mTOR, metabolism, and the immune response in HPV‐positive head and neck squamous cell cancer

Coppock, Joseph D.; Lee, John H.

doi:10.1016/j.wjorl.2016.05.010

Cited by 15 publications

(13 citation statements)

References 63 publications

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“…Many of the previous findings of tumor-induced neuroinflammation were obtained in model systems that are highly cachectic (Braun et al, 2011; Norden et al, 2015; Ropelle et al, 2007). Despite the lack of cachexia our HPV+ tumor model has a highly inflammatory nature, which aligns with the highly metabolic profile of the HPV+ tumor (Coppock and Lee, 2016; Coppock et al, 2016), in agreement with what is observed in HPV-related head and neck cancer (Krupar et al, 2014). A final advantage of our current model system is that the tumor responds to a regimen of cisplatin-based chemoradiation that is similar to the treatment regimen employed in patient populations.…”

Section: Discussionsupporting

confidence: 87%

Neuroimmune mechanisms of behavioral alterations in a syngeneic murine model of human papilloma virus-related head and neck cancer

Vichaya

Vermeer

Christian

et al. 2017

Psychoneuroendocrinology

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Patients with cancer often experience a high symptom burden prior to the start of treatment. As disease and treatment-related neurotoxicities appear to be additive, targeting disease related symptoms may attenuate overall symptom burden for cancer patients and improve the tolerability of treatment. It has been hypothesized that disease-related symptoms are a consequence of tumor-induced inflammation. We tested this hypothesis using a syngeneic heterotopic murine model of human papilloma virus (HPV)-related head and neck cancer. This model has the advantage of being mildly aggressive and not causing cachexia and weight loss. We previously showed that this tumor leads to increased IL-6, IL-1β, and TNF-α expression in the liver and increased IL-1β expression in the brain. The current study confirmed these features and demonstrated that the tumor itself exhibits high inflammatory cytokine expression (e.g., IL-6, IL-1β, and TNF-α) compared to healthy tissue. While there is a clear relationship between cytokine levels and behavioral deficits in this model, the behavioral changes are surprisingly mild. Therefore, we sought to confirm the relationship between behavior and inflammation by amplifying the effect using a low dose of lipopolysaccharide (LPS, 0.1 mg/kg). In tumor-bearing mice LPS induced deficits in nest building, tail suspension, and locomotor activity approximately 24h after LPS. However, these mice did not display an exacerbation of LPS-induced weight loss, anorexia, or anhedonia. Further, while heightened serum IL-6 was observed there was minimal priming of liver or brain cytokine expression. Next we sought to inhibit tumor-induced burrowing deficits by reducing inflammation using minocycline. Minocycline (~50 mg/kg/day in drinking water) was able to attenuate tumor-induced inflammation and burrowing deficits. These data provide evidence in favor of an inflammatory-like mechanism for the behavioral alterations associated with tumor growth in a syngeneic murine model of HPV-related head and neck cancer. However, the inflammatory state and behavioral changes induced by this tumor clearly differ from other forms of inflammation-induced sickness behavior.

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Section: Discussionsupporting

confidence: 87%

Neuroimmune mechanisms of behavioral alterations in a syngeneic murine model of human papilloma virus-related head and neck cancer

Vichaya

Vermeer

Christian

et al. 2017

Psychoneuroendocrinology

Self Cite

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“…In addition, HPV-related OPSCC patients with high raptor and rictor expression tended to have a worse prognosis than those with low or medium expression. Although there have been a number of reports describing mTOR activation in head and neck cancer (7,24,26,27,32), little is known about its role in HPV-related OPSCC (23,25,28,29). This is the first report to reveal the overexpression of raptor and rictor in HPV-related OPSCC.…”

Section: Survival Estimation In Relation To Raptor and Rictor Expressionmentioning

confidence: 75%

“…Of the many signaling pathways related to tumor growth, the phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling pathway is frequently activated in cervical cancer and HPV-related head and neck squamous cell carcinoma (HNSCC) (23)(24)(25)(26)(27)(28)(29)(30). The administration of rapamycin alone significantly prolonged survival in an HPV-positive HNSCC murine model (28).…”

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confidence: 99%

Raptor and rictor expression in patients with human papillomavirus-related oropharyngeal squamous cell carcinoma

