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1.  Oral epithelial stem cells – implications in normal development and cancer metastasis 
Experimental cell research  2014;325(2):111-129.
Oral mucosa is continuously exposed to environmental forces and has to be constantly renewed. Accordingly, the oral mucosa epithelium contains a large reservoir of epithelial stem cells necessary for tissue homeostasis. Despite considerable scientific advances in stem cell behavior in a number of tissues, fewer studies have been devoted to the stem cells in the oral epithelium. Most of oral mucosa stem cells studies are focused on identifying cancer stem cells (CSC) in oral squamous cell carcinomas (OSCCs) among other head and neck cancers. OSCCs are the most prevalent epithelial tumors of the head and neck region, marked by their aggressiveness and invasiveness. Due to their highly tumorigenic properties, it has been suggested that CSC may be the critical population of cancer cells in the development of OSCC metastasis. This review presents a brief overview of epithelium stem cells with implications in oral health, and the clinical implications of the CSC concept in OSCC metastatic dissemination.
doi:10.1016/j.yexcr.2014.04.021
PMCID: PMC4157336  PMID: 24803391
Oral squamous cell carcinoma; epithelial stem cells; invasion; metastasis; cancer stem cells; oral mucosa
2.  In vitro cytokines release profile: Predictive value for metastatic potential in head and neck squamous cell carcinomas 
Head & neck  2013;35(11):1542-1550.
Background
Head and neck squamous carcinomas (HNSCC) have devastating morbidity rates with mortality mainly because of metastasis.
Methods
Multiplex Enzyme-linked-immunosorbent-assay (ELISA) to assay a variety of cytokine levels secreted by a panel of stage- and anatomic site-specific primary, recurrent and metastatic University of Michigan-HNSCC cell lines over a 72-hour time-course.
Results
Conditioned medium from metastatic or recurrent HNSCC showed significantly higher amounts of interleukin (IL)-6, IL-6 receptor, Tumor Growth Factor-beta (TGF-β) and Vascular Endothelial Growth Factor (VEGF) than nonmetastatic cells or normal oral keratinocytes. Tumor Necrosis Factor was only secreted by the stage IV, metastatic, or recurrence-derived cell lines.
Conclusion
The cytokine profile of cultured HNSCC cells suggests that high levels of IL-6 and IL-6R, TGF-β, and VEGF are significantly related with their metastatogenic potential and provide rationale for determining if serum testing for a combination of these four soluble factors could be of predictive value for the HNSCC tumor progression and clinical outcome.
doi:10.1002/hed.23191
PMCID: PMC4157347  PMID: 23322448
Head and neck squamous carcinoma (HNSCC); cell lines; cytokines profiling; multiplex analysis; clinical outcome; metastasis
3.  In vitro evaluation of Sialyl Lewis X relationship with head and neck cancer stem cells 
Objective
To evaluate in vitro the potential links between sialyl Lewis X (sLeX) and cancer stem cells (CSC) in head and neck squamous cell carcinoma (HNSCC). HNSCC is an aggressive malignancy with high mortality mainly due to metastasis. CSC have emerged as important players in HNSCC metastasis. sLeX is a tetrasaccharide carbohydrate known to play a key-role in metastatic dissemination by promoting binding of the tumor cells to the endothelium.
Study Design
Experimental, in vitro.
Setting
Laboratory of Head and Neck Cancer Metastasis, University of Michigan.
Subjects and Methods
A panel of stage- and anatomic-site specific primary and metastatic HNSCC cell lines was assessed by flow cytometry to quantify sLeX relative expression levels. Serum-free conditioned media from the same HNSCC lines was collected over a time-course of 72 hours and assessed by Western-blot for secreted sLeX expression. Representative HNSCC cell lines were cultured as floating orospheres (condition that enhance CSC growth) or under normal adherent conditions and characterized by flow cytometry for CSC markers (CD44, aldehyde dehydrogenase [ALDH]) comparatively with sLeX expression.
Results
sLeX is predominantly expressed in carcinomas originating from the oral cavity. Secreted sLeX is also found to be high in oral carcinomas and increased over the analyzed time course. Floating orospheres were strongly positive for CD44 and ALDH confirming CSC enrichment of the orospheres. Tumor cells grown as orospheres are 95-100% positive for sLeX compared to 10-40% of adherent counterpart.
