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Publisher Copyright: Copyright © 2022 Naakka, Barros-Filho, Adnan-Awad, Al-Samadi, Marchi, Kuasne, Korelin, Suleymanova, Brown, Scapulatempo-Neto, Lourenço, Castilho, Kowalski, Mäkitie, Araújo, Leivo, Rogatto, Salo and Passador-Santos. Objectives: To integrate mRNA and miRNA expression profiles of mucoepidermoid carcinomas (MECs) and normal salivary gland (NSGs) tissue samples and identify potential drivers. Material and Methods: Gene and miRNA expression arrays were performed in 35 MECs and six NSGs. Results: We found 46 differentially expressed (DE) miRNAs and 3,162 DE mRNAs. Supervised hierarchical clustering analysis of the DE transcripts revealed two clusters in both miRNA and mRNA profiles, which distinguished MEC from NSG samples. The integrative miRNA-mRNA analysis revealed a network comprising 696 negatively correlated interactions (44 miRNAs and 444 mRNAs) involving cell signaling, cell cycle, and cancer-related pathways. Increased expression levels of miR-205-5p and miR-224-5p and decreased expression levels of miR-139-3p, miR-145-3p, miR-148a-3p, miR-186-5p, miR-338-3p, miR-363-3p, and miR-4324 were significantly related to worse overall survival in MEC patients. Two overexpressed miRNAs in MEC (miR-22 and miR-205) were selected for inhibition by the CRISPR-Cas9 method. Cell viability, migration, and invasion assays were performed using an intermediate grade MEC cell line. Knockout of miR-205 reduced cell viability and enhanced ZEB2 expression, while miR-22 knockout reduced cell migration and invasion and enhanced ESR1 expression. Our results indicate a distinct transcriptomic profile of MEC compared to NSG, and the integrative analysis highlighted miRNA-mRNA interactions involving cancer-related pathways, including PTEN and PI3K/AKT. Conclusion: The in vitro functional studies revealed that miR-22 and miR-205 deficiencies reduced the viability, migration, and invasion of the MEC cells suggesting they are potential oncogenic drivers in MEC.

Various in vitro models using primary and established 2- and 3-dimensional cultures, multicellular tumor spheroids, standardized tumor slice cultures, tumor organoids, and microfluidic systems obtained from tumor lesions/biopsies of head and neck cancer (HNC) have been employed for exploring and monitoring treatment options. All of these in vitro models are to a different degree able to capture the diversity of tumors, recapitulate the disease genetically, histologically, and functionally and retain their tumorigenic potential upon xenotransplantation. The models were used for the characterization of the malignant features of the tumors and for in vitro screens of drugs approved for the treatment of HNC, including chemotherapy and radiotherapy as well as recently developed targeted therapies and immunotherapies, or for novel treatments not yet licensed for these tumor entities. The implementation of the best suitable model will enlarge our knowledge of the oncogenic properties of HNC, expand the drug repertoire and help to develop individually tailored treatment strategies resulting in the translation of these findings into the clinic. This review summarizes the different approaches using preclinical in vitro systems with their advantages and disadvantages and their implementation as preclinical platforms to predict disease course, evaluate biomarkers and test therapy efficacy.

Lymphangiogenesis is a key process in cancer development and metastasis. Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) is a widely used marker for lymphatic endothelial cells (LEC), which also mediates immune and cancer cell migration. Recently, LYVE-1-positive tumor cells were shown to acquire LEC-like phenotype and exploit this receptor for lymphatic dissemination. Furthermore, selective targeting of LYVE-1 impaired the growth of cancer-related vasculature and reduced metastasis in vivo, signifying its role in therapeutic and prognostic applications. Although numerous studies have investigated the role of LYVE-1 in cancer, a unifying detailed review of its prognostic utility is lacking to date. Thus, we compiled and critically appraised evidence from clinical studies comprising a total of 2352 patients diagnosed with different types of cancer and using a variety of experimental approaches. Collectively, most studies revealed a significant association between LYVE-1 overexpression and dismal outcome of at least one survival estimate. Furthermore, the importance of vasculature location, intra- or peritumoral, and the influence of various lymphangiogenesis-related parameters, such as lymphatic vessel density and invasion, were discussed. However, the specificity of LYVE-1 staining is challenged by its expression in non-LEC cells, implying the need for double labelling to better estimate its prognostic significance. In conclusion, this is to our knowledge the first comprehensive systematic review on the prognostic value of LYVE-1 in cancer. More well-designed studies across different populations and the development of standardized protocols would be paramount for the consistency of LYVE-1 findings and for its potential transferability to clinical practice in future.

