Association of Oral Microbiome With Risk for Incident Head and Neck Squamous Cell Cancer

Hayes, Richard B.; Ahn, Jiyoung; Fan, Xiaozhou; Peters, Brandilyn A.; Ma, Yingfei; Yang, Liying; Agalliu, Ilir; Burk, Robert D.; Ganly, Ian; Purdue, Mark P.; Freedman, Neal D.; Gapstur, Susan M.; Pei, Zhiheng

doi:10.1001/jamaoncol.2017.4777

Cited by 217 publications

(207 citation statements)

References 36 publications

(61 reference statements)

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“…The results of the current study demonstrated that APG-157 treatment reduces salivary inflammatory cytokines, and this may be directly related to changes in the oral microbiota. Similar to prior reports, 43 the results herein demonstrated that the oral microbiome of patients with cancer is distinct from that of healthy controls (Fig. 3).…”

Section: Discussionsupporting

confidence: 91%

A randomized, phase 1, placebo‐controlled trial of APG‐157 in oral cancer demonstrates systemic absorption and an inhibitory effect on cytokines and tumor‐associated microbes

Basak

Bera

Yoon

et al. 2020

Cancer

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Background Although curcumin's effect on head and neck cancer has been studied in vitro and in vivo, to the authors' knowledge its efficacy is limited by poor systemic absorption from oral administration. APG‐157 is a botanical drug containing multiple polyphenols, including curcumin, developed under the US Food and Drug Administration's Botanical Drug Development, that delivers the active components to oromucosal tissues near the tumor target. Methods A double‐blind, randomized, placebo‐controlled, phase 1 clinical trial was conducted with APG‐157 in 13 normal subjects and 12 patients with oral cancer. Two doses, 100 mg or 200 mg, were delivered transorally every hour for 3 hours. Blood and saliva were collected before and 1 hour, 2 hours, 3 hours, and 24 hours after treatment. Electrocardiograms and blood tests did not demonstrate any toxicity. Results Treatment with APG‐157 resulted in circulating concentrations of curcumin and analogs peaking at 3 hours with reduced IL‐1β, IL‐6, and IL‐8 concentrations in the salivary supernatant fluid of patients with cancer. Salivary microbial flora analysis showed a reduction in Bacteroidetes species in cancer subjects. RNA and immunofluorescence analyses of tumor tissues of a subject demonstrated increased expression of genes associated with differentiation and T‐cell recruitment to the tumor microenvironment. Conclusions The results of the current study suggested that APG‐157 could serve as a therapeutic drug in combination with immunotherapy. Lay Summary Curcumin has been shown to suppress tumor cells because of its antioxidant and anti‐inflammatory properties. However, its effectiveness has been limited by poor absorption when delivered orally. Subjects with oral cancer were given oral APG‐157, a botanical drug containing multiple polyphenols, including curcumin. Curcumin was found in the blood and in tumor tissues. Inflammatory markers and Bacteroides species were found to be decreased in the saliva, and immune T cells were increased in the tumor tissue. APG‐157 is absorbed well, reduces inflammation, and attracts T cells to the tumor, suggesting its potential use in combination with immunotherapy drugs.

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Section: Discussionsupporting

confidence: 91%

A randomized, phase 1, placebo‐controlled trial of APG‐157 in oral cancer demonstrates systemic absorption and an inhibitory effect on cytokines and tumor‐associated microbes

Basak

Bera

Yoon

et al. 2020

Cancer

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“…Twenty‐three non‐specific sequence‐based identification studies of the microbiota were included, 14 of which were published in 2017–2018 (Table ) (Al‐Hebshi, Nasher, Idris, & Chen, ; Al‐Hebshi et al., ; Bebek et al., ; Börnigen et al., ; Guerrero‐Preston et al., , ; Hayes et al., ; Hooper et al., ; Hu, Zhang, Hua, & Chen, ; Lee et al., ; Li et al., ; Mukherjee et al., ; Perera et al., , ; Pushalkar et al., , ; Schmidt et al., ; Shin et al., ; Wang et al., ; Wolf et al., ;Yang, Huang et al., ; Yang, Yeh et al., ; Zhao et al., ). Twenty‐one studies focused on bacterial identification (all by 16S rRNA gene regions), one of which also identified fungi (ITS2 gene fragment), one only fungi, and one was restricted to viral identification (human rRNA detection followed by search for viral sequences).…”

Section: Resultsmentioning

confidence: 99%

“…Of the studies examining saliva/oral rinse/mouthwash samples, Hayes et al. () found no significant differences at the genus level between health and disease. In contrast, Guerrero‐Preston et al.…”

