Neck Squamous Cancer Research Articles

Comprehensive analysis of macrophage-related multigene signature in the tumor microenvironment of head and neck squamous cancer.

Macrophages are among the most abundant cells of the tumor microenvironment in head and neck squamous cancer (HNSC). Although the marker gene sets of macrophages have been found, the mechanism by which they affect macrophages and whether they further predict the clinical outcome is unclear. In this study, a univariate COX analysis and a random forest algorithm were used to construct a prognostic model. Differential expression of the key gene, methylation status, function, and signaling pathways were further analyzed. We cross-analyzed multiple databases to detect the relationship between the most critical gene and the infiltration of multiple immune cells, as well as its impact on the prognosis of pan-cancer. FANCE is recognized as hub gene by different algorithms. It was overexpressed in HNSC, and high expression was predictive of better prognosis. It might promote apoptosis through the Wnt/β-catenin pathway. The expression of FANCE is inversely proportional to the infiltration of CD4 + T cells and their subsets, tumor-associated macrophages (TAMs), M2 macrophages, but positively co-expressed with M1 macrophages. In summary, FANCE was identified as the hub gene from the macrophage marker gene set, and it may improve the prognosis of HNSC patients by inhibiting lymphocytes and tumor-associated macrophages infiltration.

Multiple Testing, Cut-Point Optimization, and Signs of Publication Bias in Prognostic FDG-PET Imaging Studies of Head and Neck and Lung Cancer: A Review and Meta-Analysis.

Positron emission tomography (PET) imaging with 2-deoxy-2-[18F]-fluorodeoxyglucose (FDG) was proposed as prognostic marker in radiotherapy. Various uptake metrics and cut points were used, potentially leading to inflated effect estimates. Here, we performed a meta-analysis and systematic review of the prognostic value of pretreatment FDG–PET in head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC), with tests for publication bias. Hazard ratio (HR) for overall survival (OS), disease free survival (DFS), and local control was extracted or derived from the 57 studies included. Test for publication bias was performed, and the number of statistical tests and cut-point optimizations were registered. Eggers regression related to correlation of SUVmax with OS/DFS yielded p = 0.08/p = 0.02 for HNSCC and p < 0.001/p = 0.014 for NSCLC. No outcomes showed significant correlation with SUVmax, when adjusting for publication bias effect, whereas all four showed a correlation in the conventional meta-analysis. The number of statistical tests and cut points were high with no indication of improvement over time. Our analysis showed significant evidence of publication bias leading to inflated estimates of the prognostic value of SUVmax. We suggest that improved management of these complexities, including predefined statistical analysis plans, are critical for a reliable assessment of FDG–PET.

Abstract PO-089: Spatial profiling of the tumour microenvironment using digital spatial profiling

Abstract Immune checkpoint inhibitors (ICI) have shown durable and long-term benefits in a subset of head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC). To identify patient-responders from non-responders, biomarkers are needed which are predictive of outcome to ICI therapy. Cues in the tumour microenvironment (TME) have been informative in understanding the tumour-immune contexture. Methods: In this study, the NanoString GemoMx™ Digital Spatial Profiling (DSP) technology was used to determine the immune marker and compartment specific measurements in a cohort of HNSCC and NSCLC tumours from patients receiving ICI therapy. Results: Our data revealed that markers involved with immune cell infiltration (CD8 T-cells) were not predictive of outcome to ICI therapy. A number of immune cell types (CD4, CD68, CD45, CD44, CD66b) were found to correlate with progressive disease. Conclusions: Our data shows proof of principle for use of digital spatial profiling for the identification of predictive biomarkers for ICI therapy in HNSCC and NSCLC. Citation Format: Arutha Kulasinghe. Spatial profiling of the tumour microenvironment using digital spatial profiling [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-089.

