Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2012 Aug;4(8):675-84.
doi: 10.1002/emmm.201101131. Epub 2012 Jun 25.

Role of intratumoural heterogeneity in cancer drug resistance: molecular and clinical perspectives

Nicholas A Saunders  1 , Fiona Simpson, Erik W Thompson, Michelle M Hill, Liliana Endo-Munoz, Graham Leggatt, Rodney F Minchin, Alexander Guminski
Affiliations
Review

Role of intratumoural heterogeneity in cancer drug resistance: molecular and clinical perspectives

Nicholas A Saunders et al. EMBO Mol Med. 2012 Aug.

Abstract

Drug resistance continues to be a major barrier to the delivery of curative therapies in cancer. Historically, drug resistance has been associated with over-expression of drug transporters, changes in drug kinetics or amplification of drug targets. However, the emergence of resistance in patients treated with new-targeted therapies has provided new insight into the complexities underlying cancer drug resistance. Recent data now implicate intratumoural heterogeneity as a major driver of drug resistance. Single cell sequencing studies that identified multiple genetically distinct variants within human tumours clearly demonstrate the heterogeneous nature of human tumours. The major contributors to intratumoural heterogeneity are (i) genetic variation, (ii) stochastic processes, (iii) the microenvironment and (iv) cell and tissue plasticity. Each of these factors impacts on drug sensitivity. To deliver curative therapies to patients, modification of current therapeutic strategies to include methods that estimate intratumoural heterogeneity and plasticity will be essential.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Scheme depicting the basis for heterogeneity in drug responses within a tumour
The different clonal variants present within tumours are represented by the different coloured cells. Heterogeneity, within a clonal variant, due to stromal interaction is marked by * whilst heterogeneity attributable to plasticity/EMT is marked by ⁁⁁. Finally, heterogeneity in an identical clone due to stochastic variation is marked.
Figure 2
Figure 2. Model depicting the selective resistance of specific clonal variants in response to a chemotherapeutic
Clonal variants, of varying chemotherapeutic sensitivity are represented by different colours.
Figure 3
Figure 3. Model depicting the impact of stromal interactions on the sensitivity of identical clonal variants to chemotherapeutics
Identical clonal variants are shown. Those cells that interact with the stroma are marked by a star.
Figure 4
Figure 4. Model depicting impact of tumour cell plasticity on chemotherapeutic sensitivity
In this model a cell may give rise to individual tumour cells of different lineage that differ in their sensitivity to a chemotherapeutic agent.
See this image and copyright information in PMC

References

    1. Albeck JG, Burke JM, Aldridge BB, Zhang M, Lauffenburger DA, Sorger PK. Quantitative analysis of pathways controlling extrinsic apoptosis in single cells. Mol Cell. 2008;30:11–25. - PMC - PubMed
    1. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prsospective identification of tumourigenic breast cancer cells. Proc Natl Acad Sci USA. 2003;100:3983–3988. - PMC - PubMed
    1. Arumugam T, Ramachandran V, Fourneir KF, Wang H, Marquis L, Abbruzzese JL, Gallick GE, Logsdon CD, McConkey DJ, Choi W. Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res. 2009;69:5820–5828. - PMC - PubMed
    1. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444:756–760. - PubMed
    1. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3:730–737. - PubMed

Publication types

Substances