Simple Summary Head and neck squamous cell carcinoma (HNSCC) is a group of common and aggressive tumors. Recently, oral microbiota has been credited as an important player in carcinogenesis. However, the available knowledge is not always consistent and sometimes conflicting. Therefore, the present comprehensive systematic review of the current clinical reports was conducted to evaluate the role of oral microbiota in HNSCC. Importantly, this study addresses whether oral microbiota targeting could provide diagnostic, prognostic or therapeutic utility in cancer patients. We also discussed the current limitations of this newly emerging field and the potential related strategies for the management of patients with HNSCC and possibly other solid tumors. Head and neck squamous cell carcinoma (HNSCC) comprises the majority of tumors in head and neck tissues. The prognosis of HNSCC has not significantly improved for decades, signifying the need for new diagnostic and therapeutic targets. Recent evidence suggests that oral microbiota is associated with carcinogenesis. Thus, we conducted a comprehensive systematic review to evaluate the current evidence regarding the role of oral microbiota in HNSCC and whether their targeting may confer diagnostic, prognostic or therapeutic utility. Following the screening of 233 publications retrieved from multiple databases, 34 eligible studies comprising 2469 patients were compiled and critically appraised. Importantly, many oral pathogens, such as Porphyromonas gingivalis and Fusobacterium nucleatum were linked to certain oral potentially malignant lesions and various types of HNSCC. Furthermore, we summarized the association between the expression profiles of different oral bacterial species and their tumorigenic and prognostic effects in cancer patients. We also discussed the current limitations of this newly emerging area and the potential microbiota-related strategies for preventing and treating HNSCC. Whilst many clinical studies are underway to unravel the role of oral microbiota in cancer, the limited available data and experimental approaches reflect the newness of this promising yet challenging field.

ObjectiveOver many decades, studies on histopathological features have not only presented high-level evidence of contribution for treatment directions and prognosis of oral squamous cell carcinoma (OSCC) but also provided inconsistencies, making clinical application difficult. The 8th TNM staging system of OSCC has acknowledged the importance of some histopathological features, by incorporating depth of invasion (DOI) to T category and extranodal extension (ENE) to N category. The aim of this systematic review with meta-analysis is to determine the most clinically relevant histopathological features for risk assessment and treatment planning of OSCC and to elucidate gaps in the literature. MethodsA systematic review was conducted using PRISMA guidelines, and the eligibility criteria were based on population, exposure, comparison, outcome, and study type (PECOS). PubMed, Cochrane, Scopus, and Web of Science were searched for articles exploring the impact of histopathological features on OSCC outcomes with Cox multivariate analysis. Pooled data were subjected to an inverse variance method with random effects or fixed effect model, and the risk of bias was evaluated using quality in prognosis studies (QUIPS). Quality of evidence was assessed with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. ResultsThe study included 172 articles published from 1999 to 2021. Meta-analyses confirmed the prognostic potential of DOI, ENE, perineural invasion, lymphovascular invasion, and involvement of the surgical margins and brought promising results for the association of bone invasion, tumor thickness, and pattern of invasion with increased risk for poor survival. Although with a small number of studies, the results also revealed a clinical significance of tumor budding and tumor-stroma ratio on predicted survival of patients with OSCC. Most of the studies were considered with low or moderate risk of bias, and the certainty in evidence varied from very low to high. ConclusionOur results confirm the potential prognostic usefulness of many histopathological features and highlight the promising results of others; however, further studies are advised to apply consistent designs, filling in the literature gaps to the pertinence of histopathological markers for OSCC prognosis. Systematic Review RegistrationInternational Prospective Register of Systematic Reviews (PROSPERO), identifier CRD42020219630.

Oral squamous cell carcinoma (OSCC), the most common oral malignancy, shows an increasing rate of incidence worldwide. In spite of the recent advances in cancer research, OSCC therapy continues to have unfavourable outcomes, and thus patient’s prognosis remains relatively poor. Current research has been devoted to identifying novel therapeutic targets also in the tumour microenvironment (TME). Histamine and its G-protein coupled receptors (H1R-H4R) play vital roles in multiple cancer-associated processes in TME, where histamine is mainly produced by mast cells. However, oral epithelial cells were recently shown to produce low concentrations of histamine in autocrine and paracrine modes. These findings, together with the discovery of the high-affinity histamine H4 receptor, have led to a massive increase in our understanding of histamine functions. This minireview aims to summarize the most recent findings regarding histamine and its receptors and their involvement in oral carcinogenesis—from oral potentially malignant disorders (OPMDs) to invasive OSCC. Importantly, histamine receptors are differentially expressed in OPMDs and OSCC. Furthermore, H1R and H4R are associated with clinicopathological characteristics of OSCC patients, suggesting a role in prognosis. Due to the enormous success of histamine-based medications, histamine receptors may also represent promising and viable drug targets in oral cancer.