Abstract 90: Inducing and targeting senescence in HPV-negative head and neck squamous cancer cells

Abstract Background: The loss of normal cell cycle regulation via disruption of CDKN2A in HPV-negative (-) head and neck squamous cell carcinoma (HNSCC) is universal. Targeting CDK4/6 with a specific inhibitor, such as palbociclib, is therefore a logical strategy in this disease. Previous work has demonstrated that CDK4/6 inhibition leads to cell cycle arrest and senescence in cancer cells, and specifically HPV(-) HNSCC. Recent studies have also shown that the BCL-xL inhibitor, ABT-263 (navitoclax), effectively targets senescent cells. This study aimed to evaluate the efficacy and mechanism of a combination approach utilizing palbociclib and ABT-263 in HNSCC. Methods: Three HPV (-) HNSCC cell lines (CAL27, HN31, PCI15B) were treated with palbociclib. Cresyl violet staining and annexin V apoptosis assays were used to assess cell viability in response to palbociclib, navitoclax, or the combination of the two drugs. Senescence following treatment with palbociclib was measured using β-galactosidase expression on western blot analysis, as well as via immunofluorescence staining assessed and quantified using confocal microscopy. Levels of BCL-xL were also measured using these methods. Results: Following treatment with palbociclib, all cell lines exhibited phenotypic evidence of senescence, and protein expression of β-galactosidase was significantly increased compared to untreated controls (mean fold change ± SD: CAL27 2.67±0.26; HN31 1.79±0.41; PCI15B 1.26±0.15). Protein expression of BCL-xL was concurrently increased under these conditions (mean fold change ± SD: CAL27 1.57±0.04; HN31 1.58±0.39; PCI15B 1.33±0.17). Immunofluorescent staining was also used to determine if cells exhibiting senescence specifically demonstrated higher BCL-xL expression. Co-expression of β-galactosidase and BCL-xL showed a strong positive correlation (CAL27 r = 0.94, p &amp;lt; 0.0001; HN31 r = 0.94, p &amp;lt; 0.0001; PCI15B r = 0.71, p &amp;lt; 0.0001). Treatment with the combination of palbociclib and navitoclax resulted in significantly decreased survival compared to each agent alone in all HNSCC cell lines tested (data summarized for the cell line panel: mean percent survival, navitoclax 76.40%; palbociclib 38.76%; combination 16.74%). Annexin V apoptosis assay also revealed that there was a significant increase in apoptosis observed in all cell lines tested comparing each agent to combination treatment (data summarized for the cell line panel: mean percent apoptotic cells, navitoclax 35.53%; palbociclib 29.95%; combination 60.98%). Apoptosis with combination of palbociclib and navitoclax approached or exceeded levels achieved with staurosporine treated controls. Conclusions: Palbociclib treatment leads to consistent induction of senescence in HPV (-) HNSCC. Adding a senolytic agent, such as the BCL-xL inhibitor ABT-263 (navitoclax) appears to be an effective strategy which holds promise in this disease. Citation Format: Nicholas Gadsden, Carlos Thomas, Daniel Li, Nitisha Shrivastava, Nicolas Schlecht, Michael Prystowsky, Jeffrey Segall, Thomas Ow. Inducing and targeting senescence in HPV-negative head and neck squamous cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 90.

Abstract B42: YAP1/Hippo pathway and SWI/SNF as critical players in squamous cancers and normal development

