban M. Goggins (2002) ArticleTitleOverexpression of S100A4 in pancreatic ductal adenocarcinomas is associated with poor differentiation and dna hypomethylation Am. J. Pathol. 160 IssueID1 45–50 Occurrence Handle11786397

    PubMed  Google Scholar 

  • A. Shiras A. Bhosale A. Patekar V. Shepal P. Shastry (2002) ArticleTitleDifferential expression of CD44(S) and variant isoforms v3, v10 in three-dimensional cultures of mouse melanoma cell lines Clin. Exp. Metastasis 19 IssueID5 445–455 Occurrence Handle10.1023/A:1016305611858 Occurrence Handle12198773

    Article  PubMed  Google Scholar 

  • R. Sutherland (1988) ArticleTitleCell and environment interactions in tumor microregions: the multicell spheroids model Science 240 177–184 Occurrence Handle2451290

    PubMed  Google Scholar 

  • M. Wartenberg C. Frey H. Diedershagen J. Ritgen J. Hescheler H. Sauer (1998) ArticleTitleDevelopment of an intrinsic P-glycoprotein-mediated doxorubicin resistance in quiescent cell layers of largemulticellular prostate tumor spheroids Int. J. Cancer 75 IssueID6 855–863 Occurrence Handle10.1002/(SICI)1097-0215(19980316)75:6<855::AID-IJC7>3.0.CO;2-U Occurrence Handle9506530

    Article  PubMed  Google Scholar 

  • V.M. Weaver S. Lelievre J.N. Lakins M.A. Chrenek J.C. Jones F. Giancotti Z. Werb M.J. Bissell (2002) ArticleTitleBeta4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium Cancer Cell 2 IssueID3 205–216 Occurrence Handle10.1016/S1535-6108(02)00125-3 Occurrence Handle12242153

    Article  PubMed  Google Scholar 

  • M. Wu L.G. Xu Z. Zhai H.B. Shu (2003) ArticleTitleSINK is a p65-interacting negative regulator of NF-kappaB-dependent transcription J. Biol. Chem. 278 IssueID29 27072–27079 Occurrence Handle10.1074/jbc.M209814200 Occurrence Handle12736262

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory for Biological Engineering, Department of Chemical Engineering, University of Queensland, Brisbane, QLD, Australia

    Nicholas E. Timmins & Lars K. Nielsen

  2. The Institute for Molecular Biosciences, The University of Queensland, Brisbane, QLD, 4072, Australia

    Tina L. Maguire & Sean M. Grimmond

Authors
  1. Nicholas E. Timmins
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tina L. Maguire
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sean M. Grimmond
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lars K. Nielsen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lars K. Nielsen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Timmins, N.E., Maguire, T.L., Grimmond, S.M. et al. Identification of three gene candidates for multicellular resistance in colon carcinoma. Cytotechnology 46, 9–18 (2004). https://doi.org/10.1007/s10616-005-1476-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10616-005-1476-5

Keywords

Search

Navigation