Interaction between hypoxia, AKT and HIF-1 signaling in HNSCC and NSCLC: implications for future treatment strategies.

Background: Hypoxia is a negative prognostic factor and this study investigated the relationship between hypoxia, hypoxia inducible factor 1 (HIF-1) and AKT signaling in head and neck squamous cell carcinoma (HNSCC) and non-small-cell lung cancer (NSCLC).

Results/methodology: pAKT was induced by hypoxia (0.5% O) in a part of HNSCC (3/4) and squamous (2/3) and adenocarcinoma (1/3) NSCLS lines.

Improving chemoradiation efficacy by PI3-K/AKT inhibition.

For many tumor types concurrent chemoradiation is the standard of care for locally advanced disease. Despite this intense treatment overall survival is still poor in various solid tumors. To improve outcome in these patients it is essential to develop new therapeutic strategies that enhance the efficacy of chemoradiation.

Hypoxia, metabolism, and growth factor signaling in head and neck squamous cell carcinoma: correlation between primary and xenograft tumors.

Background: Hypoxia, metabolism, and growth factor signaling are important prognostic features in most solid tumors. The purpose of this study was to determine whether head and neck squamous cell carcinoma (HNSCC) xenografts show similar biological and molecular characteristics as the primary tumor they originate from.

Methods: Eighteen HNSCC primary tumor-xenograft pairs were immunofluorescently stained for pimonidazole (hypoxia), carbonic anhydrase IX (CAIX), glucose transporter-1 (GLUT-1), monocarboxylate transporter-1 (MCT-1), monocarboxylate transporter-4 (MCT-4), epidermal growth factor receptor (EGFR), and phosphorylated protein kinase B (pAKT).

Hypoxic regulation of the PERK/ATF4/LAMP3-arm of the unfolded protein response in head and neck squamous cell carcinoma.

Background: The purpose of this study was to examine the hypoxic regulation of the PKR-like endoplasmic reticulum kinase (PERK)/activating transcription factor-4 (ATF4)/lysosome-associated membrane protein 3 (LAMP3)-arm of the unfolded protein response (UPR) in head and neck squamous cell carcinoma (HNSCC).

Methods: LAMP3 expression was determined in patient biopsies by immunohistochemistry and correlated to clinicopathological parameters. mRNA and protein expression for PERK, ATF4, and LAMP3 was evaluated after hypoxic exposure of HNSCC cell lines.

Combining radiotherapy with MEK1/2, STAT5 or STAT6 inhibition reduces survival of head and neck cancer lines.

Background: Kinases downstream of growth factor receptors have been implicated in radioresistance and are, therefore, attractive targets to improve radiotherapy outcome in head and neck squamous cell carcinoma (HNSCC) patients.

Methods: An antibody-based array was used to quantify the expression levels of multiple phospho-kinases involved in growth factor signaling in nine untreated or irradiated HNSCC lines. Radiosensitivity was assessed with clonogenic cell survival assays and correlated with the expression levels of the phospho-kinases.

111In-cetuximab-F(ab')2 SPECT imaging for quantification of accessible epidermal growth factor receptors (EGFR) in HNSCC xenografts.

Background And Purpose: Immunohistochemical epidermal growth factor receptor (EGFR) expression does not correlate with treatment response in head and neck squamous cell carcinomas (HNSCC). Aim was to apply the tracer (111)In-cetuximab-F(ab')2 for EGFR microSPECT imaging and to investigate if tracer uptake correlated with response to EGFR-inhibition by cetuximab in HNSCC xenografts. Usage of F(ab)2 fragments allows for shorter interval between tracer injection and imaging.

Dasatinib Inhibits DNA Repair after Radiotherapy Specifically in pSFK-Expressing Tumor Areas in Head and Neck Xenograft Tumors.

Src family kinases (SFKs) have been implicated in resistance to both radiation and epidermal growth factor receptor (EGFR) inhibition. Therefore, we investigated whether inhibition of SFK through dasatinib (DSB) can enhance the effect of radiotherapy in two in vivo human head and neck squamous cell carcinoma (HNSCC) models. Response to DSB and/or radiotherapy was assessed with tumor growth delay assays in two HNSCC xenograft models, SCCNij153 and SCCNij202.

Low phosphorylated AKT expression in laryngeal cancer: indications for a higher metastatic risk.

Purpose: To validate the association of phosphorylated (p)AKT with lymph node metastasis in an independent, homogeneous cohort of patients with larynx cancer.

Methods And Materials: Seventy-eight patients with laryngeal cancer were included. Epidermal growth factor receptor, pAKT, vimentin, E-cadherin, hypoxia, and blood vessels were visualized in biopsy material using immunohistochemistry.

Hypoxia regulation of phosphokinases and the prognostic value of pAKT in breast cancer.

Tumor hypoxia results in poor treatment response and is an indicator of poor outcome in cancer patients. TRIB3 is a hypoxia-upregulated protein involved in the ability of breast cancer cells to survive in hypoxic conditions. It is also involved in the prognosis of cancer patients, possibly by affecting several kinase-signaling pathways.

αB-crystallin stimulates VEGF secretion and tumor cell migration and correlates with enhanced distant metastasis in head and neck squamous cell carcinoma.

Background: αB-crystallin is able to modulate vascular endothelial growth factor (VEGF) secretion. In many solid tumors VEGF is associated with angiogenesis, metastasis formation and poor prognosis. We set out to assess whether αB-crystallin expression is correlated with worse prognosis and whether this is related to VEGF secretion and cell motility in head and neck squamous cell carcinoma (HNSCC).

Predictive value of hypoxia, proliferation and tyrosine kinase receptors for EGFR-inhibition and radiotherapy sensitivity in head and neck cancer models.

Background And Purpose: EGFR-inhibitor Cetuximab (C225) improves the efficacy of radiotherapy in only a subgroup of HNSCC patients. Identification of predictive tumor characteristics is essential to improve patient selection.

Material And Methods: Response to C225 and/or radiotherapy was assessed with tumor growth delay assays in 4 HNSCC xenograft models with varying EGFR-expression levels.

Activation of AKT by hypoxia: a potential target for hypoxic tumors of the head and neck.

Background: Only a minority of cancer patients benefits from the combination of EGFR-inhibition and radiotherapy in head and neck squamous cell carcinoma (HNSCC). A potential resistance mechanism is activation of EGFR and/or downstream pathways by stimuli in the microenvironment. The aim of this study was to find molecular targets induced by the microenvironment by determining the in vitro and in vivo expression of proteins of the EGFR-signaling network in 6 HNSCC lines.

Neural progenitor cells as models for high-throughput screens of developmental neurotoxicity: state of the science.

In vitro, high-throughput methods have been widely recommended as an approach to screen chemicals for the potential to cause developmental neurotoxicity and prioritize them for additional testing. The choice of cellular models for such an approach will have important ramifications for the accuracy, predictivity and sensitivity of the screening assays. In recent years neuroprogenitor cells from rodents and humans have become more widely available and may offer useful models having advantages over primary neuronal cultures and/or transformed cell lines.