Conclusion
These studies provide the first evidence of sLeX relationship with CSC in HNSCC.
doi:10.1177/0194599813482879
PMCID: PMC4157351  PMID: 23558285
head and neck squamous cell carcinomas; sLeX (sialyl Lewis X); CD44; stem cells; in vitro analysis
4.  Head and Neck Cancer Stem Cells: The effect of HPV - An In Vitro and Mouse Study 
Objectives
Determine if the behavior of cancer stem cells (CSC) is affected by HPV status.
Study Design
An in vitro and in vivo analysis of HPV and CSC
Setting
University Laboratory
Subjects
Head and neck cell lines
Subjects and Methods
We isolated CSC from HPV(+) and HPV(-) cell lines. Two HPV(-) cell lines underwent lentiviral transduction of E6/E7. Chemoresistence was determined using colony formation assays. Native HPV(+) and HPV-E6/E7-transduced cells were compared for lung colonization after tail vein injection in NOD/SCID mice.
Results
The proportion of CSC is not significantly different in HPV(+) or HPV(-) HNSCC cell lines. HNSCC CSC are more resistant to cisplatin than the non-CSC, however there were no significant differences between HPV(+) and HPV(-) cells. HPV(-) cancer cells yielded low colony formation after cell sorting. After transduction with HPV E6/E7, increased colony formation was observed in both CSC and non-CSC. Results from tail vein injections yielded no differences in development of lung colonies between HPV E6/E7 transduced cells vs. the non-transduced cells.
Conclusions
HPV status does correlate with the proportion of CSC present in HNSCC. HPV(+) cells and those transduced with HPV E6/E7 have a greater clonogenicity than HPV(-) cells. HNSCC CSC are more resistant to cisplatin than non-CSC. This suggests that common chemotherapeutic agents may shrink tumor bulk by eliminating non-CS, while CSC have mechanisms that facilitate evasion of cell death. HPV status does not affect CSC response to cisplatin therapy, suggesting that other factors explain the better outcomes for patients with HPV(+) cancer.
doi:10.1177/0194599813486599
PMCID: PMC4086879  PMID: 23585151
Head and Neck Cancer; HPV; Cancer Stem Cells; ALDH; Chemotherapy
5.  Circadian Rhythms Regulate Amelogenesis 
Bone  2013;55(1):158-165.
Ameloblasts, the cells responsible for making enamel, modify their morphological features in response to specialized functions necessary for synchronized ameloblast differentiation and enamel formation. Secretory and maturation ameloblasts are characterized by the expression of stage-specific genes which follows strictly controlled repetitive patterns. Circadian rhythms are recognized as key regulators of development and diseases of many tissues including bone. Our aim was to gain novel insights on the role of clock genes in enamel formation and to explore the potential links between circadian rhythms and amelogenesis. Our data shows definitive evidence that the main clock genes (Bmal1, Clock, Per1 and Per2) oscillate in ameloblasts at regular circadian (24h) intervals both at RNA and protein levels. This study also reveals that two markers of ameloblast differentiation i.e. amelogenin (Amelx; a marker of secretory ameloblasts) and kallikrein-related peptidase 4 (Klk4, a marker of maturation ameloblasts) are downstream targets of clock genes. Both, Amelx and Klk4 show 24h oscillatory expression patterns and their expression levels are up-regulated after Bmal1 over-expression in HAT-7 ameloblast cells. Taken together, these data suggest that both the secretory and the maturation stage of amelogenesis might be under circadian control. Changes in clock genes expression patterns might result in significant alterations of enamel apposition and mineralization.
doi:10.1016/j.bone.2013.02.011
PMCID: PMC3650122  PMID: 23486183
Clock genes; enamel; amelogenin; kallikrein-related peptidase 4; odontoblasts
6.  Head and Neck Squamous Cell Carcinoma in Pregnant Women 
Head & neck  2012;35(3):335-342.
Objective
To investigate oral cancer in pregnant women, a rare but therapeutically challenging patient subset.
Methods
After IRB approval, an EMERSE search was used to identify all women treated at the University of Michigan from 1998–2010 with head and neck squamous cell carcinoma (HNSCC) during pregnancy. This identified four patients with tongue cancer. Biomarkers and HPV were assessed by immunohistochemistry and multiplex PCR/Mass spectrometry, respectively.
Results
Two patients responded well to therapy and are alive more than 10 years after diagnosis; two died of disease. All tumors overexpressed EGFR and Bcl-xL, three of four overexpressed c-Met, both tumors that progressed overexpressed p53. All tumors were negative for HPV, p16, ER, PR, and HER-2.
