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17 pages, 1557 KiB

Open AccessArticle

Prognostic and Clinicopathological Significance of Epidermal Growth Factor Receptor (EGFR) Expression in Oral Squamous Cell Carcinoma: Systematic Review and Meta-Analysis

by José Luis Cívico-Ortega, Isabel González-Ruiz, Pablo Ramos-García, David Cruz-Granados, Valerie Samayoa-Descamps and Miguel Ángel González-Moles

Int. J. Mol. Sci. 2023, 24(15), 11888; https://doi.org/10.3390/ijms241511888 - 25 Jul 2023

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Abstract

The aim of this systematic review and meta-analysis was to evaluate the current evidence in relation to the clinicopathological and prognostic significance of epidermal growth factor receptor (EGFR) overexpression in patients with oral squamous cell carcinoma (OSCC). We searched MEDLINE/PubMed, Embase, Web of [...] Read more.

The aim of this systematic review and meta-analysis was to evaluate the current evidence in relation to the clinicopathological and prognostic significance of epidermal growth factor receptor (EGFR) overexpression in patients with oral squamous cell carcinoma (OSCC). We searched MEDLINE/PubMed, Embase, Web of Science, and Scopus for studies published before November 2022. We evaluated the quality of primary-level studies using the QUIPS tool, conducted meta-analyses, examined inter-study heterogeneity via subgroup analyses and meta-regressions, and performed small-study effects analyses. Fifty primary-level studies (4631 patients) met the inclusion criteria. EGFR overexpression was significantly associated with poor overall survival (hazard ratio [HR] = 1.38, 95% confidence intervals [CI] = 1.06–1.79, p = 0.02), N+ status (odds ratio [OR] = 1.37, 95%CI = 1.01–1.86, p = 0.04), and moderately–poorly differentiated OSCC (OR = 1.43, 95% CI = 1.05–1.94, p = 0.02). In addition, better results were obtained by the application of a cutoff point ≥10% tumor cells with EGFR overexpression (p < 0.001). In conclusion, our systematic review and meta-analysis supports that the immunohistochemical assessment of EGFR overexpression may be useful as a prognostic biomarker for OSCC. Full article

(This article belongs to the Special Issue Pathogenesis and Therapy of Oral Carcinogenesis)

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22 pages, 4421 KiB

Open AccessArticle

Combinations of PRI-724 Wnt/β-Catenin Pathway Inhibitor with Vismodegib, Erlotinib, or HS-173 Synergistically Inhibit Head and Neck Squamous Cancer Cells

by Robert Kleszcz, Mikołaj Frąckowiak, Dawid Dorna and Jarosław Paluszczak

Int. J. Mol. Sci. 2023, 24(13), 10448; https://doi.org/10.3390/ijms241310448 - 21 Jun 2023

Cited by 4 | Viewed by 1580

Abstract

The Wnt/β-catenin, EGFR, and PI3K pathways frequently undergo upregulation in head and neck squamous carcinoma (HNSCC) cells. Moreover, the Wnt/β-catenin pathway together with Hedgehog (Hh) signaling regulate the activity of cancer stem cells (CSCs). The aim of this study was to investigate the [...] Read more.

The Wnt/β-catenin, EGFR, and PI3K pathways frequently undergo upregulation in head and neck squamous carcinoma (HNSCC) cells. Moreover, the Wnt/β-catenin pathway together with Hedgehog (Hh) signaling regulate the activity of cancer stem cells (CSCs). The aim of this study was to investigate the effects of the combinatorial use of the Wnt/β-catenin and Hh pathway inhibitors on viability, cell cycle progression, apoptosis induction, cell migration, and expression of CSC markers in tongue (CAL 27) and hypopharynx (FaDu) cancer cells. Co-inhibition of Wnt signaling with EGFR or PI3K pathways was additionally tested. The cells were treated with selective inhibitors of signaling pathways: Wnt/β-catenin (PRI-724), Hh (vismodegib), EGFR (erlotinib), and PI3K (HS-173). Cell viability was evaluated by the resazurin assay. Cell cycle progression and apoptosis induction were tested by flow cytometric analysis after staining with propidium iodide and Annexin V, respectively. Cell migration was detected by the scratch assay and CSC marker expression by the R-T PCR method. Mixtures of PRI-724 and vismodegib affected cell cycle distribution, greatly reduced cell migration, and downregulated the transcript level of CSC markers, especially POU5F1 encoding OCT4. Combinations of PRI-724 with erlotinib or HS-173 were more potent in inducing apoptosis. Full article

