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Irina Y Dobrosotskaya,
Emily Bellile,
Matthew E Spector,
Bhavna Kumar,
Felix Feng,
Avraham Eisbruch,
Gregory T Wolf,
Mark E P Prince,
Jeffrey S Moyer,
Theodoros Teknos, [......],
Heather M Walline,
Jonathan B McHugh,
Kitrina G Cordell,
P Daniel Ward,
Serena Byrd,
Jessica H Maxwell,
Susan Urba,
Carol R Bradford, Thomas E Carey,
Francis P Worden
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ABSTRACT: Background: Optimal treatment for locally advanced SCCOP is not well defined. Here we retrospectively compare survival and toxicities from two different organ preservation protocols. Methods: The matched dataset consisted of 35 patients from each trial matched for age, stage, smoking, and tumor HPV status. Patients on University of Michigan Cancer Center (UMCC) trial 9921 were treated with induction chemotherapy followed by high-dose cisplatin and radiation in responders, or surgery in non-responders. Patients on UMCC trial 0221 were treated with weekly carboplatin and paclitaxel and radiation. Results: Survival was comparable for both studies and did not differ significantly across each trial after stratifying by HPV status. Grade 3 and 4 toxicities were more frequent in UMCC 9921. At 6 months post-treatment, G-tube dependence was not statistically different. Conclusions: These data suggest that survival outcomes in patients with locally advanced SCCOP are not compromised with weekly chemotherapy and RT, and such treatment is generally more tolerable. Head Neck, 2013.
Head & Neck 04/2013; · 2.40 Impact Factor
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ABSTRACT: Objectives
To determine if the behavior of cancer stem cells (CSCs) is affected by human papillomavirus (HPV) status.Study DesignAn in vitro and in vivo analysis of HPV and CSCs.SettingUniversity laboratory.Subjects and Methods
We isolated CSCs from HPV-positive and HPV-negative cell lines. Two HPV-negative cell lines underwent lentiviral transduction of E6/E7. Chemoresistence was determined using colony formation assays. Native HPV-positive and HPV E6/E7-transduced cells were compared for lung colonization after tail vein injection in NOD/SCID mice.ResultsThe proportion of CSC is not significantly different in HPV-positive or HPV-negative head and neck squamous cell carcinoma (HNSCC) cell lines. The HNSCC CSCs are more resistant to cisplatin than the non-CSCs, but there were no significant differences between HPV-positive and HPV-negative cells. The HPV-negative cancer cells yielded low colony formation after cell sorting. After transduction with HPV E6/E7, increased colony formation was observed in both CSCs and non-CSCs. Results from tail vein injections yielded no differences in development of lung colonies between HPV E6/E7-transduced cells and nontransduced cells.Conclusions
Human papillomavirus status does not correlate with the proportion of CSCs present in HNSCC. The HPV-positive cells and those transduced with HPV E6/E7 have a greater clonogenicity than HPV-negative cells. The HNSCC CSCs are more resistant to cisplatin than non-CSCs. This suggests that common chemotherapeutic agents may shrink tumor bulk by eliminating non-CSCs, whereas CSCs have mechanisms that facilitate evasion of cell death. Human papillomavirus status does not affect CSC response to cisplatin therapy, suggesting that other factors explain the better outcomes for patients with HPV-positive cancer.
Otolaryngology Head and Neck Surgery 04/2013; · 1.72 Impact Factor
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Elizabeth A Van Tubergen,
Rajat Banerjee,
Min Liu,
Robert J Vander Broek,
Emily Light,
Shiuhyang Kuo,
Stephen Feinberg,
Amanda L Willis,
Gregory T Wolf, Thomas E Carey,
Carol R Bradford,
Mark Prince,
Francis P Worden,
Keith L Kirkwood,
Nisha J D'Silva
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ABSTRACT: PURPOSE: Invasion is the critical step in progression of a pre-cancerous lesion to squamous cell carcinoma of the head and neck (SCCHN). Invasion is regulated by multiple pro-inflammatory mediators. Tristetraprolin (TTP) is an mRNA degrading protein that regulates multiple pro-inflammatory mediators. TTP may serve as an excellent treatment target. Rap1 is a ras-like oncoprotein that induces critical signaling pathways. In this study, the role of rap1 in TTP-mediated invasion was investigated. EXPERIMENTAL DESIGN: Using complementary approaches we modulated TTP and altered expression of IL-6 and MMP2/9, which were quantified by ELISA and zymogram. Invasion was evaluated in vitro using the Oral-Cancer-Equivalent (OCE) 3D model and in vivo in the chick chorioallantoic membrane (CAM). The role of rap1 and p38 were established using knockdown strategies. RESULTS: Downregulation of TTP significantly increased invasion via secretion of MMP9/2 and IL-6. In the novel OCE and CAM invasion models of SCCHN, cells with downregulated TTP destroyed the basement membrane to invade the underlying connective tissue. Rap1 induces p38 mitogen activated protein kinase (p38)-mediated inactivation of TTP. Inactive TTP enhances transcript stability via binding to the 3'-UTR. High IL-6 and MMP9 are prognostic for poor clinical outcomes in SCCHN patients. CONCLUSIONS: Targeting the rap1-p38-TTP cascade is an attractive novel treatment strategy in SCCHN to concurrently suppress multiple mediators of invasion.
