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16 pages, 6785 KiB

Open AccessArticle

Comprehensive Integrated Single-Cell Whole Transcriptome Analysis Revealed the p-EMT Tumor Cells—CAFs Communication in Oral Squamous Cell Carcinoma

by Nam Cong-Nhat Huynh, Tze-Ta Huang, Chi Thi-Kim Nguyen and Fang-Kuei Lin

Int. J. Mol. Sci. 2022, 23(12), 6470; https://doi.org/10.3390/ijms23126470 - 9 Jun 2022

Cited by 10 | Viewed by 3990

Abstract

Cancer-associated fibroblasts (CAFs) and partial epithelial–mesenchymal transition (p-EMT) tumor cells are closed together and contribute to the tumor progression of oral squamous cell carcinoma (OSCC). In the present study, we deeply analyzed and integrated OSCC single-cell RNA sequencing datasets to define OSCC CAFs [...] Read more.

Cancer-associated fibroblasts (CAFs) and partial epithelial–mesenchymal transition (p-EMT) tumor cells are closed together and contribute to the tumor progression of oral squamous cell carcinoma (OSCC). In the present study, we deeply analyzed and integrated OSCC single-cell RNA sequencing datasets to define OSCC CAFs and p-EMT subpopulations. We highlighted the cell–cell interaction network of CAFs and p-EMT tumor cells and suggested biomarkers for the diagnosis and prognosis of OSCC during the metastasis condition. The analysis discovered four subtypes of CAFs: one p-EMT tumor cell population, and cycling tumor cells as well as TNFSF12-TNFRSF25/TNFRSF12A interactions between CAFs and p-EMT tumor cells during tumor metastasis. This suggests the prediction of therapeutically targetable checkpoint receptor–ligand interactions between CAFs and p-EMT tumor cells in OSCC regarding the metastasis status. Full article

(This article belongs to the Special Issue Oral Cancer—Etiopathogenesis and New Mechanisms of Oral Cancerogenesis)

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15 pages, 4270 KiB

Open AccessArticle

Single-Cell RNA Sequencing Analysis for Oncogenic Mechanisms Underlying Oral Squamous Cell Carcinoma Carcinogenesis with Candida albicans Infection

by Yi-Ping Hsieh, Yu-Hsueh Wu, Siao-Muk Cheng, Fang-Kuei Lin, Daw-Yang Hwang, Shih-Sheng Jiang, Ken-Chung Chen, Meng-Yen Chen, Wei-Fan Chiang, Ko-Jiunn Liu, Nam Cong-Nhat Huynh, Wen-Tsung Huang and Tze-Ta Huang

Int. J. Mol. Sci. 2022, 23(9), 4833; https://doi.org/10.3390/ijms23094833 - 27 Apr 2022

Cited by 14 | Viewed by 4255

Abstract

Oral squamous cell carcinoma (OSCC) carcinogenesis involves heterogeneous tumor cells, and the tumor microenvironment (TME) is highly complex with many different cell types. Cancer cell–TME interactions are crucial in OSCC progression. Candida albicans (C. albicans)—frequently pre-sent in the oral potentially malignant [...] Read more.

Oral squamous cell carcinoma (OSCC) carcinogenesis involves heterogeneous tumor cells, and the tumor microenvironment (TME) is highly complex with many different cell types. Cancer cell–TME interactions are crucial in OSCC progression. Candida albicans (C. albicans)—frequently pre-sent in the oral potentially malignant disorder (OPMD) lesions and OSCC tissues—promotes malignant transformation. The aim of the study is to verify the mechanisms underlying OSCC car-cinogenesis with C. albicans infection and identify the biomarker for the early detection of OSCC and as the treatment target. The single-cell RNA sequencing analysis (scRNA-seq) was performed to explore the cell subtypes in normal oral mucosa, OPMD, and OSCC tissues. The cell composi-tion changes and oncogenic mechanisms underlying OSCC carcinogenesis with C. albicans infec-tion were investigated. Gene Set Variation Analysis (GSVA) was used to survey the mechanisms underlying OSCC carcinogenesis with and without C. albicans infection. The results revealed spe-cific cell clusters contributing to OSCC carcinogenesis with and without C. albicans infection. The major mechanisms involved in OSCC carcinogenesis without C. albicans infection are the IL2/STAT5, TNFα/NFκB, and TGFβ signaling pathways, whereas those involved in OSCC carcinogenesis with C. albicans infection are the KRAS signaling pathway and E2F target down-stream genes. Finally, stratifin (SFN) was validated to be a specific biomarker of OSCC with C. albicans infection. Thus, the detailed mechanism underlying OSCC carcinogenesis with C. albicans infection was determined and identified the treatment biomarker with potential precision medicine applications. Full article

(This article belongs to the Special Issue Oral Cancer—Etiopathogenesis and New Mechanisms of Oral Cancerogenesis)

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13 pages, 4623 KiB

Open AccessArticle

Epigenetic Deregulation of Protein Tyrosine Kinase 6 Promotes Carcinogenesis of Oral Squamous Cell Carcinoma

by Yi-Ping Hsieh, Ken-Chung Chen, Meng-Yen Chen, Ling-Yu Huang, An-Yu Su, Wei-Fan Chiang, Wen-Tsung Huang and Tze-Ta Huang

Int. J. Mol. Sci. 2022, 23(9), 4495; https://doi.org/10.3390/ijms23094495 - 19 Apr 2022

Cited by 7 | Viewed by 2246

Abstract

Oral squamous cell carcinoma (OSCC) accounts for over 90% of oral cancers and causes considerable morbidity and mortality. Epigenetic deregulation is a common mechanism underlying carcinogenesis. DNA methylation deregulation is the epigenetic change observed during the transformation of normal cells to precancerous and [...] Read more.

