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Reliability of tumor primary cultures as a model for drug response prediction: expression profiles comparison of tissues versus primary cultures from colorectal cancer patients

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Abstract

Purpose

Since primary tumor cells from patients have been used as a model for assessment of drug response for individual patients, this study aims to evaluate the reliability of such a model in colorectal cancer (CRC) in predicting the response of tumor tissues through comparison of their expression profiles.

Methods

Establishment of primary cultures from tissues obtained surgically from CRC patients allowed us to study the gene expression differences between normal and tumor tissues as well as primary cultures derived from the tumor mass. The tissues comparison highlights the molecular characteristics of tumors, while the comparison between primary tumor cells versus normal and tumor tissues allowed us to identify alterations associated with the establishment of culture. Genes-drug association analyses allowed us to fine-tune our expectations while using primary culture as a model for drug assessment.

Results

Comparison between tumor cultures and original tissues through functional analyses showed the deregulations caused by culture establishment. Investigating the impact of such changes in genes-drug associations to identify the potential alterations in drug response, we found that primary cultures may have increased susceptibility toward paclitaxel, but reduced susceptibility toward analogues of fluorouracil compared with original tumors.

Conclusions

Response of primary tumor cells toward different drugs is not linearly associated to tumor tissues. Our results highlight the importance to account for the discrepancy in responses between the primary tumor cells and original counterparts in order to provide clinicians with important insights to improve selection of drugs for individual patients based on in vitro assays.

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Acknowledgments

The authors show gratitude to Dashayini Mahalingam for technical assistance and proof reading. We express thanks to Chai Juin Hsien and Ru Jianghua for technical assistance. We also want to acknowledge the assistance given by Aw Yi Bing, Dr. Rajeev Singh, and Eng Chon Boon from NUH-NUS Tissue Repository, National University Hospital in supplying the fresh consented patient tissues. This work is supported by funding from the Academic Research Fund (AcRF) Tier 1 Faculty Research Committee (FRC) grant, National University of Singapore and from the grant NMRC/EDG/0058/2009, National Medical Research Council, Singapore.

Conflict of interest

There is no conflict of interest to be disclosed.

Author information

Correspondence to Xueying Wang.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Chromosome count in the respective metaphase spreads from tumor and normal cells (TC and NC) (PDF 6 kb)

Comparison of deregulated genes obtained from our microarray analyses (TT versus NT and TC versus NT) to those reported by Cardoso et al., 2007 (PDF 17 kb)

(A) Toppgene analysis of top deregulated pathways for TT versus NT. (B) Toppgene analysis of top deregulated pathways for TC versus NT. (C) Toppgene analysis of top deregulated pathways for TC versus TT (PDF 80 kb)

Assessment of tumorigenicity of primary cell cultures. (A) No colony was observed on soft agar of which primary culture cells were seeded (TC and NC). Colonies were observed on soft agar of HCT116 which is known to proliferate well without cellular matrices. (B) Average telomere length of primary culture cells (TC and NC). Legend: 1,3: Tumor; 2,4: Normal (PDF 146 kb)

(A) Top deregulation in molecular and cellular functions (IPA). (B) Top deregulation in diseases and disorders (IPA) (PDF 33 kb)

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Bellot, G.L., Tan, W.H., Tay, L.L. et al. Reliability of tumor primary cultures as a model for drug response prediction: expression profiles comparison of tissues versus primary cultures from colorectal cancer patients. J Cancer Res Clin Oncol 138, 463–482 (2012). https://doi.org/10.1007/s00432-011-1115-9

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Keywords

  • Colorectal cancer
  • Primary cultures
  • Drug assays
  • Microarray
  • Drug resistance