Conclusions
Biomarkers of aggressive tumors (high EGFR, Bcl-xL, c-Met; low p53) did not correlate with outcome. Additional studies are needed to determine whether perineural invasion, delay in diagnosis, and p53 overexpression are factors related to poorer survival.
doi:10.1002/hed.22973
PMCID: PMC3399935  PMID: 22422571
Oral cancer; Biomarkers; HPV; pregnancy; risk factors
7.  Beta-Catenin and Epithelial Tumors: A Study Based on 374 Oropharyngeal Cancers 
BioMed Research International  2014;2014:948264.
Introduction. Although altered regulation of the Wnt pathway via beta-catenin is a frequent event in several human cancers, its potential implications in oral/oropharyngeal squamous cell carcinomas (OSCC/OPSCC) are largely unexplored. Work purpose was to define association between beta-catenin expression and clinical-pathological parameters in 374 OSCCs/OP-SCCs by immunohistochemistry (IHC). Materials and Methods. Association between IHC detected patterns of protein expression and clinical-pathological parameters was assessed by statistical analysis and survival rates by Kaplan-Meier curves. Beta-catenin expression was also investigated in OSCC cell lines by Real-Time PCR. An additional analysis of the DNA content was performed on 22 representative OSCCs/OPSCCs by DNA-image-cytometric analysis. Results and Discussion. All carcinomas exhibited significant alterations of beta-catenin expression (P < 0.05). Beta-catenin protein was mainly detected in the cytoplasm of cancerous cells and only focal nuclear positivity was observed. Higher cytoplasmic expression correlated significantly with poor histological differentiation, advanced stage, and worst patient outcome (P < 0.05). By Real-Time PCR significant increase of beta-catenin mRNA was detected in OSCC cell lines and in 45% of surgical specimens. DNA ploidy study demonstrated high levels of aneuploidy in beta-catenin overexpressing carcinomas. Conclusions. This is the largest study reporting significant association between beta-catenin expression and clinical-pathological factors in patients with OSCCs/OPSCCs.
doi:10.1155/2014/948264
PMCID: PMC3912883  PMID: 24511551
8.  Carboplatin-Pemetrexed in Treatment of Patients with Recurrent/Metastatic Cancers of the Head and Neck; Superior Outcomes in Oropharyngeal Primaries 
Frontiers in Oncology  2015;4:362.
Background: Platinum-based therapy in combination with 5-fluorouracil with cetuximab has shown the best survival in pts with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). The purpose of this study is to evaluate the efficacy and tolerability of carboplatin, pemetrexed and to assess differential outcomes in patients with oropharyngeal primary and HPV related disease.
Patients and Methods: The charts of consecutive patients with R/M SCCHN were reviewed. All patients receiving at least one cycle of the two-drug regimen (pemetrexed 500 mg/m2, carboplatin area under the curve of five intravenously), were included for assessment of response, safety, toxicity, and survival.
Results: A total of 86 patients received this regimen between January 2008 and December 2012, of which, 63 were included in this analysis. Forty-one percent (26) of the patients had cancers of the oropharynx, and of those, 50% had HPV-positive disease, 32% (20) had cancers of the larynx, and 24% (15) of the oral cavity. Median number of cycles administered was 4 (range 1–14 cycles) with 50% of the patients receiving four or more cycles. Half the patients achieved stable disease as their best response, 8% (5) attained a partial response, 24% progressed on therapy, and the remaining patients (12) could not have their response assessed. On the basis of Kaplan–Meier analysis, median progression-free survival (PFS) was 5.1 months (95% CI 3.2, 6.2) and median overall survival (OS) was 9.4 months (95% CI 4.3, 13.1). Among pts with oropharyngeal primary (n = 26), median PFS was 6.4 months (95% CI 2.8, 7.9) and median OS was 16.6 months (95% CI 9.6, 19.5). Among HPV+ pts (n = 13), median PFS was 7.0 months (95% CI 4.8, ne) and median OS was 17.1 months (95% CI 11.2, 21.7).
Conclusion: Combination carboplatin-pemetrexed is an effective and well-tolerated treatment, associated with a median PFS of 5.1 months and a clinical benefit in at least 57% of the patients treated.
doi:10.3389/fonc.2014.00362
PMCID: PMC4306299
head and neck cancer; carboplatin; pemetrexed; recurrent; metastatic; oropharyngeal neoplasms
9.  Correlation between BRAF mutation and promoter methylation of TIMP3, RARβ2 and RASSF1A in thyroid cancer 
Epigenetics  2012;7(7):710-719.