(This article belongs to the Special Issue Pathogenesis and Therapy of Oral Carcinogenesis)

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15 pages, 8353 KiB

Open AccessArticle

The Lysyl Oxidase G473A Polymorphism Exacerbates Oral Cancer Development in Humans and Mice

by Yaser Peymanfar, Faranak Mahjour, Neha Shrestha, Ana de la Cueva, Ying Chen, Shengyuan Huang, Kathrin H. Kirsch, Xiaozhe Han and Philip C. Trackman

Int. J. Mol. Sci. 2023, 24(11), 9407; https://doi.org/10.3390/ijms24119407 - 28 May 2023

Viewed by 1323

Abstract

Oral cancer is primarily squamous-cell carcinoma with a 5-year survival rate of approximately 50%. Lysyl oxidase (LOX) participates in collagen and elastin maturation. The propeptide of LOX is released as an 18 kDa protein (LOX-PP) in the extracellular environment by procollagen C-proteinases and [...] Read more.

Oral cancer is primarily squamous-cell carcinoma with a 5-year survival rate of approximately 50%. Lysyl oxidase (LOX) participates in collagen and elastin maturation. The propeptide of LOX is released as an 18 kDa protein (LOX-PP) in the extracellular environment by procollagen C-proteinases and has tumor-inhibitory properties. A polymorphism in the propeptide region of LOX (rs1800449, G473A) results in a single amino acid substitution of Gln for Arg. Here we investigated the frequency of rs1800449 in OSCC employing TCGA database resources and determined the kinetics and severity of precancerous oral lesion development in wildtype and corresponding knockin mice after exposure to 4-nitroquinoline oxide (4 NQO) in drinking water. Data show that the OSCC is more common in humans carrying the variant compared to the wildtype. Knockin mice are more susceptible to lesion development. The immunohistochemistry of LOX in mouse tissues and in vitro studies point to a negative feedback pathway of wildtype LOX-PP on LOX expression that is deficient in knockin mice. Data further demonstrate modulations of T cell phenotype in knockin mice toward a more tumor-permissive condition. Data provide initial evidence for rs1800449 as an oral cancer susceptibility biomarker and point to opportunities to better understand the functional mechanism of LOX-PP cancer inhibitory activity. Full article

(This article belongs to the Special Issue Pathogenesis and Therapy of Oral Carcinogenesis)

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24 pages, 3013 KiB

Open AccessArticle

Nutri-PEITC Jelly Significantly Improves Progression-Free Survival and Quality of Life in Patients with Advanced Oral and Oropharyngeal Cancer: A Blinded Randomized Placebo-Controlled Trial

by Aroonwan Lam-Ubol, Jirasak Sukhaboon, Withee Rasio, Peerawitch Tupwongse, Thapana Tangshewinsirikul and Dunyaporn Trachootham

Int. J. Mol. Sci. 2023, 24(9), 7824; https://doi.org/10.3390/ijms24097824 - 25 Apr 2023

Cited by 1 | Viewed by 1896

Abstract

TP53 mutation is associated with cancer progression. Novel strategies to reboot p53 are required to stabilize the disease and improve survival. This randomized placebo-controlled trial investigated safety and efficacy of Nutri-PEITC Jelly (a texture-modified nutritious diet fortified with β-phenethyl isothiocyanate (PEITC) on oral [...] Read more.

TP53 mutation is associated with cancer progression. Novel strategies to reboot p53 are required to stabilize the disease and improve survival. This randomized placebo-controlled trial investigated safety and efficacy of Nutri-PEITC Jelly (a texture-modified nutritious diet fortified with β-phenethyl isothiocyanate (PEITC) on oral cancer. Seventy-two patients with advanced-staged oral or oropharyngeal cancer were randomly assigned to study and control groups, who consumed 200 g of Nutri-Jelly with and without 20 mg of PEITC, respectively, 5 days/week for 12 weeks. Outcomes, including adverse events, health-related quality of life (HRQOL), progression-free survival (PFS), tumor response, serum p53, and cytochrome c, were measured at 0, 1, and 3 months. Results show that the study group had a higher proportion of participants with improved HRQOL, stable disease, and increased serum p53 levels than those in the control group (p < 0.001). The PFS time in the study group was significantly longer than that of the control group (p < 0.05). Serum cytochrome c levels were non-significantly decreased in the study group. No serious intervention-related adverse events occurred in either group. In conclusion, Nutri-PEITC Jelly intake for 3 months is safe, stabilizes the disease, improves quality of life and progression-free survival, and might re-activate p53 in advanced-stage oral and oropharyngeal cancer patients. Full article

