Development and validation of in vitro methods for assaying cancer stem cell responses to therapeutic challenge

The concept of cancer stem cells (CSCs) has recently been the focus of much experimental investigation and several reports now indicate that selective survival of CSCs may be responsible for tumour recurrence after therapy. A prevailing current view is that valid information concerning CSCs can be obtained only by work with fresh tumour cells transplanted to murine hosts. With the increasing need to assay existing and new therapeutic agents for actions on CSCs, a large increase in animal use is expected unless suitable surrogate in vitro assays can be developed. We present evidence that stem cell patterns similar to those present in human tumours in situ are generally retained in malignant cell lines. In order to reduce or eliminate the use of animals in stem cell studies, we propose to investigate a wider range of cell lines, for use together with analytical techniques developed in pilot work, to develop, validate and scale up in vitro assays of CSC responses to therapeutic challenge.

Biddle A et al. (2016). Phenotypic plasticity determines cancer stem cell therapeutic resistance in oral squamous cell carcinoma. EBioMedicine. 4:138–145. doi: 10.1016/j.ebiom.2016.01.007

Gammon L and Mackenzie IC (2016). Roles of hypoxia, stem cells and epithelial-mesenchymal transition in the spread and treatment resistance of head and neck cancer. J Oral Path Med 45(2):77-82. doi: 10.1111/jop.12327

Gemenetzidis E et al. (2015). Maintenance of stem cell self-renewal in head and neck cancers requires actions of GSK3β influenced by CD44 and RHAMM. Stem Cells 6(41):43964-77. doi: 10.1002/stem.1418

Shigeishi H et al. (2015). Elevation in 5-FU-induced apoptosis in head and neck cancer stem cells by a combination of CDHP and GSK3β inhibitors. J Oral Pathol Med 44(3):201-7. doi: 10.1111/jop.12230

Vig N et al. (2015). Phenotypic plasticity and epithelial-to-mesenchymal transition in the behaviour and therapeutic response of oral squamous cell carcinoma. J Oral Pathol Med 44(9):649-55. doi: 10.1111/jop.12306

Biddle A et al. (2013). CD44 staining of cancer stem-like cells Is Influenced by down-regulation of CD44 variant Isoforms and up-regulation of the standard CD44 isoform in the population of cells that have undergone epithelial-to-mesenchymal transition. Plos One  8(2):e57314 doi: 10.1371/journal.pone.0057314

Gammon L et al. (2013). Sub-sets of cancer stem cells differ intrinsically in their patterns of oxygen metabolism. PloS One 8(4):e62493. doi: 10.1371/journal.pone.0062493

Shigeishi H et al. (2013). Maintenance of stem cell self-renewal in head and neck cancers requires actions of GSK3β influenced by CD44 and RHAMM. Stem Cells 31(10):2073-83. doi: 10.1002/stem.1418  

Biddle A and Mackenzie I (2012). Cancer stem cells and EMT in carcinoma. Cancer Metastasis Reviews 31:285–293. doi: 10.1007/s10555-012-9345-0

Biddle A et al. (2011). Cancer stem cells in squamous cell carcinoma switch between two distinct phenotypes that are preferentially migratory or proliferative. Cancer Res. 71(15):5317-26. doi: 10.1158/0008-5472

Gammon L et al. (2011). Stem cell characteristics of cell sub-populations in cell lines derived from head and neck cancers of Fanconi anemia patients. J Oral Pathol Med 40(2):143-52. doi: 10.1111/j.1600-0714.2010.00972.x

Harper LJ et al. (2010). Normal and malignant epithelial cells with stem-like properties have an extended G2 cell cycle phase that is associated with apoptotic resistance. BMC Cancer 10:166. doi: 10.1002/stem.1418

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Project grant

Status:

Closed

Principal investigator

Professor Ian MacKenzie

Institution

Queen Mary University of London

Grant reference number

G0900799/1

Award date:

Nov 2009 - Oct 2012

Grant amount

£345,086

Primary 'R'

Replacement

Scientific Discipline

Cells and systems
Cancer

Technologies/approach

Stem cells

Keywords

Cell line
Drug development