Oral squamous cell carcinoma (OSCC) accounts for over 90% of oral cancers and causes considerable morbidity and mortality. Epigenetic deregulation is a common mechanism underlying carcinogenesis. DNA methylation deregulation is the epigenetic change observed during the transformation of normal cells to precancerous and eventually cancer cells. This study investigated the DNA methylation patterns of PTK6 during the development of OSCC. Bisulfite genomic DNA sequencing was performed to determine the PTK6 methylation level. OSCC animal models were established to examine changes in PTK6 expression in the different stages of OSCC development. The DNA methylation of PTK6 was decreased during the development of OSCC. The mRNA and protein expression of PTK6 was increased in OSCC cell lines compared with human normal oral keratinocytes. In mice, the methylation level of PTK6 decreased after treatment with 4-nitroquinoline 1-oxide and arecoline, and the mRNA and protein expression of PTK6 was increased. PTK6 hypomethylation can be a diagnostic marker of OSCC. Upregulation of PTK6 promoted the proliferation, migration, and invasion of OSCC cells. PTK6 promoted carcinogenesis and metastasis by increasing STAT3 phosphorylation and ZEB1 expression. The epigenetic deregulation of PTK6 can serve as a biomarker for the early detection of OSCC and as a treatment target. Full article

(This article belongs to the Special Issue Oral Cancer—Etiopathogenesis and New Mechanisms of Oral Cancerogenesis)

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16 pages, 29941 KiB

Open AccessArticle

Impact of Spatially Heterogeneous Trop-2 Expression on Prognosis in Oral Squamous Cell Carcinoma

by Ramona Erber, Steffen Spoerl, Andreas Mamilos, Rosemarie Krupar, Arndt Hartmann, Matthias Ruebner, Juergen Taxis, Mareike Wittenberg, Torsten E. Reichert, Gerrit Spanier and Silvia Spoerl

Int. J. Mol. Sci. 2022, 23(1), 87; https://doi.org/10.3390/ijms23010087 - 22 Dec 2021

Cited by 16 | Viewed by 3141

Abstract

Oral cancer often presents with aggressive behavior and a high risk of recurrence and metastasis. For oral squamous cell carcinoma (OSCC), which is the most frequent histological subtype, therapy strategies include surgery, radiation therapy, chemotherapy, immune checkpoint inhibitors, and EGFR inhibitors. Recently, a [...] Read more.

Oral cancer often presents with aggressive behavior and a high risk of recurrence and metastasis. For oral squamous cell carcinoma (OSCC), which is the most frequent histological subtype, therapy strategies include surgery, radiation therapy, chemotherapy, immune checkpoint inhibitors, and EGFR inhibitors. Recently, a Trop-2 antibody-drug conjugate (ADC) has been approved in the United States of America for the treatment of advanced triple-negative breast cancer. However, this ADC has also been tested in other solid tumors including head & neck squamous cell carcinoma. The prognostic impact of Trop-2 has already been reported for several cancers. We studied the prognostic influence of Trop-2 protein expression on OSCC patients’ survival. The cohort comprised n = 229 OSCC patients with available archived tumor tissue and corresponding non-neoplastic oral mucosa tissue. Using immunohistochemistry, we investigated Trop-2 expression in both the central and peripheral regions of each tumor and in corresponding non-neoplastic oral mucosa. In patients suffering from OSCC with combined high central and low peripheral Trop-2 expression, five-year overall survival (OS) was 41.2%, whereas 55.6% of OSCC patients who presented lower central and/or higher peripheral tumoral Trop-2 expression were alive after five years (p = 0.075). In multivariate Cox regression, the expression pattern of high central tumoral and lower peripheral Trop-2 expression was significantly correlated with impaired OS (HR = 1.802, 95%-CI: 1.134–2.864; p = 0.013) and recurrence-free survival (RFS) (HR = 1.633, 95%-CI: 1.042–2.560; p = 0.033), respectively, when adjusting for co-variables. Hence, Trop-2 may serve as an independent prognostic biomarker in OSCC. In subsequent studies, the pathophysiological meaning of downregulated Trop-2 expression in the OSCC periphery has to be analyzed. Full article

(This article belongs to the Special Issue Oral Cancer—Etiopathogenesis and New Mechanisms of Oral Cancerogenesis)

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18 pages, 6922 KiB

Open AccessArticle

NLRP3 Inflammasome Inhibitor BAY-117082 Reduces Oral Squamous Cell Carcinoma Progression

by Sarah Adriana Scuderi, Giovanna Casili, Rossella Basilotta, Marika Lanza, Alessia Filippone, Gabriele Raciti, Ivana Puliafito, Lorenzo Colarossi, Emanuela Esposito and Irene Paterniti

Int. J. Mol. Sci. 2021, 22(20), 11108; https://doi.org/10.3390/ijms222011108 - 15 Oct 2021

Cited by 20 | Viewed by 3080

Abstract

Oral cancer is one of the most common human malignancies, and its incidence is increasing worldwide. In particular, oral squamous cell carcinoma (OSCC) is characterized by high rates of proliferation, invasiveness, and metastasis. Currently, standard treatment for OSCC includes surgical removal, chemotherapy, and [...] Read more.

Oral cancer is one of the most common human malignancies, and its incidence is increasing worldwide. In particular, oral squamous cell carcinoma (OSCC) is characterized by high rates of proliferation, invasiveness, and metastasis. Currently, standard treatment for OSCC includes surgical removal, chemotherapy, and radiotherapy; however, the survival rate of patients with OSCC remains low, thus new therapies are needed. It has been proven that excessive NLRP3 inflammasome activation and apoptosis alteration may contribute to oral cancer progression. This study aimed to investigate the effect of BAY-117082, an NLRP3 inflammasome inhibitor, in an in vitro and in vivo xenograft model of oral cancer. In vitro results revealed that BAY-117082 at concentrations of 5, 10, and 30 µM was able to reduce OSCC cell viability. BAY-117082 at higher concentrations significantly reduced NLRP3, ASC, caspase-1, IL-1β, and IL-18 expression. Moreover, Bax, Bad, and p53 expression were increased, whereas Bcl-2 expression was reduced. Furthermore, the in vivo study demonstrated that BAY-117082 at doses of 2.5 and 5 mg/kg significantly decreased subcutaneous tumor mass, and also reduced NLRP3 inflammasome pathway activation. Therefore, based on these results, the use of BAY-117082 could be considered a promising strategy to counteract oral cancer progression, thanks its ability to modulate the NLRP3 inflammasome and apoptosis pathways. Full article

(This article belongs to the Special Issue Oral Cancer—Etiopathogenesis and New Mechanisms of Oral Cancerogenesis)

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14 pages, 2158 KiB

Open AccessArticle

Effects of 6,8-Diprenylgenistein on VEGF-A-Induced Lymphangiogenesis and Lymph Node Metastasis in an Oral Cancer Sentinel Lymph Node Animal Model

by Mun Gyeong Bae, Jeon Hwang-Bo, Dae Young Lee, Youn-Hyung Lee and In Sik Chung

Int. J. Mol. Sci. 2021, 22(2), 770; https://doi.org/10.3390/ijms22020770 - 14 Jan 2021

Cited by 11 | Viewed by 2820

Abstract

Background: The major determining factor of prognosis of oral squamous cell carcinoma is cervical lymph node metastasis. 6,8-Diprenylgenistein (6,8-DG), an isoflavonoid isolated from Cudrania tricuspidata has been reported to have anti-microbial and anti-obesity activities. However, its effects on lymphangiogenesis and lymph node metastasis [...] Read more.