Background Head and neck squamous cell carcinoma (HNSCC) carries poor survival outcomes despite recent progress in cancer treatment in general. Angiogenesis is crucial for tumour survival and progression. Therefore, several agents targeting the pathways that mediate angiogenesis have been developed. We conducted a systematic review to summarise the current clinical trial data examining angiogenesis inhibitors in HNSCC. Methods We carried out a literature search on three angiogenesis inhibitor categories-bevacizumab, tyrosine kinase inhibitors and endostatin-from Ovid MEDLINE, Cochrane Library, Scopus and ClinicalTrials.gov database. Results Here, we analysed 38 clinical trials, total of 1670 patients, investigating 12 angiogenesis inhibitors. All trials were in phase I or II, except one study in phase III on bevacizumab. Angiogenesis inhibitors were used as mono- and combination therapies together with radio-, chemo-, targeted- or immunotherapy. Among 12 angiogenesis inhibitors, bevacizumab was the most studied drug, included in 13 trials. Although bevacizumab appeared effective in various combinations, it associated with high toxicity levels. Endostatin and lenvatinib were well-tolerated and their anticancer effects appeared promising. Conclusions Most studies did not show benefit of angiogenesis inhibitors in HNSCC treatment. Additionally, angiogenesis inhibitors were associated with considerable toxicity. However, some results appear encouraging, suggesting that further investigations of angiogenesis inhibitors, particularly in combination therapies, for HNSCC patients are warranted. Systematic Review Registration PROSPERO (https://www.crd.york.ac.uk/prospero/), identifier CRD42020157144.

cited By 0 Wild berries are part of traditional Nordic diets and are a rich source of phytochemicals, such as polyphenols. Various berry treatments have shown to interfere with cancer progression in vitro and in vivo. Here, we systematically reviewed the anticancer effects of two Nordic wild berries of the Vaccinium genus, lingonberry (Vaccinium vitis-idaea) and bilberry (Vaccinium myrtillus), on digestive tract cancers. The review was conducted according to the PRISMA 2020 guidelines. Searches included four databases: PubMed, Scopus, Web of Science, and CAB abstracts. Publications not written in English, case-reports, reviews, and conference abstracts were excluded. Moreover, studies with only indirect markers of cancer risk or studies with single compounds not derived from lingonberry or bilberry were not included. Meta-analysis was not performed. The majority (21/26) of studies investigated bilberry and colorectal cancer. Experimental studies on colorectal cancer indicated that bilberry inhibited intestinal tumor formation and cancer cell growth. One uncontrolled pilot human study supported the inhibitory potential of bilberry on colorectal cancer cell proliferation. Data from all 10 lingonberry studies suggests potent inhibition of cancer cell growth and tumor formation. In conclusion, in vitro and animal models support the antiproliferative and antitumor effects of various bilberry and lingonberry preparations on digestive tract cancers.

Although patients with early-stage oral tongue squamous cell carcinoma (OTSCC) show better survival than those with advanced disease, there is still a number of early-stage cases who will suffer from recurrence, cancer-related mortality and worse overall survival. Incorporation of an immune descriptive factor in the staging system can aid in improving risk assessment of early OTSCC. A total of 290 cases of early-stage OTSCC re-classified according to the American Joint Committee on Cancer (AJCC 8) staging were included in this study. Scores of tumor-infiltrating lymphocytes (TILs) were divided as low or high and incorporated in TNM AJCC 8 to form our proposed TNM-Immune system. Using AJCC 8, there were no significant differences in survival between T1 and T2 tumors (p &gt, 0.05). Our proposed TNM-Immune staging system allowed for significant discrimination in risk between tumors of T1N0M0-Immune vs. T2N0M0-Immune. The latter associated with a worse overall survival with hazard ratio (HR) of 2.87 (95% CI 1.92–4.28, p &lt, 0.001), HR of 2.41 (95% CI 1.26–4.60, p = 0.008) for disease-specific survival, and HR of 1.97 (95% CI 1.13–3.43, p = 0.017) for disease-free survival. The TNM-Immune staging system showed a powerful ability to identify cases with worse survival. The immune response is an important player which can be assessed by evaluating TILs, and it can be implemented in the staging criteria of early OTSCC. TNM-Immune staging forms a step towards a more personalized classification of early OTSCC.

