Evaluation of tyrosine receptor kinases in the interactions of head and neck squamous cell carcinoma cells and fibroblasts

Sweeny, Larissa; Zimmermann, Terence M.; Li, Yong; Rosenthal, Eben L.

doi:10.1016/j.oraloncology.2012.06.011

Cited by 18 publications

(10 citation statements)

References 32 publications

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“…Oral cancer can also develop independent of this typical progression 30,31 . In either case, the development of OSCC is accompanied by changes in intercellular signaling between tumor cells and non-tumor cells, such as fibroblasts in the tumor microenvironment leading to dysregulation of gene expression and protein products facilitating cancer progression and metastasis 8,32,33 . Understanding of the molecular mechanisms underlying OSCC progression is essential to afford the opportunity to develop novel strategies to suppress tumor progression.…”

Section: Discussionmentioning

confidence: 99%

Mechanism for oral tumor cell lysyl oxidase like-2 in cancer development: synergy with PDGF-AB

et al. 2019

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Extracellular lysyl oxidases (LOX and LOXL1–LOXL4) are critical for collagen biosynthesis. LOXL2 is a marker of poor survival in oral squamous cell cancer. We investigated mechanisms by which tumor cell secreted LOXL2 targets proximal mesenchymal cells to enhance tumor growth and metastasis. This study identified the first molecular mechanism for LOXL2 in the promotion of cancer via its enzymatic modification of a non-collagenous substrate in the context of paracrine signaling between tumor cells and resident fibroblasts. The role and mechanism of active LOXL2 in promoting oral cancer was evaluated and employed a novel LOXL2 small molecule inhibitor, PSX-S1C, administered to immunodeficient, and syngeneic immunocompetent orthotopic oral cancer mouse models. Tumor growth, histopathology, and metastases were monitored. In vitro mechanistic studies with conditioned tumor cell medium treatment of normal human oral fibroblasts were carried out in the presence and absence of the LOXL2 inhibitor to identify signaling mechanisms promoted by LOXL2 activity. Inhibition of LOXL2 attenuated cancer growth and lymph node metastases in the orthotopic tongue mouse models. Immunohistochemistry data indicated that LOXL2 expression in and around tumors was decreased in mice treated with the inhibitor. Inhibition of LOXL2 activity by administration of PXS-S1C to mice reduced tumor cell proliferation, accompanied by changes in morphology and in the expression of epithelial to mesenchymal transition markers. In vitro studies identified PDGFRβ as a direct substrate for LOXL2, and indicated that LOXL2 and PDGF-AB together secreted by tumor cells optimally activated PDGFRβ in fibroblasts to promote proliferation and the tendency toward fibrosis via ERK activation, but not AKT. Optimal fibroblast proliferation in vitro required LOXL2 activity, while tumor cell proliferation did not. Thus, tumor cell-derived LOXL2 in the microenvironment directly targets neighboring resident cells to promote a permissive local niche, in addition to its known role in collagen maturation.

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Section: Discussionmentioning

confidence: 99%

Mechanism for oral tumor cell lysyl oxidase like-2 in cancer development: synergy with PDGF-AB

et al. 2019

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“…Because other receptors targeted by the drug are not expressed at appreciable levels, the effect is assumed to be mainly mediated through VEGFR and FGFR. Sweeny et al (11) demonstrated that dovitinib yielded significant cell count reductions in their HNSCC in vitro models. Konecny et al (37) demonstrated significant cell count reductions in endometrial cancer cell lines harboring activating FGFR2 mutations, and FGFR2 was also highly expressed in all of our cell lines.…”

Section: Discussionmentioning

confidence: 99%

“…Complex relationships exist between the oncogenic stroma and its surroundings in this heterogeneous disease (11). Cells from the immune system, the tumor vasculature and lymphatic systems and cancer associated fibroblasts (CAF) can encourage tumor growth, invasion and metastasis (12,13).…”