Background: The major determining factor of prognosis of oral squamous cell carcinoma is cervical lymph node metastasis. 6,8-Diprenylgenistein (6,8-DG), an isoflavonoid isolated from Cudrania tricuspidata has been reported to have anti-microbial and anti-obesity activities. However, its effects on lymphangiogenesis and lymph node metastasis in oral cancer have not yet been reported. Methods: To investigate the in vitro inhibitory effects of 6,8-DG on VEGF-A-induced lymphangiogenesis, we performed the proliferation, tube formation, and migration assay using human lymphatic microvascular endothelial cells (HLMECs). RT-PCR, Western blot, immunoprecipitation, ELISA and co-immunoprecipitation assays were used to investigate the expression levels of proteins, and mechanism of 6,8-DG. The in vivo inhibitory effects of 6,8-DG were investigated using an oral cancer sentinel lymph node (OCSLN) animal model. Results: 6,8-DG inhibited the proliferation, migration and tube formation of rhVEGF-A treated HLMECs. In addition, the in vivo lymphatic vessel formation stimulated by rhVEGF-A was significantly reduced by 6,8-DG. 6,8-DG inhibited the expression of VEGF-A rather than other lymphangiogenic factors in CoCl₂-treated SCCVII cells. 6,8-DG inhibited the expression and activation of VEGFR-2 stimulated by rhVEGF-A in HLMECs. Also, 6,8-DG inhibited the activation of the lymphangiogenesis-related downstream signaling factors such as FAK, PI3K, AKT, p38, and ERK in rhVEGF-A-treated HLMECs. Additionally, 6,8-DG inhibited the expression of the hypoxia-inducible factor (HIF-1α), which is involved in the expression of VEGF-A in CoCl₂-treated SCCVII cells, and 6,8-DG inhibited VEGF-A signaling via interruption of the binding of VEGF-A and VEGFR-2 in HLMECs. In the VEGF-A-induced OCSLN animal model, we confirmed that 6,8-DG suppressed tumor-induced lymphangiogenesis and SLN metastasis. Conclusion: These data suggest that 6,8-DG inhibits VEGF-A-induced lymphangiogenesis and lymph node metastasis in vitro and in vivo. Furthermore, the inhibitory effects of 6,8-DG are probably mediated by inhibition of VEGF-A expression in cancer cells and suppression of the VEGF-A/VEGFR-2 signaling pathway in HLMEC. Thus, 6,8-DG could be novel and valuable therapeutic agents for metastasis prevention and treatment of oral cancer. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics 2020)

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20 pages, 5208 KiB

Open AccessArticle

Single-Cell Analysis of Different Stages of Oral Cancer Carcinogenesis in a Mouse Model

by Ling-Yu Huang, Yi-Ping Hsieh, Yen-Yun Wang, Daw-Yang Hwang, Shih Sheng Jiang, Wen-Tsung Huang, Wei-Fan Chiang, Ko-Jiunn Liu and Tze-Ta Huang

Int. J. Mol. Sci. 2020, 21(21), 8171; https://doi.org/10.3390/ijms21218171 - 31 Oct 2020

Cited by 8 | Viewed by 4584

Abstract

Oral carcinogenesis involves the progression of the normal mucosa into potentially malignant disorders and finally into cancer. Tumors are heterogeneous, with different clusters of cells expressing different genes and exhibiting different behaviors. 4-nitroquinoline 1-oxide (4-NQO) and arecoline were used to induce oral cancer [...] Read more.

Oral carcinogenesis involves the progression of the normal mucosa into potentially malignant disorders and finally into cancer. Tumors are heterogeneous, with different clusters of cells expressing different genes and exhibiting different behaviors. 4-nitroquinoline 1-oxide (4-NQO) and arecoline were used to induce oral cancer in mice, and the main factors for gene expression influencing carcinogenesis were identified through single-cell RNA sequencing analysis. Male C57BL/6J mice were divided into two groups: a control group (receiving normal drinking water) and treatment group (receiving drinking water containing 4-NQO (200 mg/L) and arecoline (500 mg/L)) to induce the malignant development of oral cancer. Mice were sacrificed at 8, 16, 20, and 29 weeks. Except for mice sacrificed at 8 weeks, all mice were treated for 16 weeks and then either sacrificed or given normal drinking water for the remaining weeks. Tongue lesions were excised, and all cells obtained from mice in the 29- and 16-week treatment groups were clustered into 17 groups by using the Louvain algorithm. Cells in subtypes 7 (stem cells) and 9 (keratinocytes) were analyzed through gene set enrichment analysis. Results indicated that their genes were associated with the MYC_targets_v1 pathway, and this finding was confirmed by the presence of cisplatin-resistant nasopharyngeal carcinoma cell lines. These cell subtype biomarkers can be applied for the detection of patients with precancerous lesions, the identification of high-risk populations, and as a treatment target. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics 2020)

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15 pages, 1358 KiB

Open AccessArticle

Pre-Operative Evaluation of DNA Methylation Profile in Oral Squamous Cell Carcinoma Can Predict Tumor Aggressive Potential

by Davide B. Gissi, Viscardo P. Fabbri, Andrea Gabusi, Jacopo Lenzi, Luca Morandi, Sofia Melotti, Sofia Asioli, Achille Tarsitano, Tiziana Balbi, Claudio Marchetti and Lucio Montebugnoli

Int. J. Mol. Sci. 2020, 21(18), 6691; https://doi.org/10.3390/ijms21186691 - 14 Sep 2020

Cited by 13 | Viewed by 2613

Abstract

Background: Prognosis of oral squamous cell carcinoma (OSCC) is difficult to exactly assess on pre-operative biopsies. Since OSCC DNA methylation profile has proved to be a useful pre-operative diagnostic tool, the aim of the present study was to evaluate the prognostic impact of [...] Read more.