Clinical Cancer Research 01/2013; · 7.74 Impact Factor
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ABSTRACT: BACKGROUND: Head and neck squamous cell carcinomas (HNSCCs) 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-specific and anatomic site-specific primary, and 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 (TNF) was only secreted by 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 4 soluble factors could be of predictive value for the HNSCC tumor progression and clinical outcome. © 2013 Wiley Periodicals, Inc. Head Neck, 2013.
Head & Neck 01/2013; · 2.40 Impact Factor
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Justin A Colacino,
Dana C Dolinoy,
Sonia A Duffy,
Maureen A Sartor,
Douglas B Chepeha,
Carol R Bradford,
Jonathan B McHugh,
Divya A Patel,
Shama Virani,
Heather M Walline,
Emily Bellile,
Jeffrey E Terrell,
Jay A Stoerker,
Jeremy M G Taylor, Thomas E Carey,
Gregory T Wolf,
Laura S Rozek
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ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) is the eighth most commonly diagnosed cancer in the United States. The risk of developing HNSCC increases with exposure to tobacco, alcohol and infection with human papilloma virus (HPV). HPV-associated HNSCCs have a distinct risk profile and improved prognosis compared to cancers associated with tobacco and alcohol exposure. Epigenetic changes are an important mechanism in carcinogenic progression, but how these changes differ between viral- and chemical-induced cancers remains unknown. CpG methylation at 1505 CpG sites across 807 genes in 68 well-annotated HNSCC tumor samples from the University of Michigan Head and Neck SPORE patient population were quantified using the Illumina Goldengate Methylation Cancer Panel. Unsupervised hierarchical clustering based on methylation identified 6 distinct tumor clusters, which significantly differed by age, HPV status, and three year survival. Weighted linear modeling was used to identify differentially methylated genes based on epidemiological characteristics. Consistent with previous in vitro findings by our group, methylation of sites in the CCNA1 promoter was found to be higher in HPV(+) tumors, which was validated in an additional sample set of 128 tumors. After adjusting for cancer site, stage, age, gender, alcohol consumption, and smoking status, HPV status was found to be a significant predictor for DNA methylation at an additional 11 genes, including CASP8 and SYBL1. These findings provide insight into the epigenetic regulation of viral vs. chemical carcinogenesis and could provide novel targets for development of individualized therapeutic and prevention regimens based on environmental exposures.
PLoS ONE 01/2013; 8(1):e54742. · 4.09 Impact Factor
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Shamir P Chandarana,
Julia S Lee,
Eric J P Chanowski,
Assuntina G Sacco,
Carol R Bradford,
Gregory T Wolf,
Mark E Prince,
Jeffrey S Moyer,
Avraham Eisbruch,
Francis P Worden,
Thomas J Giordano,
Bhavna Kumar,
Katrina G Cordell, Thomas E Carey,
Douglas B Chepeha
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ABSTRACT: BACKGROUND: The purpose of this study was to describe the relationship of p16 and epidermal growth factor receptor (EGFR) expression with survival in surgically treated patients who had oropharyngeal or oral cavity squamous cell carcinoma (SCC). METHODS: Tissue from 36 patients with oropharyngeal SCC and 49 patients with oral cavity SCC treated between 1997 and 2001 was imbedded and immunostained using a tissue microarray. RESULTS: The p16 was positive in 57% and 13% of patients with oropharyngeal SCC and oral cavity SCC, respectively. EGFR was positive in 60% and 63% of patients with oropharyngeal SCC and oral cavity SCC, respectively. In patients with oropharyngeal SCC, p16 expression was associated with improved disease-specific survival (DSS), overall survival (OS), and time to recurrence (TTR) (p < .01, < .01, and <.01, respectively). EGFR expression was associated with poorer DSS, OS, and TTR (p < .01, = .01, and < .01, respectively). For oropharyngeal SCC, when examining both p16 and EGFR expression as combined biomarkers, high p16 expression coupled with low EGFR expression was associated with improved DSS (p p16 = .01; p EGFR = .01). Patients with oral cavity SCC showed no association between biomarker and outcome. CONCLUSIONS: For patients with oropharyngeal SCC, high p16 and low EGFR were associated with improved outcome, suggesting a predictive role in surgically treated patients. © 2012 Wiley Periodicals, Inc. Head Neck, 2012.
