Abstract
Oral tongue squamous cell carcinoma (OTSCC) has a high mortality rate and the incidence is rising worldwide. Despite advances in treatment, the disease lacks specific prognostic markers and treatment modality. The spreading of OTSCC is dependent on the tumor microenvironment and involves tumor-associated macrophages (TAMs). Although the presence of TAMs is associated with poor prognosis in OTSCC, the specific mechanisms underlying this are still unknown. The aim here was to investigate the effect of macrophages (Mfs) on HSC-3 tongue carcinoma cells and NF-kappaB activity. We polarized THP-1 cells to M1 (inflammatory), M2 (TAM-like) and R848 (imidazoquinoline-treated) type Mfs. We then investigated the effect of Mfs on HSC-3 cell migration and NF-kappaB activity, cytokine production and invasion using several different in vitro migration models, a human 3D tissue invasion model, antibody arrays, confocal microscopy, immunohistochemistry and a mouse invasion model. We found that in co-culture studies all types of Mfs fused with HSC-3 cells, a process which was partially due to efferocytosis. HSC-3 cells induced expression of epidermal growth factor and transforming growth factor-beta in co-cultures with M2 Mfs. Direct cell-cell contact between M2 Mfs and HSC-3 cells induced migration and invasion of HSC-3 cells while M1 Mfs reduced HSC-3 cell invasion. M2 Mfs had an excess of NF-kappaB p50 subunit and a lack of p65 subunits both in the presence and absence of HSC-3 cells, indicating dysregulation and pro-tumorigenic NF-kappaB activation. TAM-like cells were abundantly present in close vicinity to carcinoma cells in OTSCC patient samples. We conclude that M2 Mfs/TAMs have an important role in OTSCC regulating adhesion, migration, invasion and cytokine production of carcinoma cells favouring tumor growth. These results demonstrate that OTSCC patients could benefit from therapies targeting TAMs, polarizing TAM-like M2 Mfs to inflammatory macrophages and modulating NF-kappaB activity.
Highlights
Oral squamous cell carcinoma (OSCC) is the eight most common cancer in the world
We found that cytokines shown to be associated with OSCC and increased invasion, such as Epidermal Growth Factor (EGF), Macrophage Colony-Stimulating Factor (M-CSF), Transforming Growth Factor (TGF)-β, Tissue Inhibitor of Metalloproteinases (TIMP), Plateled-derived growth factor (PDGF)-BB and migration Inhibitory Factor (MIF) were increased upon coculture with HSC-3 and M2 Mfs, and on the other hand down-regulated in HSC-3/M1 Mfs cocultures
We here show for the first time that HSC-3 cells fuse with Mfs and especially the interaction between HSC-3 cells and M2 Mfs induced migration and invasion in the 3D myoma model
Summary
Oral squamous cell carcinoma (OSCC) is the eight most common cancer in the world. 640 000 new oral cancers are reported worldwide [1]. The World Health Organization expects a worldwide increase in incidence in the few decades. The most common site affected by OSCC is the tongue and at this site OSCC is aggressive. The 5-year survival rate for tongue cancer has remained at approximately 50% without significant improvements [2]. An alarming report showed that tongue cancer is increasing especially in young adults and none of the typical etiological factors such as tobacco, alcohol or human papilloma virus can be accounted for [3]
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