Background: Prognosis of oral squamous cell carcinoma (OSCC) is difficult to exactly assess on pre-operative biopsies. Since OSCC DNA methylation profile has proved to be a useful pre-operative diagnostic tool, the aim of the present study was to evaluate the prognostic impact of DNA methylation profile to discriminate OSCC with high and low aggressive potential. Methods: 36 OSCC cases underwent neoplastic cells collection by gentle brushing of the lesion, before performing a pre-operative biopsy. The CpG islands methylation status of 13 gene (ZAP70, ITGA4, KIF1A, PARP15, EPHX3, NTM, LRRTM1, FLI1, MiR193, LINC00599, MiR296, TERT, GP1BB) was studied by bisulfite Next Generation Sequencing (NGS). A Cox proportional hazards model via likelihood-based component-wise boosting was used to evaluate the prognostic power of the CpG sites. Results: The boosting estimation identified five CpGs with prognostic significance: EPHX3-24, EPHX3-26, ITGA4-3, ITGA4-4, and MiR193-3. The combination of significant CpGs provided promising results for adverse events prediction (Brier score = 0.080, C-index = 0.802 and AUC = 0.850). ITGA4 had a strong prognostic power in patients with early OSCC. Conclusions: These data confirm that the study of methylation profile provides new insights into the molecular mechanisms of OSCC and can allow a better OSCC prognostic stratification even before surgery. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics 2020)

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20 pages, 4708 KiB

Open AccessArticle

Transfection of T-Box Transcription Factor BRACHYURY and SOX2 Synergistically Promote Self-Renewal and Invasive Phenotype in Oral Cancer Cells

by Naonari Akimoto, Kodai Nakamura, Hiroshi Hijioka, Kenichi Kume, Yoshiaki Matsumura and Tsuyoshi Sugiura

Int. J. Mol. Sci. 2018, 19(11), 3620; https://doi.org/10.3390/ijms19113620 - 16 Nov 2018

Cited by 11 | Viewed by 3958

Abstract

Recent studies suggest that epithelial–mesenchymal transition (EMT) correlates with cancer metastasis. In addition, there is growing evidence of the association of EMT with cancer stem cells (CSCs). Recently, we showed that the T-box transcription factor BRACHYURY could be a strong regulator of EMT [...] Read more.

Recent studies suggest that epithelial–mesenchymal transition (EMT) correlates with cancer metastasis. In addition, there is growing evidence of the association of EMT with cancer stem cells (CSCs). Recently, we showed that the T-box transcription factor BRACHYURY could be a strong regulator of EMT and the CSC phenotype, which were effectively suppressed by a BRACHYURY knockdown in an adenoid cystic carcinoma cell line. In this study, we further tested whether BRACHYURY is a regulator of cancer stemness by means of forced expression of BRACHYURY in oral cancer cell lines. BRACHYURY, SOX2, or both were stably transfected into oral carcinoma cell lines. We analysed these transfectants with respect to self-renewal phenotypes using a sphere-formation assay, and we assessed the expression levels of EMT markers and stem cell markers using real-time reverse transcription-polymerase chain reaction (RT-PCR). Cell migration and invasiveness in vitro were evaluated using a wound healing assay and a tumour cell dissemination assay, respectively. Forced expression of BRACHYURY or SOX2 slightly increased expression of EMT and stem cell markers and the self-renewal phenotype. The expression levels, however, were much lower compared to those of cancer stem cell-like cells. Forced co-expression of BRACHYURY and SOX2 strongly upregulated EMT and stem cell markers and the self-renewal phenotype. Cell migration and invasiveness in vitro were also remarkably enhanced. These synergistic effects increased expression levels of FIBRONECTIN, SNAIL, SLUG, ZEB1, and TGF-β2. In particular, the effects on FIBRONECTIN and TGF-β2 were significant. We found that BRACHYURY and SOX2 synergistically promote cancer stemness in oral cancer cells. This finding points to the importance of gene or protein networks associated with BRACHYURY and SOX2 in the development and maintenance of the CSC phenotype. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics)

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13 pages, 5279 KiB

Open AccessArticle

Lactate Transporter Monocarboxylate Transporter 4 Induces Bone Pain in Head and Neck Squamous Cell Carcinoma

by Kazuaki Hasegawa, Tatsuo Okui, Tsuyoshi Shimo, Soichiro Ibaragi, Hotaka Kawai, Shoji Ryumon, Koji Kishimoto, Yuka Okusha, Nur Mohammad Monsur Hassan and Akira Sasaki

Int. J. Mol. Sci. 2018, 19(11), 3317; https://doi.org/10.3390/ijms19113317 - 25 Oct 2018

Cited by 6 | Viewed by 3676

Abstract

Head and neck squamous cell carcinoma (HNSCC) poses a significant challenge clinically, as it can invade facial bones and cause bone pain that is undertreated and poorly understood. Here we studied HNSCC bone pain (HNSCC-BP) in an intratibial mouse xenograft model that uses [...] Read more.

Head and neck squamous cell carcinoma (HNSCC) poses a significant challenge clinically, as it can invade facial bones and cause bone pain that is undertreated and poorly understood. Here we studied HNSCC bone pain (HNSCC-BP) in an intratibial mouse xenograft model that uses a human HNSCC cell line (SAS cells). These mice develop HNSCC-BP associated with an upregulation of phosphorylated ERK1/2 (pERK1/2), which is a molecular indicator of neuron excitation in the dorsal root ganglia (DRGs) of sensory nerve cell bodies. Our experiments demonstrated that the inhibition of monocarboxylate transporter 4 (MCT4) by short hairpin (shRNA) transduction suppressed the HNSCC-BP, the lactate level in bone marrow, and the pERK1/2 expression in DRG. The sensory nerves also expressed increased levels of the acid-sensing receptor TRPV1. DRG neurons co-cultured with SAS cells showed increased neurite outgrowth, and were inhibited by MCT4 silencing with shRNA. Collectively, our results show that HNSCC induced an acidic bone microenvironment that evokes HNSCC-BP via MCT4 expression. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics)

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15 pages, 2776 KiB

Open AccessArticle

The Multifarious Functions of Pyruvate Kinase M2 in Oral Cancer Cells

by Miyako Kurihara-Shimomura, Tomonori Sasahira, Chie Nakashima, Hiroki Kuniyasu, Hiroyuki Shimomura and Tadaaki Kirita

Int. J. Mol. Sci. 2018, 19(10), 2907; https://doi.org/10.3390/ijms19102907 - 25 Sep 2018

Cited by 33 | Viewed by 5120

Abstract

Head and neck cancers, including oral squamous cell carcinoma (OSCC), are the sixth most common malignancies worldwide. OSCC frequently leads to oral dysfunction, which worsens a patient’s quality of life. Moreover, its prognosis remains poor. Unlike normal cells, tumor cells preferentially metabolize glucose [...] Read more.