(This article belongs to the Special Issue Pathogenesis and Therapy of Oral Carcinogenesis)

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17 pages, 2578 KiB

Open AccessArticle

Interaction between Cigarette Smoke and Human Papillomavirus 16 E6/E7 Oncoproteins to Induce SOD2 Expression and DNA Damage in Head and Neck Cancer

by Diego Carrillo-Beltrán, Julio C. Osorio, Rancés Blanco, Carolina Oliva, Enrique Boccardo and Francisco Aguayo

Int. J. Mol. Sci. 2023, 24(8), 6907; https://doi.org/10.3390/ijms24086907 - 07 Apr 2023

Cited by 4 | Viewed by 2867

Abstract

Even though epidemiological studies suggest that tobacco smoking and high-risk human papillomavirus (HR-HPV) infection are mutually exclusive risk factors for developing head and neck cancer (HNC), a portion of subjects who develop this heterogeneous group of cancers are both HPV-positive and smokers. Both [...] Read more.

Even though epidemiological studies suggest that tobacco smoking and high-risk human papillomavirus (HR-HPV) infection are mutually exclusive risk factors for developing head and neck cancer (HNC), a portion of subjects who develop this heterogeneous group of cancers are both HPV-positive and smokers. Both carcinogenic factors are associated with increased oxidative stress (OS) and DNA damage. It has been suggested that superoxide dismutase 2 (SOD2) can be independently regulated by cigarette smoke and HPV, increasing adaptation to OS and tumor progression. In this study, we analyzed SOD2 levels and DNA damage in oral cells ectopically expressing HPV16 E6/E7 oncoproteins and exposed to cigarette smoke condensate (CSC). Additionally, we analyzed SOD2 transcripts in The Cancer Genome Atlas (TCGA) Head and Neck Cancer Database. We found that oral cells expressing HPV16 E6/E7 oncoproteins exposed to CSC synergistically increased SOD2 levels and DNA damage. Additionally, the SOD2 regulation by E6, occurs in an Akt1 and ATM-independent manner. This study suggests that HPV and cigarette smoke interaction in HNC promotes SOD2 alterations, leading to increased DNA damage and, in turn, contributing to development of a different clinical entity. Full article

(This article belongs to the Special Issue Pathogenesis and Therapy of Oral Carcinogenesis)

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15 pages, 2522 KiB

Open AccessArticle

miR-125b-5p, miR-155-3p, and miR-214-5p and Target E2F2 Gene in Oral Squamous Cell Carcinoma

by Karolina Gołąbek, Dorota Hudy, Agata Świętek, Jadwiga Gaździcka, Natalia Dąbrowska, Katarzyna Miśkiewicz-Orczyk, Natalia Zięba, Maciej Misiołek and Joanna Katarzyna Strzelczyk

Int. J. Mol. Sci. 2023, 24(7), 6320; https://doi.org/10.3390/ijms24076320 - 28 Mar 2023

Cited by 2 | Viewed by 1308

Abstract

It is known that E2F2 (E2F transcription factor 2) plays an important role as controller in the cell cycle. This study aimed to analyse the expression of the E2F2 gene and E2F2 protein and demonstrate E2F2 target microRNAs (miRNAs) candidates (miR-125b-5p, miR-155-3p, and [...] Read more.

It is known that E2F2 (E2F transcription factor 2) plays an important role as controller in the cell cycle. This study aimed to analyse the expression of the E2F2 gene and E2F2 protein and demonstrate E2F2 target microRNAs (miRNAs) candidates (miR-125b-5p, miR-155-3p, and miR-214-5p) in oral squamous cell carcinoma tumour and margin samples. The study group consisted 50 patients. The E2F2 gene and miRNAs expression levels were assessed by qPCR, while the E2F2 protein was assessed by ELISA. When analysing the effect of miRNAs expression on E2F2 gene expression and E2F2 protein level, we observed no statistically significant correlations. miR-125b-5p was downregulated, while miR-155-3p, and miR-214-5p were upregulated in tumour samples compared to margin. We observed a difference between the miR-125b-5p expression level in smokers and non-smokers in margin samples. Furthermore, HPV-positive individuals had a significantly higher miR-125b-5p and miR-214-5p expression level compared to HPV-negative patients in tumour samples. The study result showed that the E2F2 gene is not the target for analysed miRNAs in OSCC. Moreover, miR-155-3p and miR-125b-5p could play roles in the pathogenesis of OSCC. A differential expression of the analysed miRNAs was observed in response to tobacco smoke and HPV status. Full article