Abstract Cancer development is a multistep process involving deregulation of transcription/epigenetic factors and signaling pathways. Accordingly, gene expression lies at the nexus of oncogenic cellular processes. The recent advent of The Cancer Genome Atlas (TCGA) has shed light on multiple genes involved in signaling, transcription, and other cellular processes that are subjected to genomic alterations in multiple cancers. These oncogenic drivers are involved in regenerative proliferation, metastasis, and other cellular processes that contribute to tumorigenesis. Epithelial-stromal interactions and the infiltrating immune response contribute significantly to tumor progression. Our recent studies revealed Hippo pathway activation as a critical component in ACTL6A (subunit of SWI/SNF chromatin remodeling complex) amplified squamous cancers. Our published genetic studies indicate that YAP is a key mediator of the oncogenic function of ACTL6A/p63 in head and neck squamous cancers. P63 is a master transcription factor in epithelial development. We have shown that YAP and p63 biochemically interact to maintain airway architecture and regeneration. YAP and p63 deletion are phenocopies and are required to maintain normal respiratory epithelial stem cells. P63/ACTL6A act as upstream regulators of YAP in squamous cancers. ACTL6A and p63 physically interact and cooperatively control a transcriptional program that promotes proliferation and suppresses differentiation, through activation of the Hippo-YAP pathway via regulators including WWC1 and GPRC5A. Consequently, loss of ACTL6A or p63 in tumor cells induces YAP phosphorylation and inactivation, associated with growth arrest and terminal differentiation, all phenocopied by WWC1 overexpression. YAP activation predicts poor patient survival in squamous cancers. These findings are also in keeping with the emerging role of the YAP pathway as a tumor driver in multiple contexts. Given interest in YAP as a therapeutic target, our studies reveal contribution of p63 and TEAD to YAP function as evident from global transcription profiling. Our most recent studies also indicate contribution of YAP in tumor progression by evading host immune response. All these indicate an important intrinsic role of YAP in development and disease, making it one of the ideal therapeutic targets to control cancer. Citation Format: Leif Ellisen, Purushothama Rao Tata, Rui Zhao, Jayaraj Rajagopal, Srinivas Vinod Saladi. YAP1/Hippo pathway and SWI/SNF as critical players in squamous cancers and normal development [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B42.

RUVBL1 is an amplified epigenetic factor promoting proliferation and inhibiting differentiation program in head and neck squamous cancers.

Mutations in histone modifying enzymes and histone variants were identified in multiple cancers in The Cancer Genome Atlas (TCGA) studies. However, very little progress and understanding has been made in identifying the contribution of epigenetic factors in head and neck squamous cell carcinoma (HNSCC). Here, we report the identification of RUVBL1 (TIP49a), a component of the TIP60 histone modifying complex as being amplified and overexpressed in HNSCC. RUVBL1 plays a key role in incorporating histone variant H2AZ in chromatin thereby regulating transcription of key genes involved in differentiation, cancer cell proliferation and invasion. H2AZ is also overexpressed in HNSCC tumors thereby regulating RUVBL1/H2AZ dependent transcriptional programs. Patient data analysis of multiple cohorts including TCGA and single cell HNSCC data indicated RUVBL1 overexpression as a poor prognostic marker and predicts poor survival. In vitro experiments indicate a pro-proliferative role for RUVBL1/H2AZ in HNSCC cells. RUVBL1 inversely correlates with differentiation program and positively correlates with oncogenic programs, making it a key contributor to tumorigenesis and a vulnerable therapeutic target in HNSCC patients.

CCTs as new biomarkers for the prognosis of head and neck squamous cancer.

The chaperonin-containing T-complex protein 1 (CCT) subunits participate in diverse diseases. However, little is known about their expression and prognostic values in human head and neck squamous cancer (HNSC). This article aims to evaluate the effects of CCT subunits regarding their prognostic values for HNSC. We mined the transcriptional and survival data of CCTs in HNSC patients from online databases. A protein–protein interaction network was constructed and a functional enrichment analysis of target genes was performed. We observed that the mRNA expression levels of CCT1/2/3/4/5/6/7/8 were higher in HNSC tissues than in normal tissues. Survival analysis revealed that the high mRNA transcriptional levels of CCT3/4/5/6/7/8 were associated with a low overall survival. The expression levels of CCT4/7 were correlated with advanced tumor stage. And the overexpression of CCT4 was associated with higher N stage of patients. Validation of CCTs’ differential expression and prognostic values was achieved by the Human Protein Atlas and GEO datasets. Mechanistic exploration of CCT subunits by the functional enrichment analysis suggests that these genes may influence the HNSC prognosis by regulating PI3K-Akt and other pathways. This study implies that CCT3/4/6/7/8 are promising biomarkers for the prognosis of HNSC.