Head and neck cancers, including oral squamous cell carcinoma (OSCC), are the sixth most common malignancies worldwide. OSCC frequently leads to oral dysfunction, which worsens a patient’s quality of life. Moreover, its prognosis remains poor. Unlike normal cells, tumor cells preferentially metabolize glucose by aerobic glycolysis. Pyruvate kinase (PK) catalyzes the final step in glycolysis, and the transition from PKM1 to PKM2 is observed in many cancer cells. However, little is known about PKM expression and function in OSCC. In this study, we investigated the expression of PKM in OSCC specimens and performed a functional analysis of human OSCC cells. We found that the PKM2/PKM1 ratio was higher in OSCC cells than in adjacent normal mucosal cells and in samples obtained from dysplasia patients. Furthermore, PKM2 expression was strongly correlated with OSCC tumor progression on immunohistochemistry. PKM2 expression was higher during cell growth, invasion, and apoptosis in HSC3 cells, which show a high energy flow and whose metabolism depends on aerobic glycolysis and oxidative phosphorylation. PKM2 expression was also associated with the production of reactive oxygen species (ROS) and integration of glutamine into lactate. Our results suggested that PKM2 has a variety of tumor progressive functions in OSCC cells. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics)

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15 pages, 3335 KiB

Open AccessArticle

Aspirin is Involved in the Cell Cycle Arrest, Apoptosis, Cell Migration, and Invasion of Oral Squamous Cell Carcinoma

by Xiaoqi Zhang, Hao Feng, Ziyu Li, Jie Guo and Minqi Li

Int. J. Mol. Sci. 2018, 19(7), 2029; https://doi.org/10.3390/ijms19072029 - 12 Jul 2018

Cited by 35 | Viewed by 4786

Abstract

Oral squamous cell carcinoma (OSCC) is one of the most common cancers worldwide. In China, its 5-year survival rate is roughly 50%, owing to acquired chemotherapeutic resistance and metastasis of the disease. Accumulating evidence demonstrates that aspirin (ASA) acts as a preventive or [...] Read more.

Oral squamous cell carcinoma (OSCC) is one of the most common cancers worldwide. In China, its 5-year survival rate is roughly 50%, owing to acquired chemotherapeutic resistance and metastasis of the disease. Accumulating evidence demonstrates that aspirin (ASA) acts as a preventive or therapeutic agent in multiple cancers; however, anti-tumor activities induced by aspirin are unclear in OSCC. To investigate the possible role of aspirin in OSCC development, we first employed bioinformatics to analyze the anti-OSCC effects of aspirin. We performed a genetic oncology (GO) enrichment analysis using the Database for Annotation, Visualization, and Integrated Discovery (DAVID), and the protein–protein interaction (PPI) network analysis by Cytoscape for differentially expressed genes (DEGs). We also evaluated the potential effects of aspirin on cell proliferation, invasion, migration, and apoptosis in two well-characterized OSCC cell lines (TCA8113 and CAL27). The bioinformatic results revealed that aspirin could inhibit proliferation by blocking the cell cycle, and could reduce migration and invasion via the PI3K-Akt and focal adhesion pathways. We found that ASA could downregulate the OSCC cell proliferation colony formation, invasion, and migration, as well as upregulate apoptosis. Furthermore, we found that ASA suppressed the activation of the focal adhesion kinase (FAK) and the phosphorylation of Akt, NF-κB, and STAT3. Overall, our data suggested that ASA may be developed as a chemopreventive agent to effectively treat OSCC. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics)

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23 pages, 4664 KiB

Open AccessArticle

Nerve Growth Factor (NGF)—Receptor Survival Axis in Head and Neck Squamous Cell Carcinoma

by József Dudás, Wolfgang Dietl, Angela Romani, Susanne Reinold, Rudolf Glueckert, Anneliese Schrott-Fischer, Daniel Dejaco, Lejo Johnson Chacko, Raphaela Tuertscher, Volker Hans Schartinger and Herbert Riechelmann

Int. J. Mol. Sci. 2018, 19(6), 1771; https://doi.org/10.3390/ijms19061771 - 14 Jun 2018

Cited by 24 | Viewed by 5077

Abstract

Neurotrophins and their receptors might regulate cell survival in head and neck squamous cell carcinoma (HNSCC). mRNA expression of nerve growth factor (NGF) and protein synthesis of high (NTRK1) and low affinity neurotrophin (p75 neurotrophin receptor; NTR) receptors were investigated in normal oral [...] Read more.

Neurotrophins and their receptors might regulate cell survival in head and neck squamous cell carcinoma (HNSCC). mRNA expression of nerve growth factor (NGF) and protein synthesis of high (NTRK1) and low affinity neurotrophin (p75 neurotrophin receptor; NTR) receptors were investigated in normal oral mucosa and in HNSCC. HNSCC cell lines were treated with mitomycin C (MMC) and cell survival was investigated. Normal and malignant epithelial cells expressed NGF mRNA. NTRK1 was upregulated in 80% of HNSCC tissue, and 50% of HNSCC samples were p75NTR positive. Interestingly, in HNSCC tissue: NTRK1 and p75NTR immunohistochemical reactions were mutually exclusive. Detroit 562 cell line contained only p75NTR, UPCI-SCC090 cells synthesized NTRK1 but not p75NTR and SCC-25 culture had p75NTR and NTRK1 in different cells. NGF (100 ng/mL) significantly improved (1.4-fold) the survival of cultured UPCI-SCC090 cells after MMC-induced cell cycle arrest, while Detroit 562 cells with high levels of p75NTR did not even get arrested by single short MMC treatment. p75NTR in HNSCC might be related with NGF-independent therapy resistance, while NTRK1 might transduce a survival signal of NGF and contribute in this way to improved tumor cell survival after cell cycle arrest. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics)

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17 pages, 18756 KiB

Open AccessArticle

Photodynamic Effect of Methylene Blue and Low Level Laser Radiation in Head and Neck Squamous Cell Carcinoma Cell Lines

by Barbara Kofler, Angela Romani, Christian Pritz, Teresa Bernadette Steinbichler, Volker Hans Schartinger, Herbert Riechelmann and Jozsef Dudas

Int. J. Mol. Sci. 2018, 19(4), 1107; https://doi.org/10.3390/ijms19041107 - 7 Apr 2018

Cited by 56 | Viewed by 7463

Abstract

Photodynamic therapy (PDT) is suggested to have an impact on the treatment of early stage head and neck cancers (HNSCC). We investigated the effect of PDT with methylene blue (MB) and a diode laser (660 nm) as the laser source on HNSCC cell [...] Read more.