(This article belongs to the Special Issue Pathogenesis and Therapy of Oral Carcinogenesis)

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18 pages, 6589 KiB

Open AccessArticle

Cholesterol Is a Regulator of CAV1 Localization and Cell Migration in Oral Squamous Cell Carcinoma

by Nyein Nyein Chan, Manabu Yamazaki, Satoshi Maruyama, Tatsuya Abé, Kenta Haga, Masami Kawaharada, Kenji Izumi, Tadaharu Kobayashi and Jun-ichi Tanuma

Int. J. Mol. Sci. 2023, 24(7), 6035; https://doi.org/10.3390/ijms24076035 - 23 Mar 2023

Cited by 5 | Viewed by 2296

Abstract

Cholesterol plays an important role in cancer progression, as it is utilized in membrane biogenesis and cell signaling. Cholesterol-lowering drugs have exhibited tumor-suppressive effects in oral squamous cell carcinoma (OSCC), suggesting that cholesterol is also essential in OSCC pathogenesis. However, the direct effects [...] Read more.

Cholesterol plays an important role in cancer progression, as it is utilized in membrane biogenesis and cell signaling. Cholesterol-lowering drugs have exhibited tumor-suppressive effects in oral squamous cell carcinoma (OSCC), suggesting that cholesterol is also essential in OSCC pathogenesis. However, the direct effects of cholesterol on OSCC cells remain unclear. Here, we investigated the role of cholesterol in OSCC with respect to caveolin-1 (CAV1), a cholesterol-binding protein involved in intracellular cholesterol transport. Cholesterol levels in OSCC cell lines were depleted using methyl-β-cyclodextrin and increased using the methyl-β-cyclodextrin-cholesterol complex. Functional analysis was performed using timelapse imaging, and CAV1 expression in cholesterol-manipulated cells was investigated using immunofluorescence and immunoblotting assays. CAV1 immunohistochemistry was performed on surgical OSCC samples. We observed that cholesterol addition induced polarized cell morphology, along with CAV1 localization at the trailing edge, and promoted cell migration. Moreover, CAV1 was upregulated in the lipid rafts and formed aggregates in the plasma membrane in cholesterol-added cells. High membranous CAV1 expression in tissue specimens was associated with OSCC recurrence. Therefore, cholesterol promotes the migration of OSCC cells by regulating cell polarity and CAV1 localization to the lipid raft. Furthermore, membranous CAV1 expression is a potential prognostic marker for OSCC patients. Full article

(This article belongs to the Special Issue Pathogenesis and Therapy of Oral Carcinogenesis)

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29 pages, 21841 KiB

Open AccessArticle

Nuclear Epidermal Growth Factor Receptor Overexpression as a Survival Predictor in Oral Squamous Cell Carcinoma

by Marko Tarle, Marina Raguž, Danko Muller and Ivica Lukšić

Int. J. Mol. Sci. 2023, 24(6), 5816; https://doi.org/10.3390/ijms24065816 - 18 Mar 2023

Cited by 2 | Viewed by 1538

Abstract

The aim of this study was to determine, by immunohistochemical methods, the expression of nEGFR and markers of cell proliferation (Ki-67), cell cycle (mEGFR, p53, cyclin D1), and tumor stem cells (ABCG2) in 59 pathohistological samples of healthy oral mucosa, 50 oral premalignant [...] Read more.

The aim of this study was to determine, by immunohistochemical methods, the expression of nEGFR and markers of cell proliferation (Ki-67), cell cycle (mEGFR, p53, cyclin D1), and tumor stem cells (ABCG2) in 59 pathohistological samples of healthy oral mucosa, 50 oral premalignant changes (leukoplakia and erythroplakia), and 52 oral squamous cell carcinomas (OSCC). An increase in the expression of mEGFR and nEGFR was found with the development of the disease (p < 0.0001). In the group of patients with leukoplakia and erythroplakia, we found a positive correlation between nEGFR and Ki67, p53, cyclin D1, and mEGFR, whereas in the group of patients with OSCC, we found a positive correlation between nEGFR and Ki67, mEGFR (p < 0.05). Tumors without perineural (PNI) invasion had a higher expression of p53 protein than tumors with PNI (p = 0.02). Patients with OSCC and overexpression of nEGFR had shorter overall survival (p = 0.004). The results of this study suggest a potentially important independent role of nEGFR in oral carcinogenesis. Full article

