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Effects of proton versus photon irradiation on (lymph)angiogenic, inflammatory, proliferative and anti-tumor immune responses in head and neck squamous cell carcinoma.

ABSTRACT: The proximity of organs at risk makes the treatment of head and neck squamous cell carcinoma (HNSCC) challenging by standard radiotherapy. The higher precision in tumor targeting of proton (P) therapy could promote it as the treatment of choice for HNSCC. Besides the physical advantage in dose deposition, few is known about the biological impact of P versus photons (X) in this setting. To investigate the comparative biological effects of P versus X radiation in HNSCC cells, we assessed the relative biological effectiveness (RBE), viability, proliferation and mRNA levels for genes involved in (lymph)angiogenesis, inflammation, proliferation and anti-tumor immunity. These parameters, particularly VEGF-C protein levels and regulations, were documented in freshly irradiated and/or long-term surviving cells receiving low/high-dose, single (SI)/multiple (MI) irradiations with P/X. The RBE was found to be 1.1 Key (lymph)angiogenesis and inflammation genes were downregulated (except for vegf-c) after P and upregulated after X irradiation in MI surviving cells, demonstrating a more favorable profile after P irradiation. Both irradiation types stimulated vegf-c promoter activity in a NF-?B-dependent transcriptional regulation manner, but at a lesser extent after P, as compared to X irradiation, which correlated with mRNA and protein levels. The cells surviving to MI by P or X generated tumors with higher volume, anarchic architecture and increased density of blood vessels. Increased lymphangiogenesis and a transcriptomic analysis in favor of a more aggressive phenotype were observed in tumors generated with X-irradiated cells. Increased detection of lymphatic vessels in relapsed tumors from patients receiving X radiotherapy was consistent with these findings. This study provides new data about the biological advantage of P, as compared to X irradiation. In addition to its physical advantage in dose deposition, P irradiation may help to improve treatment approaches for HNSCC.

SUBMITTER: Lupu-Plesu M

PROVIDER: S-EPMC5541708 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Effects of proton versus photon irradiation on (lymph)angiogenic, inflammatory, proliferative and anti-tumor immune responses in head and neck squamous cell carcinoma.

Lupu-Plesu M M Claren A A Martial S S N'Diaye P-D PD Lebrigand K K Pons N N Ambrosetti D D Peyrottes I I Feuillade J J Hérault J J Dufies M M Doyen J J Pagès G G

Oncogenesis 20170703 7

The proximity of organs at risk makes the treatment of head and neck squamous cell carcinoma (HNSCC) challenging by standard radiotherapy. The higher precision in tumor targeting of proton (P) therapy could promote it as the treatment of choice for HNSCC. Besides the physical advantage in dose deposition, few is known about the biological impact of P versus photons (X) in this setting. To investigate the comparative biological effects of P versus X radiation in HNSCC cells, we assessed the relat ...[more]

PMID: 28671677

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Project description:The literature contains numerous references describing heterogeneity for tumor phenotypes including cell proliferation, invasiveness, metastatic potential, and response to therapies. However, data regarding angiogenic heterogeneity are limited. In this study, we investigated the degree of intertumoral angiogenic heterogeneity present in head and neck squamous cell carcinomas (HNSCC). In addition, we investigated the biological relevance that this heterogeneity may have in the context of cytokine directed antiangiogenic therapy. Keratinocytes were harvested from HNSCC specimens using laser capture microdissection (LCM). Gene expression profiling of the RNA extracted from these specimens demonstrated variability in the expression of angiogenesis-related genes. Hierarchical clustering and principal component analyses (PCA) demonstrated the presence of unique patient clusters, suggesting that there may be two potentially distinct pathways by which HNSCC induce angiogenesis. Immunohistochemistry for VEGF, IL-8/CXCL8, HGF, and FGF-2, cytokines that play functional roles in HNSCC angiogenesis was performed on the original patient samples as well as a larger panel of normal, dysplastic and HNSCC specimens to validate the heterogeneous expression observed in the gene expression profiling studies. Finally, the therapeutic response of HNSCC tumor xenografts to anti-VEGF therapy was found to be dependent on the amount of VEGF produced by the tumor cells. These findings support the hypothesis of intertumoral angiogenic heterogeneity. They imply that there are differences with regard to the specific molecular mechanisms by which individual tumors within the same histological type induce angiogenesis. Moreover, they demonstrate the need for a more in-depth understanding of the variability of the angiogenic phenotype within a given type of neoplasm when designing cytokine targeted antiangiogenic therapies. Finally, they suggest that studies in conjunction with the ongoing clinical trials that explore the correlation between target expression and clinical outcome are warranted.

Project description:BackgroundOral cavity (OC), oropharyngeal (OP), hypopharyngeal (HP), and laryngeal (LA) squamous cell carcinoma (SCC) have a high incidence of regional lymph node metastasis (LNM). Elective irradiation for clinically node-negative neck is routinely administered to treat lymph nodes harboring occult metastasis. However, the optimal elective irradiation schemes are still inconclusive. In this study, we aimed to establish individualized elective irradiation schemes for the ipsilateral and contralateral node-negative neck of these four types of cancer.MethodsFrom July 2005 to December 2018, 793 patients with OC-SCC, 464 with OP-SCC, 413 with HP-SCC, and 645 with LA-SCC were recruited retrospectively. Based on the actual incidence of LNM and the tumor characteristics, risk factors for contralateral LNM, as well as node level coverage schemes for elective irradiation, were determined using logistic regression analysis. Additionally, we developed a publicly available online tool to facilitate the widespread clinical use of these schemes.ResultsFor the ipsilateral node-negative neck, elective irradiation at levels I-III for OC-SCC and levels II-IVa for OP-, HP- and LA-SCC are generally recommended. In addition, level VIIa should be included in patients with OP-SCC. Multivariate analyses revealed that posterior hypopharyngeal wall and post-cricoid region involvement were independently associated with level VIIa metastasis in HP-SCC (all P < 0.05). For the contralateral node-negative neck, multivariate analyses revealed that ipsilateral N2b2-N3, tumors with body midline involvement, and degree of tumor invasion were the independent factors for contralateral LNM (all P < 0.05). In patients who require contralateral neck irradiation, levels I-II are recommended for OC-SCC, and additional level III is recommended for patients with ipsilateral N3 disease. Levels II-III are recommended for OP-, HP-, and LA-SCC, and additional level IVa is recommended for patients with advanced T or ipsilateral N classifications. Furthermore, additional level VIIa is recommended only for OP-SCC with T4 and ipsilateral N3 disease.ConclusionBased on our findings, we suggest that individualized and computer-aided elective irradiation schemes could reduce irradiation volumes in OC-, OP- and HP-SCC patients, as compared to current guidelines, and could thus positively impact the patients' quality of life after radiotherapy.

Dataset Information

Effects of proton versus photon irradiation on (lymph)angiogenic, inflammatory, proliferative and anti-tumor immune responses in head and neck squamous cell carcinoma.

Publications

Effects of proton versus photon irradiation on (lymph)angiogenic, inflammatory, proliferative and anti-tumor immune responses in head and neck squamous cell carcinoma.

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