Photodynamic therapy (PDT) is suggested to have an impact on the treatment of early stage head and neck cancers (HNSCC). We investigated the effect of PDT with methylene blue (MB) and a diode laser (660 nm) as the laser source on HNSCC cell lines as an in vitro model of surface oral squamous cell carcinoma. Cell-cultures were exposed to 160 µM MB for 4 min and to laser light for 8 min. Viability was proven via cell viability assay and clonogenic survival via clone counting assay. The combination of MB and diode laser evidenced high efficient loss of cell viability by 5% of the control, while treatment with the same concentration of MB for 4 min alone showed a viability of 46% of the control. In both SCC-25 and Detroit 562 HNSCC cells, MB combined with the laser allowed a significant abrogation of clonogenic growth (p < 0.01), especially in the case of Detroit 562 cells less than 1% of the suspension plated cells were able to grow tumor cell nests. Multiresistant (Detroit 562) HNSCC cells expressing cancer stem cell markers are sensitive to MB/red laser combined PDT. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics)

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Open AccessArticle

Midkine and NANOG Have Similar Immunohistochemical Expression Patterns and Contribute Equally to an Adverse Prognosis of Oral Squamous Cell Carcinoma

by Hyun-Min Kim, Young-Hoon Kang, June-Ho Byun, Si-Jung Jang, Gyu-Jin Rho, Jong-Sil Lee and Bong-Wook Park

Int. J. Mol. Sci. 2017, 18(11), 2339; https://doi.org/10.3390/ijms18112339 - 6 Nov 2017

Cited by 17 | Viewed by 4204

Abstract

To increase the overall survival rate and obtain a better prognosis for oral squamous cell carcinoma (OSCC) patients, the detection of more effective and reliable tumor prognostic markers is needed. This study is focused on the analysis of correlation between the clinicopathological features [...] Read more.

To increase the overall survival rate and obtain a better prognosis for oral squamous cell carcinoma (OSCC) patients, the detection of more effective and reliable tumor prognostic markers is needed. This study is focused on the analysis of correlation between the clinicopathological features of OSCCs and the immunohistochemical (IHC) expression patterns of MIDKINE (MK) and NANOG. Sixty-two primary OSCC patients were selected and their pretreatment biopsy specimens were immunohistochemically analyzed for the MK and NANOG proteins. The IHC expression patterns, clinicopathological features, and overall survival rates were assessed to identify any correlations. MK and NANOG showed significantly similar IHC expression patterns: both demonstrated enhanced expression in histologically high-grade and clinically late-stage OSCCs. Weak or negative expression of MK and NANOG was correlated with negative neck node metastasis. Clinicopathologically, late tumor stage, neck node metastasis, high-grade tumor, and palliative treatment groups showed significantly lower overall survival rates. The enhanced expression of MK and NANOG was associated with lower overall survival rates. In particular, enhanced co-detection of MK and NANOG showed significant correlation with poor prognosis. In conclusion, enhanced IHC expression patterns of MK and NANOG in OSCC patients was significantly associated with lower overall survival rates and unfavorable clinicopathological features. These results demonstrate that analysis of IHC expression patterns of MK and NANOG in pretreatment biopsy specimens during the work-up period can provide a more definitive prognosis prediction for each OSCC patient that can help clinicians to develop a more precise individual treatment modality. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics)

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21 pages, 2347 KiB

Open AccessReview

Microenvironment in Oral Potentially Malignant Disorders: Multi-Dimensional Characteristics and Mechanisms of Carcinogenesis

by Shuzhi Deng, Shimeng Wang, Xueke Shi and Hongmei Zhou

Int. J. Mol. Sci. 2022, 23(16), 8940; https://doi.org/10.3390/ijms23168940 - 11 Aug 2022

Cited by 9 | Viewed by 3033

Abstract

Oral potentially malignant disorders (OPMDs) are a group of diseases involving the oral mucosa and that have a risk of carcinogenesis. The microenvironment is closely related to carcinogenesis and cancer progression by regulating the immune response, cell metabolic activities, and mechanical characteristics. Meanwhile, [...] Read more.

Oral potentially malignant disorders (OPMDs) are a group of diseases involving the oral mucosa and that have a risk of carcinogenesis. The microenvironment is closely related to carcinogenesis and cancer progression by regulating the immune response, cell metabolic activities, and mechanical characteristics. Meanwhile, there are extensive interactions between the microenvironments that remodel and provide favorable conditions for cancer initiation. However, the changes, exact roles, and interactions of microenvironments during the carcinogenesis of OPMDs have not been fully elucidated. Here, we present an updated landscape of the microenvironments in OPMDs, emphasizing the changes in the immune microenvironment, metabolic microenvironment, mechanical microenvironment, and neural microenvironment during carcinogenesis and their carcinogenic mechanisms. We then propose an immuno–metabolic–mechanical–neural interaction network to describe their close relationships. Lastly, we summarize the therapeutic strategies for targeting microenvironments, and provide an outlook on future research directions and clinical applications. This review depicts a vivid microenvironment landscape and sheds light on new strategies to prevent the carcinogenesis of OPMDs. Full article

(This article belongs to the Special Issue Oral Cancer—Etiopathogenesis and New Mechanisms of Oral Cancerogenesis)

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21 pages, 1303 KiB

Open AccessReview

Fourier Transform Infrared Spectroscopy in Oral Cancer Diagnosis

by Rong Wang and Yong Wang

Int. J. Mol. Sci. 2021, 22(3), 1206; https://doi.org/10.3390/ijms22031206 - 26 Jan 2021

Cited by 62 | Viewed by 10132

Abstract

Oral cancer is one of the most common cancers worldwide. Despite easy access to the oral cavity and significant advances in treatment, the morbidity and mortality rates for oral cancer patients are still very high, mainly due to late-stage diagnosis when treatment is [...] Read more.