Head & Neck 08/2012; · 2.40 Impact Factor
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Justin A Colacino,
Anna E Arthur,
Dana C Dolinoy,
Maureen A Sartor,
Sonia A Duffy,
Douglas B Chepeha,
Carol R Bradford,
Heather M Walline,
Jonathan B McHugh,
Nisha D'Silva, Thomas E Carey,
Gregory T Wolf,
Jeremy M G Taylor,
Karen E Peterson,
Laura S Rozek
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ABSTRACT: Diet is associated with cancer prognosis, including head and neck cancer (HNC), and has been hypothesized to influence epigenetic state by determining the availability of functional groups involved in the modification of DNA and histone proteins. The goal of this study was to describe the association between pretreatment diet and HNC tumor DNA methylation. Information on usual pretreatment food and nutrient intake was estimated via food frequency questionnaire (FFQ) on 49 HNC cases. Tumor DNA methylation patterns were assessed using the Illumina Goldengate Methylation Cancer Panel. First, a methylation score, the sum of individual hypermethylated tumor suppressor associated CpG sites, was calculated and associated with dietary intake of micronutrients involved in one-carbon metabolism and antioxidant activity, and food groups abundant in these nutrients. Second, gene specific analyses using linear modeling with empirical Bayesian variance estimation were conducted to identify if methylation at individual CpG sites was associated with diet. All models were controlled for age, sex, smoking, alcohol and HPV status. Individuals reporting in the highest quartile of folate, vitamin B12 and vitamin A intake, compared with those in the lowest quartile, showed significantly less tumor suppressor gene methylation, as did patients reporting the highest cruciferous vegetable intake. Gene specific analyses identified differential associations between DNA methylation and vitamin B12 and vitamin A intake when stratifying by HPV status. These preliminary results suggest that intake of folate, vitamin A and vitamin B12 may be associated with the tumor DNA methylation profile in HNC and enhance tumor suppression.
Epigenetics: official journal of the DNA Methylation Society 08/2012; 7(8):883-91. · 4.58 Impact Factor
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Anna M Eliassen,
Samantha J Hauff,
Alice L Tang,
Dafydd H Thomas,
Jonathan B McHugh,
Heather M Walline,
Jay Stoerker,
Jessica H Maxwell,
Francis P Worden,
Avraham Eisbruch,
Michael J Czerwinski,
Silvana M Papagerakis,
Douglas B Chepeha,
Carol R Bradford,
David A Hanauer, Thomas E Carey,
Mark E Prince
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ABSTRACT: BACKGROUND: The aim of this study was to investigate oral cancer in pregnant women, a rare but therapeutically challenging patient subset. METHODS: After institutional review board approval, an EMERSE search was used to identify all women treated at the University of Michigan from 1998 to 2010 with head and neck squamous cell carcinoma (HNSCC) during pregnancy. This identified 4 patients with tongue cancer. Biomarkers and human papillomavirus (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; 2 patients died of disease. All tumors overexpressed EGFR and Bcl-xL, 3 of 4 overexpressed c-Met, both tumors that progressed overexpressed p53. All tumors were negative for HPV, p16, estrogen receptor, progesterone receptor, and HER-2. CONCLUSIONS: Biomarkers of aggressive tumors (high EGFR, c-Met; high Bcl-xL-low p53) did not correlate with outcome. Additional studies are needed to determine whether perineural invasion, delay in diagnosis, and p53 overexpression are factors in poor survival. © 2012 Wiley Periodicals, Inc. Head Neck, 2012.
