Macrophages Modulate Migration and Invasion of Human Tongue Squamous Cell Carcinoma

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.

Senescent fibroblast-derived Chemerin promotes squamous cell carcinoma migration

“…Even though these SASP factors, such as CCL5/RANTES [37, 38], were able to significantly stimulate cSCC cell migration (Supplementary Figure S3), they were produced at even higher levels by SCC cells themselves in an autocrine manner, as have been previously reported [39, 40]. Therefore, any significant paracrine contribution from senescent dermal fibroblasts was ruled out.…”

HLA class II expression on tumor cells and low numbers of tumor‐associated macrophages predict clinical outcome in oropharyngeal cancer

“…In addition, CD68+ TAMs, commonly identified by the expression of CD163, CD206, or CD204, also sustain the development and progression of many tumors, including oropharyngeal cancer, by suppressing the cytotoxic activity of CD8+ T cells, and promoting angiogenesis and tumor cell migration …”

“…24 In addition, CD68+ TAMs, commonly identified by the expression of CD163, CD206, or CD204, 25 also sustain the development and progression of many tumors, including oropharyngeal cancer, by suppressing the cytotoxic activity of CD8+ T cells, and promoting angiogenesis and tumor cell migration. [26][27][28] In this retrospective study, we aim to obtain a comprehensive "immune signature" of the HPV-negative and HPVpositive OPSCCs using immunohistochemistry (IHC) and immunofluorescence (IF) techniques for HLA expression, the presence of innate and adaptive immune cells and explore their correlation with clinical outcome. Ultimately, with the implementation of univariate and multivariate analysis, we aim to find independent prognostic factors for DFS and DSS of OPSCC patients.…”

Association of infiltrating cells with microvessel density in oral squamous cell carcinoma

“…Several lines of evidence indicate that immune cells in the tumor microenvironment play an important role in regulating tumor progression, which may determine the clinical parameters and prognosis [2,3,4,5,6]. Macrophages have been implicated as key contributors to the tumor-microenvironment dynamics [7].…”

“…They also play an important role in tumor cell migration and metastasis [9]. Several reports have suggested that TAMs are associated with tumor growth, disease progression, and poor prognosis in some human cancers [2,10].…”