Oral cancer is one of the most common cancers worldwide. Despite easy access to the oral cavity and significant advances in treatment, the morbidity and mortality rates for oral cancer patients are still very high, mainly due to late-stage diagnosis when treatment is less successful. Oral cancer has also been found to be the most expensive cancer to treat in the United States. Early diagnosis of oral cancer can significantly improve patient survival rate and reduce medical costs. There is an urgent unmet need for an accurate and sensitive molecular-based diagnostic tool for early oral cancer detection. Fourier transform infrared spectroscopy has gained increasing attention in cancer research due to its ability to elucidate qualitative and quantitative information of biochemical content and molecular-level structural changes in complex biological systems. The diagnosis of a disease is based on biochemical changes underlying the disease pathology rather than morphological changes of the tissue. It is a versatile method that can work with tissues, cells, or body fluids. In this review article, we aim to summarize the studies of infrared spectroscopy in oral cancer research and detection. It provides early evidence to support the potential application of infrared spectroscopy as a diagnostic tool for oral potentially malignant and malignant lesions. The challenges and opportunities in clinical translation are also discussed. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics 2020)

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13 pages, 887 KiB

Open AccessReview

Current Trends and Future Prospects of Molecular Targeted Therapy in Head and Neck Squamous Cell Carcinoma

by Naoya Kitamura, Shinya Sento, Yasumasa Yoshizawa, Eri Sasabe, Yasusei Kudo and Tetsuya Yamamoto

Int. J. Mol. Sci. 2021, 22(1), 240; https://doi.org/10.3390/ijms22010240 - 29 Dec 2020

Cited by 139 | Viewed by 9330

Abstract

In recent years, advances in drug therapy for head and neck squamous cell carcinoma (HNSCC) have progressed rapidly. In addition to cytotoxic anti-cancer agents such as platinum-based drug (cisplatin and carboplatin) and taxane-based drugs (docetaxel and paclitaxel), epidermal growth factor receptor-tyrosine kinase inhibitors [...] Read more.

In recent years, advances in drug therapy for head and neck squamous cell carcinoma (HNSCC) have progressed rapidly. In addition to cytotoxic anti-cancer agents such as platinum-based drug (cisplatin and carboplatin) and taxane-based drugs (docetaxel and paclitaxel), epidermal growth factor receptor-tyrosine kinase inhibitors (cetuximab) and immune checkpoint inhibitors such as anti-programmed cell death-1 (PD-1) antibodies (nivolumab and pembrolizumab) have come to be used. The importance of anti-cancer drug therapy is increasing year by year. Therefore, we summarize clinical trials of molecular targeted therapy and biomarkers in HNSCC from previous studies. Here we show the current trends and future prospects of molecular targeted therapy in HNSCC. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics 2020)

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20 pages, 269 KiB

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Leukoplakia and Immunology: New Chemoprevention Landscapes?

by Roberto Grigolato, Maria Eleonora Bizzoca, Luca Calabrese, Stefania Leuci, Michele Davide Mignogna and Lorenzo Lo Muzio

Int. J. Mol. Sci. 2020, 21(18), 6874; https://doi.org/10.3390/ijms21186874 - 19 Sep 2020

Cited by 13 | Viewed by 3541

Abstract

Oral potentially malignant disorders (OPMDs) comprise a range of clinical-pathological alterations frequently characterized by an architectural and cytological derangements upon histological analysis. Among them, oral leukoplakia is the most common type of these disorders. This work aims to analyze the possible use of [...] Read more.

Oral potentially malignant disorders (OPMDs) comprise a range of clinical-pathological alterations frequently characterized by an architectural and cytological derangements upon histological analysis. Among them, oral leukoplakia is the most common type of these disorders. This work aims to analyze the possible use of drugs such as immunochemopreventive agents for OPMDs. Chemoprevention is the use of synthetic or natural compounds for the reversal, suppression, or prevention of a premalignant lesion conversion to malignant form. Experimental and in vivo data offer us the promise of molecular prevention through immunomodulation; however, currently, there is no evidence for the efficacy of these drugs in the chemoprevention action. Alternative ways to deliver drugs, combined use of molecules with complementary antitumor activities, diet influence, and better definition of individual risk factors must also be considered to reduce toxicity, improve compliance to the protocol treatment and offer a better individualized prevention. In addition, we must carefully reconsider the mode of action of many traditional cancer chemoprevention agents on the immune system, such as enhancing immunosurveillance and reversing the immune evasion. Several studies emphasize the concept of green chemoprevention as an alternative approach to accent healthy lifestyle changes in order to decrease the incidence of HNSCC. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics 2020)

10 pages, 567 KiB

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Involvement of Fusobacterium Species in Oral Cancer Progression: A Literature Review Including Other Types of Cancer

by Natsumi Fujiwara, Naoya Kitamura, Kaya Yoshida, Tetsuya Yamamoto, Kazumi Ozaki and Yasusei Kudo

Int. J. Mol. Sci. 2020, 21(17), 6207; https://doi.org/10.3390/ijms21176207 - 27 Aug 2020

Cited by 40 | Viewed by 6159

Abstract

Chronic inflammation caused by infections has been suggested to be one of the most important cause of cancers. It has recently been shown that there is correlation between intestinal bacteria and cancer development including metastasis. As over 700 bacterial species exist in an [...] Read more.

Chronic inflammation caused by infections has been suggested to be one of the most important cause of cancers. It has recently been shown that there is correlation between intestinal bacteria and cancer development including metastasis. As over 700 bacterial species exist in an oral cavity, it has been concerning that bacterial infection may cause oral cancer. However, the role of bacteria regarding tumorigenesis of oral cancer remains unclear. Several papers have shown that Fusobacterium species deriving the oral cavities, especially, play a crucial role for the development of colorectal and esophageal cancer. F. nucleatum is a well-known oral bacterium involved in formation of typical dental plaque on human teeth and causing periodontal diseases. The greatest characteristic of F. nucleatum is its ability to adhere to various bacteria and host cells. Interestingly, F. nucleatum is frequently detected in oral cancer tissues. Moreover, detection of F. nucleatum is correlated with the clinical stage of oral cancer. Although the detailed mechanism is still unclear, Fusobacterium species have been suggested to be associated with cell adhesion, tumorigenesis, epithelial-to-mesenchymal transition, inflammasomes, cell cycle, etc. in oral cancer. In this review, we introduce the reports focused on the association of Fusobacterium species with cancer development and progression including oral, esophageal, and colon cancers. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics 2020)

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21 pages, 667 KiB

Open AccessReview

Hallmarks of Cancer-Related Newly Prognostic Factors of Oral Squamous Cell Carcinoma

by Tomonori Sasahira and Tadaaki Kirita

Int. J. Mol. Sci. 2018, 19(8), 2413; https://doi.org/10.3390/ijms19082413 - 16 Aug 2018

Cited by 187 | Viewed by 16497

Abstract

Head and neck cancer, including oral squamous cell carcinoma (OSCC), is the sixth leading malignancy worldwide. OSCC is an aggressive tumor and its prognosis has exhibited little improvement in the last three decades. Comprehensive elucidation of OSCC’s molecular mechanism is imperative for early [...] Read more.