Section: Resultsmentioning

confidence: 99%

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World Workshop on Oral Medicine VII: Targeting the oral microbiome Part 2: Current knowledge on malignant and potentially malignant oral disorders

et al. 2019

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Objective The World Workshop on Oral Medicine VII chose the oral microbiome as a focus area. Part 1 presents the methodological state of the science for oral microbiome studies. Part 2 was guided by the question: What is currently known about the microbiome associated with oral squamous cell carcinoma and potentially malignant disorders of the oral mucosa? Materials and Methods A scoping review methodology was followed to identify and analyse relevant studies on the composition and potential functions of the oral microbiota using high‐throughput sequencing techniques. The authors performed searches in PubMed and EMBASE. After removal of duplicates, a total of 239 potentially studies were identified. Results Twenty‐three studies on oral squamous cell carcinoma, two on oral leukoplakia and four on oral lichen planus were included with substantial differences in diagnostic criteria, sample type, region sequenced and sequencing method utilised. The majority of studies focused on bacterial identification and recorded statistically significant differences in the oral microbiota associated with health and disease. However, even when comparing studies of similar methodology, the microbial differences between health and disease varied considerably. No consensus on the composition of the microbiomes associated with these conditions on genus and species level could be obtained. Six studies on oral squamous cell carcinoma had included in silico predicted microbial functions (genes and/or pathways) and found some similarities between the studies. Conclusions Attempts to reveal the microbiome associated with oral mucosal diseases are still in its infancy, and the studies demonstrate significant clinical and methodological heterogeneity across disease categories. The immense richness and diversity of the microbiota clearly illustrate that there is a need for additional methodologically comparable studies utilising deep sequencing approaches in significant cohorts of subjects together with functional analyses. Our hope is that following the recipe as outlined in our preceding companion paper, that is Part 1, will enhance achieving this in the future and elucidate the role of the oral microbiome in oral squamous cell carcinoma and potentially malignant disorders of the oral mucosa.

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“…The oral microbiome has been suggested as a modulating factor for susceptibility to oral carcinogenesis . Variations in the composition of the oral microbiome are associated with oral cancer . However, the precise role of the microbiome in tumorigenesis is still poorly understood.…”

Section: Introductionmentioning

confidence: 99%

No difference in 4‐nitroquinoline induced tumorigenesis between germ‐free and colonized mice

Zhou

Fuentes-Creollo

Ponce

et al. 2019

Molecular Carcinogenesis

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Variations in oral bacterial communities have been linked to oral cancer suggesting that the oral microbiome is an etiological factor that can influence oral cancer development. The 4‐nitroquinoline 1‐oxide (4‐NQO)‐induced murine oral and esophageal cancer model is frequently used to assess the effects of preventive and/or therapeutic agents. We used this model to assess the impact of the microbiome on tumorigenesis using axenic (germ‐free) and conventionally housed mice. Increased toxicity was observed in germ‐free mice, however, no difference in tumor incidence, multiplicity, and size was observed. Transcriptional profiling of liver tissue from germ‐free and conventionally housed mice identified 254 differentially expressed genes including ten cytochrome p450 enzymes, the largest family of phase‐1 drug metabolizing enzymes in the liver. Gene ontology revealed that differentially expressed genes were enriched for liver steatosis, inflammation, and oxidative stress in livers of germ‐free mice. Our observations emphasize the importance of the microbiome in mediating chemical toxicity at least in part by altering host gene expression. Studies on the role of the microbiome in chemical‐induced cancer using germ‐free animal models should consider the potential difference in dose due to the microbiome‐mediated changes in host metabolizing capacity, which might influence the ability to draw conclusions especially for tumor induction models that are dose dependent.

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Association of Oral Microbiome With Risk for Incident Head and Neck Squamous Cell Cancer

Abstract: This study demonstrates that greater oral abundance of commensal Corynebacterium and Kingella is associated with decreased risk of HNSCC, with potential implications for cancer prevention.

Cited by 217 publications

References 36 publications

A randomized, phase 1, placebo‐controlled trial of APG‐157 in oral cancer demonstrates systemic absorption and an inhibitory effect on cytokines and tumor‐associated microbes

A randomized, phase 1, placebo‐controlled trial of APG‐157 in oral cancer demonstrates systemic absorption and an inhibitory effect on cytokines and tumor‐associated microbes

World Workshop on Oral Medicine VII: Targeting the oral microbiome Part 2: Current knowledge on malignant and potentially malignant oral disorders

No difference in 4‐nitroquinoline induced tumorigenesis between germ‐free and colonized mice

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