Loss of TGF-β signaling and PTEN promotes head and neck squamous cell carcinoma through cellular senescence evasion and cancer-related inflammation

Bian, Yansong; Hall, Bradford; Sun, Zhi‐Jun; Molinolo, Alfredo A.; Chen, W; Gutkind, J. Silvio; Cv, Waes; Ab, Kulkarni

doi:10.1038/onc.2011.494

Cited by 148 publications

(195 citation statements)

References 51 publications

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“…21 By combining deletion of important tumor suppressors, Pten and Tgfbr1, we constructed a spontaneous immune competent HNSCC mouse model (HPV-). 22 In tumor bearing mice, significant increases in CD11b…”

Section: Cd8mentioning

confidence: 99%

CTLA4 blockade reduces immature myeloid cells in head and neck squamous cell carcinoma

Zhao

et al. 2016

OncoImmunology

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Immature myeloid cells such as myeloid-derived suppressor cells (MDSCs) and M2 macrophages play a vital role in the tumor immune escape and tumor progression. Cytotoxic T lymphocyte-associated antigen 4 (CTLA4), as a negative immune checkpoint, is highly expressed in numerous solid tumors. However, precise functions of CTLA4 in head and neck squamous cell carcinoma (HNSCC) have not yet been elucidated. In this study, we demonstrated that the ratio of CD8 C /CTLA4 can be used as a potential index with a clinical prognostic value for HNSCC. Using immunocompetent transgenic mouse model with spontaneous HNSCC, we directly observed that targeting CTLA4 decreases MDSCs and M2 macrophages and promotes T cell activation in both tumor microenvironment and macro-environment. In all, our study provides direct evidence in vivo and proposes a rationale for CTLA4 inhibition as a future therapeutic strategy in patients with HNSCC.

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Section: Cd8mentioning

confidence: 99%

CTLA4 blockade reduces immature myeloid cells in head and neck squamous cell carcinoma

Zhao

et al. 2016

OncoImmunology

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“…26 Pten deletion in the mice head and neck epithelia give rise to the activation of PI3K/Akt pathway, and loss of Tgfbr1 in the head and neck epithelia enhances paracrine effect of TGF-b on the tumor stroma. 27 Meanwhile, conditional deletion of Pten and Tgfbr1 (2cKO) in head and neck epithelia could result in SCC in mice with complete penetrance and immunocompetent. 27 Given the multiple molecular alternation and pathology of the 2cKO mice tumor resembling human HNSCC, the 2cKO mouse model is suitable for studying the development of cancer and strategies for prevention of HNSCC, especially for immunotherapy.…”

Section: Lag-3 Expression Is Significantly Upregulated In Tgfbr1/ Ptementioning

confidence: 99%

“…27 Meanwhile, conditional deletion of Pten and Tgfbr1 (2cKO) in head and neck epithelia could result in SCC in mice with complete penetrance and immunocompetent. 27 Given the multiple molecular alternation and pathology of the 2cKO mice tumor resembling human HNSCC, the 2cKO mouse model is suitable for studying the development of cancer and strategies for prevention of HNSCC, especially for immunotherapy. 24,28 To confirm the upregulation of LAG-3 in HNSCC mouse model, we quantified LAG-3 expression on CD4…”

Section: Lag-3 Expression Is Significantly Upregulated In Tgfbr1/ Ptementioning

confidence: 99%

“…The inducible head and neck tissue-specific Tgfbr1/Pten 2cKO mice (Tgfbr1 flox/flox ; Pten flox/flox ; K14-CreER tamC/¡ ) were generated by crossing K14-CreER tam ; Tgfbr1 flox/flox mice with Pten flox/flox mice. 27 The tissue-specific deletion of Pten, together with Tgfbr1 in mice head and neck epithelia, causes multiple hyperproliferative and tumor lesions in head and neck area. 27 Deletion of Pten enhanced PI3K/Akt pathway activation in mouse head and neck epithelia.…”