Our aim was to comprehensively analyze promoter hypermethylation of a panel of novel and known methylation markers for thyroid neoplasms and to establish their relationship with BRAF mutation and clinicopathologic parameters of thyroid cancer. A cohort of thyroid tumors, consisting of 44 cancers and 44 benign thyroid lesions, as well as 15 samples of adjacent normal thyroid tissue, was evaluated for BRAF mutation and promoter hypermethylation. Genes for quantitative methylation specific PCR (QMSP) were selected by a candidate gene approach. Twenty-two genes were tested: TSHR, RASSF1A, RARβ2, DAPK, hMLH1, ATM, S100, p16, CTNNB1, GSTP1, CALCA, TIMP3, TGFßR2, THBS1, MINT1, CTNNB1, MT1G, PAK3, NISCH, DCC, AIM1 and KIF1A. The PCR-based “mutector assay” was used to detect BRAF mutation. All p values reported are two sided. Considerable overlap was seen in the methylation markers among the different tissue groups. Significantly higher methylation frequency and level were observed for KIF1A and RARß2 in cancer samples compared with benign tumors. A negative correlation between BRAF mutation and RASSF1A methylation, and a positive correlation with RARß2 methylation were observed in accordance with previous results. In addition, positive correlation with TIMP3 and a marginal correlation with DCC methylation were observed. The present study constitutes a comprehensive promoter methylation profile of thyroid neoplasia and shows that results must be analyzed in a tissue-specific manner to identify clinically useful methylation markers. Integration of genetic and epigenetic changes in thyroid cancer will help identify relevant biologic pathways that drive its development.
doi:10.4161/epi.20524
PMCID: PMC3414391  PMID: 22694820
BRAF; RARβ2; RASSF1A; TIMP3; biomarkers; hypermethylation; thyroid cancer; thyroid tissue
10.  Molecular and circadian controls of ameloblasts 
European journal of oral sciences  2011;119(Suppl 1):35-40.
Stage-specific expression of ameloblast-specific genes is controlled by differential expression of transcription factors. In addition, ameloblasts follow daily rhythms in their main activities i.e. enamel protein secretion and enamel mineralization. This time related control is orchestrated by oscillations of clock proteins involved in circadian rhythms regulation. Our aim was to identify the potential links between daily rhythms and developmental controls of ameloblast differentiation. The effects of selected transcriptional factors Distal-less homeobox 3 (Dlx3) and Runt related transcription factor 2 (Runx2) and clock gene Nuclear receptor subfamily 1, group D, member 1 (Nr1d1) on secretory and maturation ameloblasts [using stage-specific markers amelogenin (Amel), enamelin (Enam) and kallikrein related-peptidase 4 (Klk4)] were evaluated in HAT-7 ameloblast cell line. Amel and Enam steady-state RNA expression levels were down-regulated in Runx2 over-expressing cells and up-regulated in Dlx3 over-expressing cells. In contrast, Klk4 was up-regulated by both Dlx3 and Runx2. Furthermore, a temporal and spatial relationship between clock genes and ameloblast differentiation markers was detected. Of interest, clock genes not only affected rhythmic expression of ameloblast specific genes but also influenced the expression of Runx2. Multi-scale mathematical modeling is being explored to further understand the temporal and developmental controls of ameloblast differentiation. Our study provides novel insights into the regulatory mechanisms sustaining ameloblast differentiation.
doi:10.1111/j.1600-0722.2011.00918.x
PMCID: PMC3516856  PMID: 22243224
Ameloblast gene regulation; circadian rhythms; clock genes; multi-scale modeling; enamel
11.  Innovative Approaches to Regenerate Enamel and Dentin 
The process of tooth mineralization and the role of molecular control of cellular behavior during embryonic tooth development have attracted much attention the last few years. The knowledge gained from the research in these fields has improved the general understanding about the formation of dental tissues and the entire tooth and set the basis for teeth regeneration. Tissue engineering using scaffold and cell aggregate methods has been considered to produce bioengineered dental tissues, while dental stem/progenitor cells, which can differentiate into dental cell lineages, have been also introduced into the field of tooth mineralization and regeneration. Some of the main strategies for making enamel, dentin, and complex tooth-like structures are presented in this paper. However, there are still significant barriers that obstruct such strategies to move into the regular clinic practice, and these should be overcome in order to have the regenerative dentistry as the important mean that can treat the consequences of tooth-related diseases.
doi:10.1155/2012/856470
PMCID: PMC3359805  PMID: 22666253
12.  Metastatic Potential of Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma 
Objective
Subpopulations of highly tumorigenic cells, which have the unique capacity to self-renew and produce differentiated progeny, have been identified in multiple malignancies. In head and neck squamous cell carcinoma (HNSCC), this subpopulation of cells, termed cancer stem cells (CSCs) are contained within the population with high CD44 expression. It has been postulated that CSCs play a role in invasion and metastasis; however, there is little evidence to support this theory. We designed in vitro and in vivo models of metastasis to study the behavior of CSCs in HNSCC.