B Cells Improve Overall Survival in HPV-Associated Squamous Cell Carcinomas and Are Activated by Radiation and PD-1 Blockade.

To characterize the role of B cells on human papilloma virus (HPV)-associated cancer patient outcomes and determine the effects of radiation and PD-1 blockade on B-cell populations. Tumor RNA-sequencing data from over 800 patients with head and neck squamous cell carcinoma (HNSCC) and cervical cancer, including a prospective validation cohort, was analyzed to study the impact of B-cell gene expression on overall survival (OS). A novel murine model of HPV+ HNSCC was used to study the effects of PD-1 blockade and radiotherapy on B-cell activation, differentiation, and clonality including analysis by single-cell RNA-sequencing and B-cell receptor (BCR)-sequencing. Human protein microarray was then used to quantify B-cell-mediated IgG and IgM antibodies to over 16,000 proteins in the serum of patients treated on a clinical trial with PD-1 blockade. RNA-sequencing identified CD19 and IGJ as novel B-cell prognostic biomarkers for 3-year OS (HR, 0.545; P < 0.001). PD-1 blockade and radiotherapy enhance development of memory B cells, plasma cells, and antigen-specific B cells. BCR-sequencing found that radiotherapy enhances B-cell clonality, decreases CDR3 length, and induces B-cell somatic hypermutation. Single-cell RNA-sequencing identified dramatic increases in B-cell germinal center formation after PD-1 blockade and radiotherapy. Human proteome array revealed enhanced IgG and IgM antibody responses in patients who derived clinical benefit but not those with progressive disease after treatment with PD-1 blockade. These findings establish a key role for B cells in patient outcomes and responses to PD-1 blockade in HPV-associated squamous cell carcinomas and demonstrate the need for additional diagnostics and therapeutics targeting B cells.

Abstract PR06: Tumor-infiltrating B cells colocalize with CD4 T effector cells within tertiary lymphoid structures to present antigen and educate the antitumor immune response in human primary tumors

Abstract Despite the success of checkpoint blockade immunotherapies, i.e., anti-PD1, only 20% of patients produce a durable response to these treatments. Thus, a need exists to develop additional therapeutic strategies to treat these patients, which includes evaluation of other tumor-infiltrating immune cells that could further augment the CD8+ and CD4+ T-cell response. Tumor-infiltrating B cells (TIL-B) represent a possible target for immunotherapy due to their predominance in the tumor microenvironment and crucial role in the immune response. In fact, current evidence suggests an antitumor role for TIL-Bs. Specifically, detection of TIL-Bs within tertiary lymphoid structures (TLS) correlates with both increased survival in patients with solid tumors and enhanced response to anti-PD1 immunotherapy. We hypothesize that TIL-Bs help generate potent, long-term immune responses against cancer by presenting tumor antigens to CD4 TILs within TLS. Utilizing single-cell RNAseq and high-level flow cytometry, we observed increased numbers of activated TIL-Bs in the primary tumors of head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) patients. We further assessed the location of TIL-Bs within the TME and determined that they predominantly sit adjacent to CD4+ tumor-infiltrating lymphocytes (TILs) within TLS. Thus, we generated an antigen presentation assay in vitro, and we observed increased CD4+ TIL responses when TIL-Bs presented autologous tumor antigens. Further, there was a differential impact on CD4+ TIL phenotype; specifically, if TIL-Bs were activated (CD27+), the CD4+ TILs were T helper (anti-tumor) CD4+ T cells and if the TIL-Bs were nonactivated (CD27-), the CD4+ TILs were T regulatory cells (protumor). These data suggest that TIL-Bs influence the phenotype and function of CD4+ TILs in patient tumors within TLS. Ultimately, results from this study will increase effective targeting of TIL-Bs within patient primary tumors. Citation Format: Ayana T. Ruffin, Anthony R. Cillo, Sheryl Kunning, Robert L. Ferris, Dario A.A. Vignali, Tullia C. Bruno. Tumor-infiltrating B cells colocalize with CD4 T effector cells within tertiary lymphoid structures to present antigen and educate the antitumor immune response in human primary tumors [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr PR06.

