Abstract
We established the NHRI-HN1 cell line from a mouse tongue tumor induced by 4-nitroquinoline 1-oxide (4-NQO)/arecoline, with further selection for cell stemness via in vitro sphere culture, to evaluate potential immunotherapies for oral squamous cell carcinoma (OSCC) in East and Southeast Asia. In vivo and in vitro phenotypic characterization, including tumor growth, immune modulator administration, gene expression, morphology, migration, invasion, and sphere formation assays, were conducted. NHRI-HN1 cells are capable of generating orthotopic tumors in syngeneic mice. Interestingly, immune stimulation via CpG oligodeoxynucleotide (CpG-ODN) dramatically reduced the tumor growth in NHRI-HN1 cell-injected syngeneic mice. The pathways enriched in genes that were differentially expressed in NHRI-HN1 cells when compared to non-tumorigenic cells were similar to those that were identified when comparing human OSCC and non-tumorous tissues. NHRI-HN1 cells have characteristics of epithelial–mesenchymal transition (EMT), including enhanced migration and invasion. NHRI-HN1 cells showed aggressive cell growth and sphere formation. The blockage of extracellular signal-regulated kinase (ERK) activation suppressed cell migration and reduced stemness characteristics in NHRI-HN1 cells, similar to human OSCC cell lines. Our data suggest that NHRI-HN1 cells, showing tumorigenic characteristics of EMT, cancer stemness, and ERK activation, are sufficient in modeling human OSCC and also competent for use in investigating oral cancer immunotherapies.
Highlights
Oral squamous cell carcinoma (OSCC), which is a subset of head and neck squamous cell carcinoma (HNSCC), is one of the most common human malignancies [1], and its incidence has risen recently [2].Patients with oral squamous cell carcinoma (OSCC) continue to have poor prognosis, with an estimated five-year overall disease-free survival rate of ~50%, despite significant advances in conventional and combination treatments [3].Targeted cancer therapy might provide more effective treatment and it is less harmful to normal cells.Until recently, cetuximab was the only targeted therapy approved for HNSCC [4]
C57BL/6 mice with OSCC of the tongue, established through co-administration of 4-nitroquinoline 1-oxide (4-NQO) and arecoline, were sacrificed, and the tumors were carefully separated into two parts
One part was processed for histopathology and it demonstrated characteristics of well-differentiated squamous cell carcinomas with keratinization and keratin-pearl formation (Figure 1A)
Summary
Oral squamous cell carcinoma (OSCC), which is a subset of head and neck squamous cell carcinoma (HNSCC), is one of the most common human malignancies [1], and its incidence has risen recently [2].Patients with OSCC continue to have poor prognosis, with an estimated five-year overall disease-free survival rate of ~50%, despite significant advances in conventional and combination treatments [3].Targeted cancer therapy might provide more effective treatment and it is less harmful to normal cells.Until recently, cetuximab was the only targeted therapy approved for HNSCC [4]. Oral squamous cell carcinoma (OSCC), which is a subset of head and neck squamous cell carcinoma (HNSCC), is one of the most common human malignancies [1], and its incidence has risen recently [2]. Targeted cancer therapy might provide more effective treatment and it is less harmful to normal cells. Cetuximab was the only targeted therapy approved for HNSCC [4]. The FDA (Food and Drug Administration) approved the immune checkpoint programmed cell death protein 1. (PD-1) inhibitor pembrolizumab for the treatment of HNSCC, regardless of human papillomavirus expression [5]. The activation of immune response leads to better tumor control, suggesting a crucial role for immunosuppression in disease progression. The treatment might impact immune response and therapeutic outcome in unexpected ways. It is important to fully characterize immunoresponse to novel OSCC therapies in vivo
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