Abstract
Most solid tumors contain a subfraction of cells with stem/progenitor cell features. Stem cells are naturally chemoresistant suggesting that chronic chemotherapeutic stress may select for cells with increased "stemness". We carried out a comprehensive molecular and functional analysis of six independently selected colorectal cancer (CRC) cell lines with acquired resistance to three different chemotherapeutic agents derived from two distinct parental cell lines. Chronic drug exposure resulted in complex alterations of stem cell markers that could be classified into three categories: 1) one cell line, HT-29/5-FU, showed increased "stemness" and WNT-signaling, 2) three cell lines showed decreased expression of stem cell markers, decreased aldehyde dehydrogenase activity, attenuated WNT-signaling and lost the capacity to form colonospheres and 3) two cell lines displayed prominent expression of ABC transporters with a heterogeneous response for stem cell markers. While WNT-signaling could be attenuated in the HT-29/5-FU cells by the WNT-signaling inhibitors ICG-001 and PKF-118, this was not accompanied by any selective growth inhibitory effect suggesting that the cytotoxic activity of these compounds is not directly linked to WNT-signaling inhibition. We conclude that classical WNT-signaling inhibitors have toxic off-target activities that need to be addressed for clinical development.
Highlights
Increasing experimental and clinical evidence indicates that tumors evolve over time which is driven by clonal heterogeneity, selection, non-genetic instability and adaptation to environmental stress like exposure to therapeutic agents [1,2,3,4,5,6,7]
Normal epithelial cells in the colon express the standard form of CD44 (CD44s) whereas adenomas, carcinomas and colorectal cancer (CRC) metastasis may express CD44 variants (CD44v) containing additional exons that are coding for insertions in the membrane-proximal extracellular region [19]
This suggests that chronic chemotherapeutic stress may provide a selective advantage to cells with a high degree of “stemness”
Summary
Increasing experimental and clinical evidence indicates that tumors evolve over time which is driven by clonal heterogeneity, selection, non-genetic instability and adaptation to environmental stress like exposure to therapeutic agents [1,2,3,4,5,6,7]. Analysis of biopsies from non-small cell lung cancer (NSCLC) patients with acquired resistance to small molecule epidermal growth factor receptor (EGFR) inhibitors displayed MET gene amplifications, epithelial to www.impactjournals.com/oncotarget mesenchymal transition (EMT) as well as a transformation from NSCLC into small cell lung cancer [13]. Exposure of colorectal cancer (CRC) cells to oxaliplatin was associated with up-regulation of VEGF ligands and receptors [14] while chronic exposure to irinotecan was accompanied by activation of EGFR- and SRC-signaling in CRC models [15]. Stem cells are naturally chemoresistant due to high expression of certain ATP-binding cassette transporters, proficient DNA repair, a slow cell cycle and activation of various signaling pathways including WNT [16]. One potential mechanism of acquired resistance to chemotherapeutic stress would be selection of cells with increased “stemness”
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