CHK1/2 Inhibitor Prexasertib Suppresses NOTCH Signaling and Enhances Cytotoxicity of Cisplatin and Radiation in Head and Neck Squamous Cell Carcinoma.

Platinum-based chemoradiotherapy is a mainstay of organ-preserving therapy for patients with head and neck squamous cell carcinoma cancer (HNSCC). However, the disease eventually becomes resistant to treatment necessitating new therapies. Checkpoint kinase 1 and 2 (CHK1/2) are serine/threonine kinases that activate cell-cycle checkpoints and serve a critical role in the DNA-damage response (DDR). As resistance to cisplatin and radiation may involve a heightened DDR, we hypothesized that prexasertib, an inhibitor of CHK1/2, may enhance the cytotoxicity induced by cisplatin and irradiation in HNSCC. In this study, we found that combining prexasertib with cisplatin and radiation significantly decreased the in vitro survival fraction in HNSCC cell lines both with and without radiotherapy. Reduced survival was accompanied by inhibition of DNA repair checkpoint activation, which resulted in persistent DNA damage and increased apoptosis. In addition, NanoString analysis with the PanCancer Pathways Panel revealed that prexasertib downregulated NOTCH signaling target genes (NOTCH1, NOTCH2, and NOTCH3) and their associated ligands (JAG1, JAG2, SKP2, MAML2, and DLL1). Prexasertib also reduced NOTCH1, NOTCH3 and HES1 protein expression. Importantly, a significant tumor growth delay was observed in vivo in both human papillomavirus (HPV)-positive UM-SCC47 and HPV-negative UM-SCC1 cell line xenografts treated with prexasertib, cisplatin, and radiotherapy without increased toxicity as measured by mouse body weight. Taken together, prexasertib reduced NOTCH signaling and enhanced the in vitro and in vivo response of HNSCCs to cisplatin and radiation, suggesting combination therapy may increase clinical benefit. A clinical trial has recently completed accrual (NCT02555644).

Cover Image

The cover image is based on the Original Article Oncolytic effect of Midkine-promoter based conditionally replicating adenoviruses expressing EGFR siRNA in head and neck squamous cancer cell line T891 by Natsumi Uehara et al., https://doi.org/10.1002/cnr2.1231.

The Effect of NNK, A Tobacco Smoke Carcinogen, on the miRNA and Mismatch DNA Repair Expression Profiles in Lung and Head and Neck Squamous Cancer Cells.

Tobacco smoking is a common risk factor for lung cancer and head and neck cancer. Molecular changes such as deregulation of miRNA expression have been linked to tobacco smoking in both types of cancer. Dysfunction of the Mismatch DNA repair (MMR) mechanism has also been associated with a poor prognosis of these cancers, while a cross-talk between specific miRNAs and MMR genes has been previously proposed. We hypothesized that exposure of lung and head and neck squamous cancer cells (NCI and FaDu, respectively) to tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is capable of altering the expression of MSH2 and MLH1, key MMR components, by promoting specific miRNA deregulation. We found that either a low (1 μM) or high (2 μM) dose of NNK induced significant upregulation of “oncomirs” miR-21 and miR-155 and downregulation of “tumor suppressor” miR-422a, as well as the reduction of MMR protein and mRNA expression, in NCI and FaDu, compared to controls. Inhibition of miR-21 restored the NNK-induced reduced MSH2 phenotype in both NCI and FaDu, indicating that miR-21 might contribute to MSH2 regulation. Finally, NNK exposure increased NCI and FaDu survival, promoting cancer cell progression. We provide novel findings that deregulated miR-21, miR-155, and miR-422a and MMR gene expression patterns may be valuable biomarkers for lung and head and neck squamous cell cancer progression in smokers.

Genome-wide CRISPR screen uncovers a synergistic effect of combining Haspin and Aurora kinase B inhibition.