(This article belongs to the Special Issue Pathogenesis and Therapy of Oral Carcinogenesis)

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14 pages, 1948 KiB

Open AccessArticle

Potential of uPAR, αvβ6 Integrin, and Tissue Factor as Targets for Molecular Imaging of Oral Squamous Cell Carcinoma: Evaluation of Nine Targets in Primary Tumors and Metastases by Immunohistochemistry

by Mads Lawaetz, Anders Christensen, Karina Juhl, Kirstine Karnov, Giedrius Lelkaitis, Anne-Marie Kanstrup Fiehn, Andreas Kjaer and Christian von Buchwald

Int. J. Mol. Sci. 2023, 24(4), 3853; https://doi.org/10.3390/ijms24043853 - 14 Feb 2023

Cited by 5 | Viewed by 1526

Abstract

No clinically approved tumor-specific imaging agents for head and neck cancer are currently available. The identification of biomarkers with a high and homogenous expression in tumor tissue and minimal expression in normal tissue is essential for the development of new molecular imaging targets [...] Read more.

No clinically approved tumor-specific imaging agents for head and neck cancer are currently available. The identification of biomarkers with a high and homogenous expression in tumor tissue and minimal expression in normal tissue is essential for the development of new molecular imaging targets in head and neck cancer. We investigated the expression of nine imaging targets in both primary tumor and matched metastatic tissue of 41 patients with oral squamous cell carcinoma (OSCC) to assess their potential as targets for molecular imaging. The intensity, proportion, and homogeneity in the tumor and the reaction in neighboring non-cancerous tissue was scored. The intensity and proportion were multiplied to obtain a total immunohistochemical (IHC) score ranging from 0–12. The mean intensity in the tumor tissue and normal epithelium were compared. The expression rate was high for the urokinase-type plasminogen activator receptor (uPAR) (97%), integrin αvβ6 (97%), and tissue factor (86%) with a median total immunostaining score (interquartile range) for primary tumors of 6 (6–9), 12 (12–12), and 6 (2.5–7.5), respectively. For the uPAR and tissue factor, the mean staining intensity score was significantly higher in tumors compared to normal epithelium. The uPAR, integrin αvβ6, and tissue factor are promising imaging targets for OSCC primary tumors, lymph node metastases, and recurrences. Full article

(This article belongs to the Special Issue Pathogenesis and Therapy of Oral Carcinogenesis)

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9 pages, 1818 KiB

Open AccessCommunication

Is CCL2 an Important Mediator of Mast Cell–Tumor Cell Interactions in Oral Squamous Cell Carcinoma?

by Bernhard Hemmerlein, Luisa Reinhardt, Bernhard Wiechens, Tatjana Khromov, Henning Schliephake and Phillipp Brockmeyer

Int. J. Mol. Sci. 2023, 24(4), 3641; https://doi.org/10.3390/ijms24043641 - 11 Feb 2023

Viewed by 1258

Abstract

In this study, we aimed to evaluate the influence of interactions between mast cells (MCs) and oral squamous cell carcinoma (OSCC) tumor cells on tumor proliferation and invasion rates and identify soluble factors mediating this crosstalk. To this end, MC/OSCC interactions were characterized [...] Read more.

In this study, we aimed to evaluate the influence of interactions between mast cells (MCs) and oral squamous cell carcinoma (OSCC) tumor cells on tumor proliferation and invasion rates and identify soluble factors mediating this crosstalk. To this end, MC/OSCC interactions were characterized using the human MC cell line LUVA and the human OSCC cell line PCI-13. The influence of an MC-conditioned (MCM) medium and MC/OSCC co-cultures on the proliferative and invasive properties of the tumor cells was investigated, and the most interesting soluble factors were identified by multiplex ELISA analysis. LUVA/PCI-13 co-cultures increased tumor cell proliferation significantly (p = 0.0164). MCM reduced PCI-13 cell invasion significantly (p = 0.0010). CC chemokine ligand 2 (CCL2) secretion could be detected in PCI-13 monocultures and be significantly (p = 0.0161) increased by LUVA/PCI-13 co-cultures. In summary, the MC/OSCC interaction influences tumor cell characteristics, and CCL2 could be identified as a possible mediator. Full article

(This article belongs to the Special Issue Pathogenesis and Therapy of Oral Carcinogenesis)