Design
Cells were sorted for CD44 expression using flow cytometry. Sorted cells were used in an in vitro invasion assay. For in vivo studies, CSCs and non-CSCs were injected into the tail veins of mice, and lungs were either harvested or imaged to evaluate for metastases.
Results
In vitro, CD44high cells were more motile but less invasive than CD44low cells. In vivo, 4/5 mice injected with CD44high cells and 0/5 mice injected with CD44low cells formed lung metastases. Two of the metastases arose from CSCs from a primary tumor and three from CSCs from HNSCC cell lines.
Conclusions
In vitro, CSCs do not have an increased ability to invade through basement membrane, but they do migrate more efficiently through a porous barrier. In contrast, CSCs formed metastases quite efficiently in vivo, whereas non-CSCs did not form metastases at all. This phenomenon could be due to enhanced migratory capacity of CSCs, which may be more important than basement membrane degradation in vivo.
doi:10.1001/archoto.2010.219
PMCID: PMC3315371  PMID: 21173377
13.  Expression of Clock Proteins in Developing Tooth 
Gene expression patterns : GEP  2010;11(3-4):202-206.
Morphological and functional changes during ameloblast and odontoblast differentiation suggest that enamel and dentin formation is under circadian control. Circadian rhythms are endogenous self-sustained oscillations with periods of 24 hours that control diverse physiological and metabolic processes. Mammalian clock genes play a key role in synchronizing circadian functions in many organs. However, close to nothing is known on clock genes expression during tooth development. In this work, we investigated the expression of four clock genes during tooth development. Our results showed that circadian clock genes Bmal1, clock, per1, and per2 mRNAs were detected in teeth by RT-PCR. Immunohistochemistry showed that clock protein expression was first detected in teeth at the bell stage (E17), being expressed in EOE and dental papilla cells. At post-natal day four (PN4), all four clock proteins continued to be expressed in teeth but with different intensities, being strongly expressed within the nucleus of ameloblasts and odontoblasts and down-regulated in dental pulp cells. Interestingly, at PN21 incisor, expression of clock proteins was down-regulated in odontoblasts of the crown-analogue side but expression was persisting in root-analogue side odontoblasts. In contrast, both crown and root odontoblasts were strongly stained for all four clock proteins in first molars at PN21. Within the periodontal ligament (PDL) space, epithelial rests of Malassez (ERM) showed the strongest expression among other PDL cells. Our data suggests that clock genes might be involved in the regulation of ameloblast and odontoblast functions, such as enamel and dentin protein secretion and matrix mineralization.
doi:10.1016/j.gep.2010.12.002
PMCID: PMC3073654  PMID: 21156215
Clock genes; Tooth development; Bmal1; Clock; Per1; Per2; expression pattern; immunohistochemistry
14.  Evaluation of a combined triple method to detect causative HPV in oral and oropharyngeal squamous cell carcinomas: p16 Immunohistochemistry, Consensus PCR HPV-DNA, and In Situ Hybridization 
Background
Recent emerging evidences identify Human Papillomavirus (HPV) related Head and Neck squamous cell carcinomas (HN-SCCs) as a separate subgroup among Head and Neck Cancers with different epidemiology, histopathological characteristics, therapeutic response to chemo-radiation treatment and clinical outcome. However, there is not a worldwide consensus on the methods to be used in clinical practice. The endpoint of this study was to demonstrate the reliability of a triple method which combines evaluation of: 1. p16 protein expression by immunohistochemistry (p16-IHC); 2. HPV-DNA genotyping by consensus HPV-DNA PCR methods (Consensus PCR); and 3 viral integration into the host by in situ hybridization method (ISH). This triple method has been applied to HN-SCC originated from oral cavity (OSCC) and oropharynx (OPSCC), the two anatomical sites in which high risk (HR) HPVs have been clearly implicated as etiologic factors. Methylation-Specific PCR (MSP) was performed to study inactivation of p16-CDKN2a locus by epigenetic events. Reliability of multiple methods was measured by Kappa statistics.