Aurora kinases are a family of serine/threonine kinases vital for cell division. Because of the overexpression of Aurora kinases in a broad range of cancers and their important roles in mitosis, inhibitors targeting Aurora kinases have attracted attention in cancer therapy. VX-680 is an effective pan-Aurora kinase inhibitor; however, its clinical efficacy was not satisfying. In this study, we performed CRISPR/Cas9 screens to identify genes whose depletion shows synthetic lethality with VX-680. The top hit from these screens was GSG2 (also known as Haspin), a serine/threonine kinase that phosphorylates histone H3 at Thr-3 during mitosis. Moreover, both Haspin knockout and Haspin inhibitor-treated HCT116 cells were hypersensitive to VX-680. Furthermore, we showed that the synthetic lethal interaction between Haspin depletion and VX-680 was mediated by the inhibition of Haspin with Aurora kinase B (AURKB), but not with Aurora kinase A (AURKA). Strikingly, combined inhibition of Haspin and AURKB had a better efficacy than single-agent treatment in both head and neck squamous cell carcinoma and non-small cell lung cancer. Taken together, our findings have uncovered a synthetic lethal interaction between AURKB and Haspin, which provides a strong rationale for this combination therapy for cancer patients.

Effects of S‑adenosyl‑L‑methionine on the invasion and migration of head and neck squamous cancer cells and analysis of the underlying mechanisms.

S-Adenosyl-L-methionine (AdoMet) is the principal methyl donor in transmethylation reactions fundamental to sustaining epigenetic modifications. Over the past decade, AdoMet has been extensively investigated for its anti- proliferative, pro-apoptotic and anti-metastatic roles in several types of human cancer. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of cancer worldwide, and is an aggressive type of cancer that is associated with a high recurrence rate, metastasis and poor treatment outcomes. The present study demonstrates, for the first time, to the best of our knowledge, that AdoMet induces cell cycle arrest and inhibits the migratory and invasive ability of two different HNSCC cell lines, oral Cal-33 and laryngeal JHU-SCC-011 cells. In both cell lines, AdoMet attenuated cell cycle progression, decreased the protein level of several cyclins and downregulated the expression of p21 cell cycle inhibitor. Moreover, AdoMet was able to inhibit Cal-33 and JHU-SCC-011 cell migration in a dose-dependent manner after 24 and 48 h, respectively, and also induced a significant reduction in the cell invasive ability, as demonstrated by Matrigel invasion assay monitored by the xCELLigence RTCA system. Western blot analysis of several migration and invasion markers confirmed the inhibitory effects exerted by AdoMet on these processes and highlighted AKT, β-catenin and small mothers against decapentaplegic (SMAD) as the main signaling pathways modulated by AdoMet. The present study also demonstrated that the combination of AdoMet and cisplatin synergistically inhibited HNSCC cell migration. Taken together, these findings demonstrate that the physiological compound, AdoMet, affects the motility and extracellular matrix invasive capability in HNSCC. Thus, AdoMet may prove to be a good candidate for future drug development against metastatic cancer.

Clinical data analysis reveals the role of OGR1 (GPR68) in head and neck squamous cancer.

BackgroundHead and neck squamous cancer (HNSC) frequently occurs in the clinic. Revealing the role of the genes that correlate with cancer cell outgrowth will contribute to potential treatment target identification and tumor inhibition.MethodsThe gene expression profiles and gene ontology of the proton‐sensing G‐protein‐coupled receptor OGR1 were analyzed using the TCGA (The Cancer Genome Atlas) database. The effects of sex, age, race, and degree of malignancy on HNSC were investigated, and the survival times of HNSC patients with high or low/medium expression levels of OGR1 were compared. Methylation of the OGR1 promoter CpG sites was also investigated and OGR1‐related genes were analyzed using gene set enrichment analysis.ResultsOGR1 is overexpressed in HNSC patients. However, compared with the low/median expression group, the high OGR1 expression group did not have different survival rates. The OGR1 expression level differed across sex, age, race, and degree of malignancy, while the methylation of the OGR1 promoter CpG sites was maintained at a similar level. Gene set enrichment analysis revealed that OGR1 was positively correlated with head and neck cancer, cisplatin resistance, hypoxia, angiogenesis, cell migration, and TGF‐β.ConclusionThe expression of OGR1 correlated with HNSC progression and survival and thus can serve as a potential treatment target and prognostic marker.

