Cisplatin induces Bmi-1 and enhances the stem cell fraction in head and neck cancer.
Recent evidence has unveiled a subpopulation of highly tumorigenic, multipotent cells capable of self-renewal in head and neck squamous cell carcinomas (HNSCCs). These unique cells, named here cancer stem cells (CSCs), proliferate slowly and might be involved in resistance to conventional chemotherapy. We have shown that CSCs are found in perivascular niches and rely on endothelial cell-secreted factors [particularly interleukin-6 (IL-6)] for their survival and self-renewal in HNSCC. Here, we hypothesized that cisplatin enhances the stem cell fraction in HNSCC. To address this hypothesis, we generated xenograft HNSCC tumors with University of Michigan-squamous cell carcinoma 22B (UM-SCC-22B) cells and observed that cisplatin treatment increased (P = .0013) the fraction of CSCs [i.e., aldehyde dehydrogenase activity high and cluster of differentiation 44 high (ALDH(high)CD44(high))]. Cisplatin promoted self-renewal and survival of CSCs in vitro, as seen by an increase in the number of orospheres in ultralow attachment plates and induction in B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) and octamer-binding transcription factor 4 expression. Cisplatin-resistant cells expressed more Bmi-1 than cisplatin-sensitive cells. IL-6 potentiated cisplatin-induced orosphere formation generated when primary human HNSCC cells were sorted for ALDH(high)CD44(high) immediately after surgery and plated onto ultralow attachment plates. IL-6-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation (indicative of stemness) was unaffected by treatment with cisplatin in UM-SCC-22B cells, whereas IL-6-induced extracellular signal-regulated kinase (ERK) phosphorylation (indicative of differentiation processes) was partially inhibited by cisplatin. Notably, cisplatin-induced Bmi-1 was inhibited by interleukin-6 receptor blockade in parental and cisplatin-resistant cells. Taken together, these results demonstrate that cisplatin enhances the fraction of CSCs and suggest a mechanism for resistance to cisplatin therapy in head and neck cancer.
Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI; Cancer Research Laboratory, University Hospital Research Center (CPE-HCPA), Universidade Federal do Rio Grande do Sul, Rio Grande do Sul, Brazil; National Institute for Translational Medicine (INCT-TM), Porto Alegre, Brazil.
Carolina
C
Nör
Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI.
Zhaocheng
Z
Zhang
Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI.
Kristy A
KA
Warner
Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI.
Lisiane
L
Bernardi
Oral Pathology Department, School of Dentistry, Universidade Federal do Rio Grande do Sul, Rio Grande do Sul, Brazil.
Fernanda
F
Visioli
Department of Oral and Maxillofacial Surgery, University of Michigan School of Dentistry, Ann Arbor, MI.
Joseph I
JI
Helman
Cancer Research Laboratory, University Hospital Research Center (CPE-HCPA), Universidade Federal do Rio Grande do Sul, Rio Grande do Sul, Brazil; National Institute for Translational Medicine (INCT-TM), Porto Alegre, Brazil; Laboratory of Molecular Neuropharmacology and Neural Tumor Biology, Institute for Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Rio Grande do Sul, Brazil.
Rafael
R
Roesler
Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI; Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI; Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, MI. Electronic address: jenor@med.umich.edu.
Jacques E
JE
Nör
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C069077:BMI1 protein, human; D063150:Polycomb Repressive Complex 1; D002945:Cisplatin