Results
All the HN-SCCs confirmed HPV positive by PCR and/or ISH were also p16 positive by IHC, with the latter showing a very high level of sensitivity as single test (100% in both OSCC and OPSCC) but lower specificity level (74% in OSCC and 93% in OPSCC).
Concordance analysis between ISH and Consensus PCR showed a faint agreement in OPSCC (κ = 0.38) and a moderate agreement in OSCC (κ = 0.44). Furthermore, the addition of double positive score (ISHpositive and Consensus PCR positive) increased significantly the specificity of HR-HPV detection on formalin-fixed paraffin embedded (FFPE) samples (100% in OSCC and 78.5% in OPSCC), but reduced the sensitivity (33% in OSCC and 60% in OPSCC). The significant reduction of sensitivity by the double method was compensated by a very high sensitivity of p16-IHC detection in the triple approach.
Conclusions
Although HR-HPVs detection is of utmost importance in clinical settings for the Head and Neck Cancer patients, there is no consensus on which to consider the 'golden standard' among the numerous detection methods available either as single test or combinations. Until recently, quantitative E6 RNA PCR has been considered the 'golden standard' since it was demonstrated to have very high accuracy level and very high statistical significance associated with prognostic parameters. In contrast, quantitative E6 DNA PCR has proven to have very high level of accuracy but lesser prognostic association with clinical outcome than the HPV E6 oncoprotein RNA PCR. However, although it is theoretically possible to perform quantitative PCR detection methods also on FFPE samples, they reach the maximum of accuracy on fresh frozen tissue. Furthermore, worldwide diagnostic laboratories have not all the same ability to analyze simultaneously both FFPE and fresh tissues with these quantitative molecular detection methods. Therefore, in the current clinical practice a p16-IHC test is considered as sufficient for HPV diagnostic in accordance with the recently published Head and Neck Cancer international guidelines. Although p16-IHC may serve as a good prognostic indicator, our study clearly demonstrated that it is not satisfactory when used exclusively as the only HPV detecting method. Adding ISH, although known as less sensitive than PCR-based detection methods, has the advantage to preserve the morphological context of HPV-DNA signals in FFPE samples and, thus increase the overall specificity of p16/Consensus PCR combination tests.
doi:10.1186/1750-9378-7-4
PMCID: PMC3313884  PMID: 22376902
Head and neck squamous cell carcinoma; HN-SCC; OSCC; OPSCC; Human papillomavirus; HPV; DNA consensus PCR; Immunohistochemistry; IHC; p16-IHC; Epigenetic; Methylation-Specific PCR
15.  The role of human papillomavirus in the pathogenesis of head & neck squamous cell carcinoma: an overview 
Cancer statistics report an increased incidence of OSCC and OPSCC around the world. Though improvements in screening and early diagnosis have dramatically reduced the incidence of this neoplasm in recent years, the 5-year-disease-free survival, is still poor, specially for oropharyngeal cancer, despite the great scientific and financial efforts. Recently, several papers showed that HPV may be involved at least in the pathogenesis of a subgroup of oral and cervical SCC, leading to distinct molecular characteristics compared with HPV-negative ones. Nevertheless, OPSCCs associated with HPV infection seem to show a better prognosis and affect younger patients (< 40 yrs.), especially females. Therefore, there is the need to properly assess oropharyngeal SCC subgroups: 1) not HPV associated/classic oral SCC: less responsive to anticancer drugs: needs novel post-surgical treatment; 2) HPV associated/oral SCC: needs several management options and suitable "target" therapy against the virus, and/or immune-stimulating therapy. Further issues are: 1) the disclosure of putative targets for more efficient molecular therapy, which may work as cervical cancer post-surgical treatment, in anticipation of the effects of "global prevention" performed by WHO anti-HPV vaccination programs; 2) careful identification of precancerous lesions in both sites; dysplasia is currently treated by excisional or ablative procedures, which don't consider the concept of field carcinogenesis. In fact, it is probable that near or far from an excised precancerous lesion new foci of cell transformation may exist, which are not yet macroscopically evident, but, if detected, would put the patient into a high risk subgroup.
Comparing findings reported in the recent literature, the data of this state of the art about HPV might add useful informations concerning oropharyngeal carcinogenesis. Moreover, our review would be useful in order to define novel perspectives of treatment choice for Head & Neck cancer patients, by combining well known chemotherapeutical drugs with new molecular "target" therapy.
doi:10.1186/1750-9378-6-4
PMCID: PMC3072321  PMID: 21447181

Results 1-15 (15)