Vasculogenic Mimicry: A Promising Prognosticator in Head and Neck Squamous Cell Carcinoma and Esophageal Cancer? A Systematic Review and Meta-Analysis.

Vasculogenic mimicry (VM) is an intratumoral microcirculation pattern formed by aggressive cancer cells, which mediates tumor growth. In this study, we compiled the evidence from studies evaluating whether positive VM status can serve as a prognostic factor to patients with squamous cell carcinoma of the head and neck (HNSCC) or esophagus (ESCC). Comprehensive systematic searches were conducted using Cochrane Library, Ovid Medline, PubMed, and Scopus databases. We appraised the quality of studies and the potential for bias, and performed random-effect meta-analysis to assess the prognostic impact of VM on the overall survival (OS). Seven studies with 990 patients were eligible, where VM was detected in 34.24% of patients. Positive-VM was strongly associated with poor OS (hazard ratio = 0.50; 95% confidence interval: 0.38–0.64), which remained consistent following the subgroup analysis of the studies. Furthermore, VM was associated with more metastasis to local lymph nodes and more advanced stages of HNSCC and ESCC. In conclusion, this study provides clear evidence showing that VM could serve as a promising prognosticator for patients with either HNSCC or ESCC. Further studies are warranted to assess how VM can be implemented as a reliable staging element in clinical practice and whether it could provide a new target for therapeutic intervention.

Oncolytic effect of Midkine promoter-based conditionally replicating adenoviruses expressing EGFR siRNA in head and neck squamous cancer cell line T891.

BackgroundEpidermal growth factor receptor (EGFR) is overexpressed in head and neck squamous cell carcinomas (HNSCCs). Midkine expression is restricted in adult tissues but is increased in several malignant tumors, including HNSCCs.AimHere, we evaluated the antitumor effect of Midkine promoter–based conditionally replicative adenovirus expressing siRNA against EGFR for targeting HNSCCs expressing Midkine.Methods and resultsA conditionally replicative adenovirus vector controlled by the Midkine promoter, Ad‐MK‐siEGFR, was generated by integrating gene‐expressing siRNA against EGFR. Antitumor effect of Ad‐MK‐siEGFR was tested in vitro using established HNSCC cell line, T891 with strong Midkine expression. Expression of EGFR in T891 infected with Ad‐MK‐siEGFR was significantly lower than that of T891 infected with control. Cytotoxicity assays showed significant growth suppression of Ad‐MK‐siEGFR in T891 cells.ConclusionsThis study demonstrated the possibility of oncolytic therapy using the Midkine promoter–based conditional replication‐selective adenovirus containing siRNA against EGFR in HNSCC cell line T891. Further validation of the findings in more cell lines and in vivo should be performed to clarify the potential clinical application.

Multicomponent Analysis in Head and Neck Squamous Cancer: Based on Genome, Epigenome and Transcriptome