Head and neck cancer, including oral squamous cell carcinoma (OSCC), is the sixth leading malignancy worldwide. OSCC is an aggressive tumor and its prognosis has exhibited little improvement in the last three decades. Comprehensive elucidation of OSCC’s molecular mechanism is imperative for early detection and treatment, improving patient survival. Based on broadly accepted notions, OSCC arises from multiple genetic alterations caused by chronic exposure to carcinogens. In 2011, research revealed 10 key alterations fundamental to cancer cell development: sustaining proliferative signaling, evading growth suppressors, avoiding immune destruction, activating invasion and metastasis, tumor-promoting inflammation, enabling replicative immortality, inducing angiogenesis, genome instability and mutation, resisting cell death, and deregulating energetics. This review describes molecular pathological findings on conventional and novel hallmarks of OSCC prognostic factors. In addition, the review summarizes the functions and roles of several molecules as novel OSCC prognosticators. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics)

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15 pages, 571 KiB

Open AccessReview

Liquid Biopsy in Oral Cancer

by Fatima Lousada-Fernandez, Oscar Rapado-Gonzalez, Jose-Luis Lopez-Cedrun, Rafael Lopez-Lopez, Laura Muinelo-Romay and Maria Mercedes Suarez-Cunqueiro

Int. J. Mol. Sci. 2018, 19(6), 1704; https://doi.org/10.3390/ijms19061704 - 8 Jun 2018

Cited by 82 | Viewed by 10996

Abstract

Oral cancer is one of the most prevalent forms of cancer worldwide. Carcinogenesis is a complex process, in which heterogeneity plays an important role in the development and progression of the disease. This review provides an overview of the current biological and clinical [...] Read more.

Oral cancer is one of the most prevalent forms of cancer worldwide. Carcinogenesis is a complex process, in which heterogeneity plays an important role in the development and progression of the disease. This review provides an overview of the current biological and clinical significance of circulating tumour cells (CTCs), circulating tumour DNA (ctDNA), and exosomes for diagnosis and prognosis of oral cancer. We highlight the importance of liquid biopsy—using blood and saliva—which represents a potential alternative to solid biopsy for diagnosis and prognosis. Moreover, liquid biomarkers allow for the real-time monitoring of tumour evolution and therapeutic responses, initiating the era of personalized medicine. However, in oral cancer, the impact of liquid biopsies in clinical settings is still limited, requiring further studies to discover the best scenario for its clinical use. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics)

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20 pages, 1231 KiB

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by Samadarani B. S. M. Siriwardena, Takaaki Tsunematsu, Guangying Qi, Naozumi Ishimaru and Yasusei Kudo

Int. J. Mol. Sci. 2018, 19(5), 1462; https://doi.org/10.3390/ijms19051462 - 14 May 2018

Cited by 44 | Viewed by 5763

Abstract

It is well recognized that the presence of cervical lymph node metastasis is the most important prognostic factor in oral squamous cell carcinoma (OSCC). In solid epithelial cancer, the first step during the process of metastasis is the invasion of cancer cells into [...] Read more.

It is well recognized that the presence of cervical lymph node metastasis is the most important prognostic factor in oral squamous cell carcinoma (OSCC). In solid epithelial cancer, the first step during the process of metastasis is the invasion of cancer cells into the underlying stroma, breaching the basement membrane (BM)—the natural barrier between epithelium and the underlying extracellular matrix (ECM). The ability to invade and metastasize is a key hallmark of cancer progression, and the most complicated and least understood. These topics continue to be very active fields of cancer research. A number of processes, factors, and signaling pathways are involved in regulating invasion and metastasis. However, appropriate clinical trials for anti-cancer drugs targeting the invasion of OSCC are incomplete. In this review, we summarize the recent progress on invasion-related factors and emerging molecular determinants which can be used as potential for diagnostic and therapeutic targets in OSCC. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics)

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24 pages, 30261 KiB

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Survivin-Based Treatment Strategies for Squamous Cell Carcinoma

by Andrea Santarelli, Marco Mascitti, Lucio Lo Russo, Davide Sartini, Giuseppe Troiano, Monica Emanuelli and Lorenzo Lo Muzio

Int. J. Mol. Sci. 2018, 19(4), 971; https://doi.org/10.3390/ijms19040971 - 24 Mar 2018

Cited by 43 | Viewed by 7163

Abstract

Survivin, an anti-apoptotic molecule abundantly expressed in most human neoplasms, has been reported to contribute to cancer initiation and drug resistance in a wide variety of human tumors. Efficient downregulation of survivin can sensitize tumor cells to various therapeutic interventions, generating considerable efforts [...] Read more.

Survivin, an anti-apoptotic molecule abundantly expressed in most human neoplasms, has been reported to contribute to cancer initiation and drug resistance in a wide variety of human tumors. Efficient downregulation of survivin can sensitize tumor cells to various therapeutic interventions, generating considerable efforts in its validation as a new target in cancer therapy. This review thoroughly analyzes up-to-date information on the potential of survivin as a therapeutic target for new anticancer treatments. The literature dealing with the therapeutic targeting of survivin will be reviewed, discussing specifically squamous cell carcinomas (SCCs), and with emphasis on the last clinical trials. This review gives insight into the recent developments undertaken in validating various treatment strategies that target survivin in SCCs and analyze the translational possibility, identifying those strategies that seem to be the closest to being incorporated into clinical practice. The most recent developments, such as dominant-negative survivin mutants, RNA interference, anti-sense oligonucleotides, small-molecule inhibitors, and peptide-based immunotherapy, seem to be helpful for effectively downregulating survivin expression and reducing tumor growth potential, increasing the apoptotic rate, and sensitizing tumor cells to chemo- and radiotherapy. However, selective and efficient targeting of survivin in clinical trials still poses a major challenge. Full article

(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics)

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