Section: Introductionmentioning

confidence: 99%

Targeting VEGFR and FGFR in head and neck squamous cell carcinoma in vitro

et al. 2017

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Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease characterized by a tumor microenvironment (TME) that overexpresses vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR), which can lead to neovascularization, tumor growth and metastasis. Therapeutic strategies inhibiting these signaling pathways might lead to innovative HNSCC treatments. Five HNSCC cell lines were characterized based on VEGFR1-3 and FGFR1-4 expression by sqRT-PCR and treated with three different tyrosine kinase inhibitors (TKIs) (nintedanib, dovitinib and pazopanib), all of which are effective against VEGFR and FGFR family members. Crystal violet assays were performed to analyze the effect of the treatments on cell growth (viability). Additionally, VEGFR1-3 and FGFR1-4 expression data were retrieved from The Cancer Genome Atlas (TCGA), and statistical analyses were performed to investigate the receptor expression level in the different cell lines and the efficacy of the single-agent treatments. A correlation analysis was performed to quantify the degree of relationship between receptor expression and drug efficacy. With the exception of VEGFR2, the targeted receptors were expressed at different levels in all of the cell lines. The cell lines exhibited concentration-dependent responses with cell line-specific differences toward two of the three TKIs (nintedanib and dovitinib). Notably, all of the cell lines were resistant to pazopanib. TKIs have potential as therapeutic agents for HNSCC. Cell line-specific differences were observed in our in vitro experiments. The observed pazopanib resistance could be explained by receptor expression. Further investigation is required to determine TKI efficacy in HNSCC.

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“…PIP3 is converted back into PIP2 through the action of the lipid phosphatase PTEN, thus terminating the PI3K-initiated signal and avoiding further Akt activation [ 14 ]. Growth factor receptor over-expression [ 15 , 16 ], mutation and down-regulation of PTEN protein [ 17 ] and amplification of the PIK3CA gene (the gene coding for the catalytic unit of PI3K) [ 18 ] can lead to increased Akt activity. Enhanced Akt activity has indeed been found in 20 to 60% of tumor samples and in the majority of HNSCC-derived cell lines [ 18 – 21 ].…”

Section: Introductionmentioning

confidence: 99%

Activation of Akt at T308 and S473 in alcohol, tobacco and HPV-induced HNSCC: is there evidence to support a prognostic or diagnostic role?

et al. 2014

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BackgroundTobacco, alcohol and HPV infection are associated with increased risk of HNSCC. However, little is known about the underlying signaling events influencing risk. We aimed to investigate the relationship between these risk factors and Akt phosphorylation, to determine prognostic value.MethodVEGF-positive HNSCC biopsies, with known HPV status, were analyzed by immunohistochemistry (IHC) for Akt, phosphorylated at residues S473 and T308. Comparisons between the tissues were carried out using a Mann–Whitney U test. Associations between the variables and continuous immunohistochemical parameters were evaluated with general linear models. Patient characteristics and pAkt IHC score were analyzed for possible association with overall survival by Cox proportional hazard models.ResultsImmunohistochemistry revealed that cancer patients had significantly higher levels of pAkt T308 than S473 (P < 0.001). Smoking and alcohol were found to be independent risk factors for Akt phosphorylation at T308 (P = 0.022 and 0.027, respectively). Patients with tumors positive for HPV or pAkt S473 had a poorer prognosis (P = 0.005, and 0.004, respectively). Patients who were heavy drinkers were 49 times more likely to die than non-drinkers (P = 0.003). Patients with low pAkt T308 were more likely to be HPV positive (P = 0.028). Non-drinkers were also found to have lower levels of pAkt T308 and were more likely to have tumors positive for HPV than heavy drinkers (P = 0.044 and 0.007, respectively).ConclusionThis study suggests different mechanisms of carcinogenesis are initiated by smoking, alcohol and HPV. Our data propose higher phosphorylation of Akt at T308 as a reliable biomarker for smoking and alcohol induced HNSCC progression and higher phosphorylation of Akt at S473 as a prognostic factor for HNSCC.

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Evaluation of tyrosine receptor kinases in the interactions of head and neck squamous cell carcinoma cells and fibroblasts

Cited by 18 publications

References 32 publications

Mechanism for oral tumor cell lysyl oxidase like-2 in cancer development: synergy with PDGF-AB

Mechanism for oral tumor cell lysyl oxidase like-2 in cancer development: synergy with PDGF-AB

Targeting VEGFR and FGFR in head and neck squamous cell carcinoma in vitro

Activation of Akt at T308 and S473 in alcohol, tobacco and HPV-induced HNSCC: is there evidence to support a prognostic or diagnostic role?

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