Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy.
By Xiaoxian Li, M. Lewis, Jian Huang, C. Gutierrez, C. Osborne, Meng-Fen Wu, S. Hilsenbeck, A. Pavlick, Xiaomei Zhang, G. Chamness and 3 more. Journal of the National Cancer Institute, 2008
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BACKGROUND Tumorigenic breast cancer cells that express high levels of CD44 and low or undetectable levels of CD24 (CD44(>)/CD24(>/low)) may be resistant to chemotherapy and therefore responsible for cancer relapse. These tumorigenic cancer cells can be isolated from breast cancer biopsies and propagated as mammospheres in vitro. In this study, we aimed to test directly in human breast cancers the effect of conventional chemotherapy or lapatinib (an epidermal growth factor receptor [EGFR]/HER2 pathway inhibitor) on this tumorigenic CD44(>) and CD24(>/low) cell population. METHODS Paired breast cancer core biopsies were obtained from patients with primary breast cancer before and after 12 weeks of treatment with neoadjuvant chemotherapy (n = 31) or, for patients with HER2-positive tumors, before and after 6 weeks of treatment with the EGFR/HER2 inhibitor lapatinib (n = 21). Single-cell suspensions established from these biopsies were stained with antibodies against CD24, CD44, and lineage markers and analyzed by flow cytometry. The potential of cells from biopsy samples taken before and after treatment to form mammospheres in culture was compared. All statistical tests were two-sided. RESULTS Chemotherapy treatment increased the percentage of CD44(>)/CD24(>/low) cells (mean at baseline vs 12 weeks, 4.7%, 95% confidence interval [CI] = 3.5% to 5.9%, vs 13.6%, 95% CI = 10.9% to 16.3%; P < .001) and increased mammosphere formation efficiency (MSFE) (mean at baseline vs 12 weeks, 13.3%, 95% CI = 6.0% to 20.6%, vs 53.2%, 95% CI = 42.4% to 64.0%; P < .001). Conversely, lapatinib treatment of patients with HER2-positive tumors led to a non-statistically significant decrease in the percentage of CD44(>)/CD24(>/low) cells (mean at baseline vs 6 weeks, 10.0%, 95% CI = 7.2% to 12.8%, vs 7.5%, 95% CI = 4.1% to 10.9%) and a statistically non-significant decrease in MSFE (mean at baseline vs 6 weeks, 16.1%, 95% CI = 8.7% to 23.5%, vs 10.8%, 95% CI = 4.0% to 17.6%). CONCLUSION These studies provide clinical evidence for a subpopulation of chemotherapy-resistant breast cancer-initiating cells. Lapatinib did not lead to an increase in these tumorigenic cells, and, in combination with conventional therapy, specific pathway inhibitors may provide a therapeutic strategy for eliminating these cells to decrease recurrence and improve long-term survival.
Subfields: Cancer Research, Oncology
View Paper: https://www.semanticscholar.org/paper/53c808c2666d08be7e821898470cf3bed0baff91
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Citations in the corpus
- A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer (2009, background): “, chemoresistance observed in this study could be related to the widely held opinion that tumor stem cells and progenitors are more resistant to chemotherap”
- Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits (2009, background): “Highlighting the importance of EMT in therapeutic resistance, cancer cells with stem cell characteristics have been found to be enriched in the residual tumours remaining after standard chemotherapeutic treatment”
- Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways (2011, background): “An increase in chemoresistant CD44 + /CD24 −/low cells has been demonstrated in HER2-positive breast cancer following treatment with neoadjuvant chemotherapy”
- Evolution of the cancer stem cell model. (2014, background): “…as a number of biological properties that distinguish them from the remainder of tumor cells; not only resistance to treatment (Bao et al., 2006; Li et al., 2008; Tehran-chi et al., 2010) but also evasion of cell death (Majeti et al., 2009; Todaro et al., 2007) and dormancy (Kreso et al., 2013).”
- Cancer stem cells: current status and evolving complexities. (2012, background): “There is clinical evidence for a subpopulation of chemotherapy-resistant ‘‘CSCs’’ in a number of solid tumors including breast cancer (Li et al., 2008; Yu et al., 2007).”
- Hypoxia-Inducible Factors Regulate Tumorigenic Capacity of Glioma Stem Cells (2009, positive): “…of breast cancer in which patients undergoing treatment with cytotoxic chemotherapy experienced an increase in breast cancer stem cells in the surviving tumor, whereas the use of a targeted therapeutic against the stem cell population stabilized the cancer stem cell population (Li et al., 2008).”
- The cancer stem cell: premises, promises and challenges (2011, background): “CD44 high CD24 low breast cancer CSCs appear intrinsically resistant to conventional chemotherap”
- The Cancer Stem Cell Niche: How Essential is the Niche in Regulating Stemness of Tumor Cells? (2015, positive): “Generally, CSCs appear to be resistant to conventional cancer therapies such as ionizing radiation and conventional anti-proliferative chemotherapy due to their quiescence (Bao et al., 2006; Li et al., 2008).”
- Identification of selective inhibitors of cancer stem cells by high-throughput screening (2009, background): “CSCs are resistant to many current cancer treatments, including chemo- and radiation therapy (Bao et al., 2006; Dean et al., 2005; Diehn et al., 2009; Diehn and Clarke, 2006; Eyler and Rich, 2008; Li et al., 2008; Woodward et al., 2007).”
- Epithelial–mesenchymal plasticity in carcinoma metastasis (2013, background): “These CSCs were also found to be responsible for tumor reoccurrence and capable of establishing metastases (Phillips et al. 2006; Li et al. 2008).”