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10 pages, 1413 KiB

Open AccessCommunication

Positive Linear Relationship between Nucleophosmin Protein Expression and the Viral Load in HPV-Associated Oropharyngeal Squamous Cell Carcinoma: A Possible Tool for Stratification of Patients

by Marco D’Agostino, Marco Di Cecco, Carla Marani, Maurizio Giovanni Vigili, Sara Sileno, Chiara Costanza Volpi, Annunziata Gloghini, Daniele Avitabile, Alessandra Magenta and Siavash Rahimi

Int. J. Mol. Sci. 2023, 24(4), 3482; https://doi.org/10.3390/ijms24043482 - 09 Feb 2023

Cited by 1 | Viewed by 1574

Abstract

Most oropharyngeal squamous cell carcinomas (OPSCCs) are human papillomavirus (HPV)-associated, high-risk (HR) cancers that show a better response to chemoradiotherapy and are associated with improved survival. Nucleophosmin (NPM, also called NPM1/B23) is a nucleolar phosphoprotein that plays different roles within the cell, such [...] Read more.

Most oropharyngeal squamous cell carcinomas (OPSCCs) are human papillomavirus (HPV)-associated, high-risk (HR) cancers that show a better response to chemoradiotherapy and are associated with improved survival. Nucleophosmin (NPM, also called NPM1/B23) is a nucleolar phosphoprotein that plays different roles within the cell, such as ribosomal synthesis, cell cycle regulation, DNA damage repair and centrosome duplication. NPM is also known as an activator of inflammatory pathways. An increase in NPM expression has been observed in vitro in E6/E7 overexpressing cells and is involved in HPV assembly. In this retrospective study, we investigated the relationship between the immunohistochemical (IHC) expression of NPM and HR-HPV viral load, assayed by RNAScope in situ hybridization (ISH), in ten patients with histologically confirmed p16-positive OPSCC. Our findings show that there is a positive correlation between NPM expression and HR-HPV mRNA (Rs = 0.70, p = 0.03), and a linear regression (r² = 0.55; p = 0.01). These data support the hypothesis that NPM IHC, together with HPV RNAScope, could be used as a predictor of transcriptionally active HPV presence and tumor progression, which is useful for therapy decisions. This study includes a small cohort of patients and, cannot report conclusive findings. Further studies with large series of patients are needed to support our hypothesis. Full article

(This article belongs to the Special Issue Pathogenesis and Therapy of Oral Carcinogenesis)

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Review

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15 pages, 969 KiB

Open AccessReview

Impact of Circulating Cell-Free DNA (cfDNA) as a Biomarker of the Development and Evolution of Periodontitis

by Gaia Viglianisi, Simona Santonocito, Alessandro Polizzi, Giuseppe Troiano, Mariacristina Amato, Khrystyna Zhurakivska, Paolo Pesce and Gaetano Isola

Int. J. Mol. Sci. 2023, 24(12), 9981; https://doi.org/10.3390/ijms24129981 - 10 Jun 2023

Cited by 3 | Viewed by 1939

Abstract

In the last few decades, circulating cell-free DNA (cfDNA) has been shown to have an important role in cell apoptosis or necrosis, including in the development and evolution of several tumors and inflammatory diseases in humans. In this regard, periodontitis, a chronic inflammatory [...] Read more.

In the last few decades, circulating cell-free DNA (cfDNA) has been shown to have an important role in cell apoptosis or necrosis, including in the development and evolution of several tumors and inflammatory diseases in humans. In this regard, periodontitis, a chronic inflammatory disease that can induce the destruction of supporting components of the teeth, could represent a chronic inflammatory stimulus linked to a various range of systemic inflammatory diseases. Recently, a possible correlation between periodontal disease and cfDNA has been shown, representing new important diagnostic–therapeutic perspectives. During the development of periodontitis, cfDNA is released in biological fluids such as blood, saliva, urine and other body fluids and represents an important index of inflammation. Due to the possibility of withdrawing some of these liquids in a non-invasive way, cfDNA could be used as a possible biomarker for periodontal disease. In addition, discovering a proportional relationship between cfDNA levels and the severity of periodontitis, expressed through the disease extent, could open the prospect of using cfDNA as a possible therapeutic target. The aim of this article is to report what researchers have discovered in recent years about circulating cfDNA in the development, evolution and therapy of periodontitis. The analyzed literature review shows that cfDNA has considerable potential as a diagnostic, therapeutic biomarker and therapeutic target in periodontal disease; however, further studies are needed for cfDNA to be used in clinical practice. Full article

(This article belongs to the Special Issue Pathogenesis and Therapy of Oral Carcinogenesis)

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