In recent years, with the rapid development and application of a series of high-throughput proteomics technologies such as gene chip, high-throughput sequencing, and mass spectrometry, people have a more comprehensive and systematic understanding of diseases (including tumors) at genome, transcriptome, proteome and metabolome levels. The research papers on genome sequencing and gene expression profiling of head and neck tumors are increasing year by year, which provides a lot of basic data for revealing the pathogenesis of tumors and excavating new biomarkers. Although there are some articles on the joint analysis of multi-genomics, most of them are based on the speculation of coding amino acid mutations based on gene expression patterns and gene mutations. In this study, our analysis revealed four distinct head and neck squamous cancer (HNSC) subtypes through genome, epigenome and transcriptome data, which provides the possibility for molecular pathological diagnosis, subtyping, invasion and metastasis, chemoradiotherapy resistance and tumor heterogeneity of head and neck tumors. Funding: The work was supported by The Natural Science Youth Founds of Jiangxi Province (no.2016BAB215249), The Natural Science Foundation of Fujian Province (no. 2015J01512), The Middle- and Young-Aged Key Personnel Projects of Fujian Provincial Health and Family Planning Commission, China (no. 2015-ZQN-JC-39). Declaration of Interest: The authors declare that they have no competing interests. Ethical Approval: It is considered by the Ethic Committee of the Quanzhou First Hospital Affiliated to Fujian Medical University, The experimental design and scheme of this study fully considered the principle of safety and fairness, this study does not cause harm or risk to the study subjects. The subjects will be based on the principle of voluntariness, the right to know is guaranteed, protect the interests and privacy of research subjects to the maximum extent, There is no conflict of interest between the research results and the research content. Ethics Committee agrees the program to carry out as planned (No. [2019] 109).

Prognosis Value of Platelet Counts, Albumin and Neutrophil-Lymphocyte Ratio of Locoregional Recurrence in Patients with Operable Head and Neck Squamous Cell Carcinoma.

BackgroundPeripheral blood inflammation factor neutrophil-lymphocyte ratio (NLR), platelet count (PLT) and nutritional factor serum albumin (ALB) have been proposed as prognostic markers of head and neck squamous carcinoma cancer (HNSCC) in recent years. In the current study, nomogram predict models based on pre-treatment hematological parameters and a modified risk-stratified score system have been built.MethodsA total of 197 patients with oropharyngeal, hypopharyngeal and laryngeal cancers receiving multimodality treatment between 2012 and 2014 were included. The pre-treatment ALB, neutrophil, lymphocyte and platelet count (PLT) were detected. Cancer-specific survival and locoregional recurrence (LRC) by 5 years’ follow-up in the cases were obtained. To integrate clinical characteristics, we propose a modified risk-stratified score system. Kaplan–Meier method, proportional hazards COX model, logistic models were used to establish nomograms within external validation.ResultsFive-year LRC was decreased (p=0.004) for 140 patients with pre-treatment NLR <2.77. Five-year LRC and 5-year cancer-specific survival were decreased (p=0.031, p=0.021) with pre-treatment PLT ≥248×109/L. Comparison of univariate parametric models demonstrated that pre-treatment NLR evaluation and PLT>248×109/L were better among tested models. On Bayesian information criteria (BIC) analysis, the optimal prognostic model was then used to develop nomograms predicting 3- and 5-year LRC. The external validation of this predictive model was confirmed in 57 patients from another hospital.ConclusionPre-treatment NLR elevation and PLT>248×109/L are promising predictors of prognosis in patients with operable HNSCC. Nomograms based on the pre-treatment hematological markers and modified risk-stratified score system provide distinct risk stratifications. There results provided the feasibility of anti-inflammatory and antiplatelet treatments for HNSCC patients.

The FSHR Expression in Head and Neck Squamous Cell Cancer. A Pilot Immunohistochemical Study.

Follicle-stimulating hormone receptor (FSHr), expressed on endothelial cells of vessels in different malignant tumors, has been recently investigated as a potential pan-receptor of cancer treatment. However, the expression of this receptor has also been confirmed in other tissues under pathological conditions including cancer. The aim of the presented pilot study was to evaluate the expression of FSHr in head and neck squamous cancer (HNSCC). A total of 28 HNSCC patient samples were immunohistochemically analyzed for the presence of FSHr using a commercially available primary antibody. FSHr was detected not only in the tumor tissue, but also in the basal layer or dysplastic parts of squamous mucosa and also in fibroblasts surrounding the tumor tissue. FSHr is present on different benign or malignant mesenchymal and epithelial structures in HNSCC. A brief literature review revealed a wider role of FSHr in the development of neoplasia.