Kondo

Hirakawa

Ikegami

et al. 2020

Preprint

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Background Despite reports of a link between human papillomavirus (HPV) infection and mechanistic target of rapamycin (mTOR) signaling activation, the role of the mTOR pathway, especially raptor and rictor, in HPV-related head and neck cancer is still unclear. The aim of the present study was to elucidate the role of the mTOR pathway in HPV-related oropharyngeal squamous cell carcinoma (OPSCC). Methods The present study involved two strategies. The first was to investigate the activity of mTOR and mTOR-related complexes in high-risk HPV-positive (UM-SCC47 and CaSki) and HPV-negative (SCC-4 and SAS) cancer cell lines. The second was to elucidate mTOR complex expression in 80 oropharyngeal cancer tissues and to examine the relationship between mTOR complex expression and survival in patients with OPSCC. Results The UM-SCC47 and CaSki cell lines showed high gene and protein expression of raptor. They also exhibited G1/S and G2/M phase cell cycle arrest following 24 h incubation with 6 μM temsirolimus, a rapamycin analog, and temsirolimus administration inhibited their growth. HPV-related OPSCC samples showed high gene expression of raptor and rictor compared with HPV-unrelated OPSCC. In addition, HPV-related OPSCC patients with high raptor and rictor expression tended to have a worse prognosis than those with low or medium expression. Conclusions These results suggest that raptor has an important role in HPV-related OPSCC and that temsirolimus is a potential therapeutic agent for patients with HPV-related OPSCC. This is the first report to reveal overexpression of raptor and rictor in HPV-related OPSCC.

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“…Glucose is the main energy source for tumor cells and GLUT-1 is a key transporter of extracellular glucose [6,7,29]. GLUT-1 is overexpressed in many cancers, including laryngeal carcinoma, and is associated with their metastasis, drug resistance, and prognosis [6,7,[30][31][32][33][34][35][36].…”

Section: Discussionmentioning

confidence: 99%

Effect of Inhibition of GLUT1 Expression and Autophagy Modulation on the Growth and Migration of Laryngeal Carcinoma Stem Cells under Hypoxic and Low-Glucose Conditions

Chen

Liu

Zhong

et al. 2020

Preprint

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Background: Enhanced glucose uptake and autophagy are means by which cells adapt to stressful microenvironments. We investigated the roles of glucose transporter-1 (GLUT-1) and autophagy in laryngeal carcinoma stem cells under hypoxic and low-glucose conditions.Methods: CD133+ Tu212 laryngeal carcinoma stem cells were purified by magnetic-activated cell sorting and subjected to hypoxic and/or low-glucose conditions. Proliferation was evaluated using a cell-counting kit and a clone-formation assay, and migration was evaluated through a Transwell assay. Autophagy was assessed via transmission electron microscopy. GLUT-1 and beclin-1 expression were silenced using an shRNA and autophagy was manipulated using rapamycin, 3-MA, or chloroquine. Gene expression levels were evaluated by quantitative reverse transcription-polymerase chain reaction and protein concentrations were assessing via Western blotting.Results: Compared to CD133– stem cells, CD133+ cells showed increased proliferation and migration, and reduced apoptosis, under hypoxic or low-glucose conditions. They also showed increased expression of GLUT-1 and autophagy markers. Finally, GLUT-1 knockdown or autophagy inhibition reduced their proliferation and migration.Conclusions: Enhanced glucose uptake and autophagy maintain the functions of CD133+ laryngeal carcinoma stem cells under hypoxic and low-glucose conditions.

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mTOR, metabolism, and the immune response in HPV‐positive head and neck squamous cell cancer

Cited by 15 publications

References 63 publications

Neuroimmune mechanisms of behavioral alterations in a syngeneic murine model of human papilloma virus-related head and neck cancer

Neuroimmune mechanisms of behavioral alterations in a syngeneic murine model of human papilloma virus-related head and neck cancer

Raptor and rictor expression in patients with human papillomavirus-related oropharyngeal squamous cell carcinoma

Effect of Inhibition of GLUT1 Expression and Autophagy Modulation on the Growth and Migration of Laryngeal Carcinoma Stem Cells under Hypoxic and Low-Glucose Conditions

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