Section: Micementioning

confidence: 99%

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LAG-3 confers poor prognosis and its blockade reshapes antitumor response in head and neck squamous cell carcinoma

et al. 2016

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Immunotherapy with immune checkpoint molecule-specific monoclonal antibody have obtained encouraging results from preclinical studies and clinical trials, which promoted us to explore whether this kind of immunotherapy could be applicable to head and neck squamous cell carcinoma (HNSCC). Lymphocyte activation gene-3 (LAG-3) is an immune checkpoint control protein that negatively regulates T cells and immune response. Here, using the human tissue samples, we report these findings that LAG-3 is overexpressed on tumorinfiltrating lymphocytes (TILs; p < 0.001) and its overexpression correlates with the high pathological grades, lager tumor size and positive lymph node status in human primary HNSCC. Survival analysis identifies LAG-3 as a prognostic factor independent of tumor size and pathological grades for primary HNSCC patients with negative lymph node status (p D 0.014). Study in immunocompetent genetically defined HNSCC mouse model reports that LAG-3 is upregulated on CD4 C T cells, CD8 C T cells and CD4 C Foxp3 C regulatory T cells (Tregs). In vivo study, administration of LAG-3-specific antibody retards tumor growth in a way associated with enhanced systemic antitumor response by potentiating the antitumor response of CD8 C T cells and decreasing the population of immunosuppressive cells. Taken together, our results offer a preclinical proof supporting the immunomodulatory effects of LAG-3 and suggest a potential therapeutic target of immunotherapy for HNSCC.

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“…Therefore, activation of the PI3K/Akt pathway due to PTEN deletion alone is insufficient for the induction of invasive HNSCC. Bian et al (18) promoted HNSCC via the deletion of transforming growth factor-β1 and PTEN. Squarize et al (19) demonstrated that mice harboring a PTEN deficiency developed multiple oral SCC lesions on exposure to a tobacco surrogate, whereas the control mice did not.…”

Section: Discussionmentioning

confidence: 99%

Role of microRNA-296-3p in the malignant transformation of sinonasal inverted papilloma

et al. 2017

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Abstract. Inverted papilloma (IP) is a benign tumor occurring in the nasal cavity and paranasal sinuses. It is reported that 5-15% of IPs undergo malignant transformation into squamous cell carcinoma (SCC), and the role of microRNAs (miRNA/miR) in this process remains to be elucidated. In the present study, whole miRNA profiles using samples of IP and SCC were investigated, in order to detect the function of miRNA in the carcinogenesis of IP. Samples from IPs (n=5) and SCC lesions (n=5), which arose from IPs, were used for miRNA analysis. A total of 200 miRNAs exhibited a >2-fold differential expression between IP and SCC. miR-296-3p was markedly upregulated in SCC with a 23-fold difference. Computational analysis indicated that miR-296-3p targeted PTEN, which regulates the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway and PTEN is involved in the carcinogenesis of SCC. miR-296-3p directly regulated PTEN expression in head and neck cancer cells, with PTEN protein levels decreased in 4/19 the SCCs (21.0%), as compared with those in the IPs (76.4%). Positive p21 staining was observed in 64.7% of IPs; this was a significantly increased rate compared with that for SCCs (26.3%, P=0.0086). The results of the present study indicated that there were marked changes in the miRNA expression signature during the malignant transition. miR-296-3p may serve an important role in the malignant transformation of IPs via the regulation of PTEN, combined with the subsequent inhibition of the PI3K/Akt signaling pathway, and may be a novel agent for cancer prevention.

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Loss of TGF-β signaling and PTEN promotes head and neck squamous cell carcinoma through cellular senescence evasion and cancer-related inflammation

Cited by 148 publications

References 51 publications

CTLA4 blockade reduces immature myeloid cells in head and neck squamous cell carcinoma

CTLA4 blockade reduces immature myeloid cells in head and neck squamous cell carcinoma

LAG-3 confers poor prognosis and its blockade reshapes antitumor response in head and neck squamous cell carcinoma

Role of microRNA-296-3p in the malignant transformation of sinonasal inverted papilloma

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