Head and neck squamous cell carcinoma (HNSCC) is a group of common cancers characterized by a swift growth pattern, early metastasis, and dismal 5-year survival rates. Despite the recent advances in cancer management, the multimodality approach is not effective in eradicating HNSCC. Moreover, the clinical response to the antiangiogenic therapy remains considerably limited in HNSCC patients, suggesting that tumour perfusion can take place through other non-angiogenic pathways. Tumour cell-induced angiogenesis is one of the main hallmarks of cancer. However, at the end of the previous millennium, a new paradigm of tumour cell-associated neovascularization has been reported in human melanoma cells. This new phenomenon, which was named “vasculogenic mimicry” or “vascular mimicry” (VM), describes the ability of aggressively growing tumour cells to form perfusable, matrix-rich, vessel-like networks in 3-dimenstional matrices in vitro. Similar matrix-rich VM networks were also identified in tissue samples obtained from cancer patients. To date, myriad studies have reported intriguing features of VM in a wide variety of cancers including HNSCC. We aim in this mini-review to summarize the current evidence regarding the phenomenon of VM in HNSCC—from the available detection protocols and potentially involved mechanisms, to its prognostic value and the present limitations.

Simple Summary Head and neck squamous cell carcinomas (HNSCCs) are common and among the deadliest neoplasms worldwide, wherein metastasis represents the main cause of the poor survival outcomes. Tumour cells require blood vessels in order to grow and invade the surrounding tissues. Recently, a new phenomenon termed vascular mimicry (VM) was introduced, whereby tumour cells can independently form vessel-like structures to promote their growth and metastasis. VM has been characterized in many solid tumours, including HNSCC. A large body of research evidence shows that patients with positive VM exhibit poor treatment response and dismal survival rates. Thus, VM represents a promising therapeutic and prognostic target in cancer. However, there is limited knowledge regarding the identification of VM in HNSCC (in vitro and in vivo) and what factors may influence such a phenomenon. This study aims to address these limitations, which may facilitate the therapeutic exploitation of VM in HNSCC. Abstract Tissue vasculature provides the main conduit for metastasis in solid tumours including head and neck squamous cell carcinoma (HNSCC). Vascular mimicry (VM) is an endothelial cell (EC)-independent neovascularization pattern, whereby tumour cells generate a perfusable vessel-like meshwork. Yet, despite its promising clinical utility, there are limited approaches to better identify VM in HNSCC and what factors may influence such a phenomenon in vitro. Therefore, we employed different staining procedures to assess their utility in identifying VM in tumour sections, wherein mosaic vessels may also be adopted to further assess the VM-competent cell phenotype. Using 13 primary and metastatic HNSCC cell lines in addition to murine- and human-derived matrices, we elucidated the impact of the extracellular matrix, tumour cell type, and density on the formation and morphology of cell-derived tubulogenesis in HNSCC. We then delineated the optimal cell numbers needed to obtain a VM meshwork in vitro, which revealed cell-specific variations and yet consistent expression of the EC marker CD31. Finally, we proposed the zebrafish larvae as a simple and cost-effective model to evaluate VM development in vivo. Taken together, our findings offer a valuable resource for designing future studies that may facilitate the therapeutic exploitation of VM in HNSCC and other tumours.

The cyclooxygenase-2 (COX-2) is a potent enzyme that converts arachidonic acid to prostaglandins (PG), including PGE2, a key mediator of inflammation and angiogenesis. Importantly, COX-2 is activated in response to inflammatory stimuli, where it is also believed to promote the development and progression of head and neck cancers (HNC). COX-2 can mediate its protumorigenic effect through various mechanisms, such as inducing cell proliferation, inhibition of apoptosis, and suppressing the host’s immune response. Furthermore, COX-2 can induce the production of vascular endothelial growth factors, hence, promoting angiogenesis. Indeed, the ability of COX-2 inhibitors to selectively restrict the proliferation of tumor cells and mediating apoptosis provides promising therapeutic targets for cancer patients. Thus, in this comprehensive review, we summarized the reported differential expression patterns of COX-2 in different stages of head and neck carcinogenesis—from potentially premalignant lesions to invasive carcinomas. Furthermore, we examined the available meta-analysis evidence for COX-2 role in the carcinogenesis of HNC. Finally, further understanding of the biological processes of COX-2 and its role in orchestrating cell proliferation, apoptosis, and angiogenesis may give therapeutically beneficial insight to develop the management plan of HNC patients and improve their clinical outcomes.