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  • Riociguat R co localizes Golgi marker GM Fig Our


    R co-localizes Golgi marker GM130 (Fig. 5). Our metabolic pulse-chase studies carried out in the presence of CSF-1 exposed the newly synthesized CSF-1R to its ligand, which promoted its rapid degradation. While this was clearly seen in control BMDMs, the mature band of CSF-1R remained intact for the duration of the experiment in EHD1-KO BMDMs (Fig. 4B), supporting the conclusion that 35S-labeled CSF-1R did not reach the cell surface, consistent with results from flow cytometry (Fig. 3A-B) and immunofluorescence microscopy (Suppl. Fig. 3A-B) analyses. When combined with the observed reduction in total CSF-1R levels in EHD1-KO BMDMs,. It is of obvious interest to assess if the EHD1-dependent CSF-1R transport pathway we describe is also important for other RTKs or represents a more restricted Riociguat for CSF-1R. How the balance of these pathway operates and whether it is tunable during development, differentiation or functional responses of macrophage-lineage or other cells will be of great interest, especially in the context of human diseases in which inhibition of CSF-1R signalling would be desirable [3], [9], [54], [55].
    Conclusions The following are the supplementary data related to this article.
    Conflict of interest
    Author contributions
    Introduction According to recent estimates, cancers of the lip, oral cavity, pharynx, and larynx account for almost 700,000 new cases and 400,000 cancer deaths worldwide every year, thus ranking seventh in both the incidence and mortality, and fifth in the 5-year prevalence among all reported cancers [1]. Despite advances in treatment, prevention, and disease biology understanding, prognosis in patients with oral cavity or pharynx cancer remains dismal. Although 5-year overall survival is about 84% in localized stages, it decreases to 64% and 39% in advanced setting with regional and distant spread, respectively [2]. The microenvironment of solid tumors has been increasingly regarded as a new therapeutic target. The immune cells, including macrophages, represent a major component of tumor microenvironment, that constitute a link between the innate and adaptative responses [3]. Macrophages can be classified into two subgroups: M1 phenotype, which is considered proinflammatory and antitumoral; as opposed to M2 phenotype, possessing immunosuppressive and protumoral effects [4], [5], [6]. Under physiological conditions or induced by interferon-γ lipopolysaccharides (LPS) and tumor necrosis factor α (TNFα), macrophages are polarized into M1 macrophages. The M1 macrophages produce high levels of interleukin (IL)- 1β, IL-6, CXC ligand 10 (CXCL10), TNFα and inducible nitric oxide synthase (iNOS) and human leukocyte antigen (HLA)-DR that have antitumoral effects (Fig. 1). On the opposite way, tumor cells via several pathways Riociguat (CCL-2, IL6, CSF-1, PD-1/PD-L1, CD47/SIRPα) activate or switch macrophages to M2 phenotype (Fig. 2). The M2 macrophages express high levels of IL-10, IL-4 tumor growth factor β (TGFβ), CC ligands, vascular endothelial growth factors (VEGFs) and matrix metalloproteinases (MMPs) to directly or indirectly increase local inflammation, promote tumor progression and metastasis, and induce treatment resistance. Tumor-promoting function of macrophages is related to their capacity of secreting proangiogenic and growth factors and suppressing T-cell effector function by releasing immunosuppressive cytokines and by affecting their metabolism [7], [8], [9], [10]. However, given a continuum between the M1 and M2 subtypes, the macrophages demonstrate certain plasticity. Tumor-associated macrophages (TAMs) are defined as macrophages located in, or at the close vicinity of the tumor. TAMs are primarily showing characteristics and functions related to M2 protumoral macrophages [11], [12]. Several recent preclinical studies demonstrated the protumoral functions of TAMs. In solid tumors (pancreatic, breast, ovarian, gastric, bladder, ovarian and thyroid cancers), the presence of TAMs correlates with poor outcome [13], [14], [15]. The relevance of TAMs in solid tumor was well described for some type of cancer, particularly for breast cancers [16]. This observation was also reported in oral squamous cell carcinoma (OSCC) but to a lesser extent in other head and neck cancer subsites [17], [18]. Therefore, further improvement of our knowledge of TAMs in head and neck cancer is necessary for an effective development of novel anticancer strategies.