Head & Neck 03/2012; · 2.40 Impact Factor
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Alice L Tang,
Samantha J Hauff,
John H Owen,
Martin P Graham,
Michael J Czerwinski,
Jung Je Park,
Heather Walline,
Silvana Papagerakis,
Jay Stoerker,
Jonathan B McHugh,
Douglas B Chepeha,
Carol R Bradford, Thomas E Carey,
Mark E Prince
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ABSTRACT: Few human papillomavirus (HPV)(+) head and neck squamous cell carcinoma (HNSCC) cell lines exist. We established University of Michigan-squamous cell carcinoma-104 (UM-SCC-104), a new HPV(+) HNSCC cell line from a recurrent oral cavity tumor, and characterized it for the presence of cancer stem cells (CSCs).
Tumor cells were tested for biomarker expression by immunohistology, and the presence of HPV was assessed by several methods.
UM-SCC-104 has a unique genotype, contains HPV-16, and expresses E6/E7. Inoculation of aldehyde dehydrogenase (ALDH)(+) and ALDH(-) cells in an immunocompromised mouse resulted in tumor growth from the ALDH(+) cells after 6 weeks that recapitulated the histology of the primary, whereas ALDH(-) cells did not produce tumors.
UM-SCC-104, a new HPV-16, CSC-containing HNSCC cell line will aid in studying recurrent HPV(+) tumors. The aggressive nature of this tumor is consistent with high uniform expression of epidermal growth factor receptor (EGFR) and a functionally significant proportion of ALDH(+) CSCs. © 2011 Wiley Periodicals, Inc. Head Neck, 2011.
Head & Neck 12/2011; 34(10):1480-91. · 2.40 Impact Factor
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ABSTRACT: The membrane glycoprotein CTL2/SLC44A2 is expressed by supporting cells in the inner ear and has been identified as a target of antibodies that may induce auto-immune hearing loss. To determine if CTL2/SLC44A2 also has roles in inner ear development and to distinguish between isoform-specific roles, we assessed age-related changes in expression of CTL2/SLC44A2 isoforms and protein in the developing murine inner ear. We determined that both isoform p1 and isoform p2 (named for the upstream p1 and proximal p2 promoters that control alternate exons 1a and 1b) were robustly expressed as early as E14 and persisted during embryonic development, but after birth the p1 isoform fell to barely detectable levels while isoform p2 levels were maintained. This trend continued and became even more apparent later in post-natal development and remained in mature ears until at least 6 weeks of age. In aged (18 mo old) mice, the level of isoform p1 transcripts rose again to levels similar to the p2 isoform like that seen early in development. At the earliest stage examined, CTL2/SLC44A2 protein was expressed in both immature supporting cells and immature sensory cells, but after birth expression in the sensory cells declined in both the utricle and cochlea and by day P1 expression of CTL2/SLC44A2 was restricted to supporting cells. The changes we observed in isoform distribution are indicative of differential developmental roles and age related changes between the two isoforms of CTL2/SLC44A2 in the inner ear.
Hearing research 12/2011; 282(1-2):63-8. · 2.18 Impact Factor
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Mei Zhao,
Daisuke Sano,
Curtis R Pickering,
Samar A Jasser,
Ying C Henderson,
Gary L Clayman,
Erich M Sturgis,
Thomas J Ow,
Reuben Lotan, Thomas E Carey,
Peter G Sacks,
Jennifer R Grandis,
David Sidransky,
Nils Erik Heldin,
Jeffrey N Myers
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ABSTRACT: Human cell lines are useful for studying cancer biology and preclinically modeling cancer therapy, but can be misidentified and cross-contamination is unfortunately common. The purpose of this study was to develop a panel of validated head and neck cell lines representing the spectrum of tissue sites and histologies that could be used for studying the molecular, genetic, and phenotypic diversity of head and neck cancer.
A panel of 122 clinically and phenotypically diverse head and neck cell lines from head and neck squamous cell carcinoma, thyroid cancer, cutaneous squamous cell carcinoma, adenoid cystic carcinoma, oral leukoplakia, immortalized primary keratinocytes, and normal epithelium was assembled from the collections of several individuals and institutions. Authenticity was verified by carrying out short tandem repeat analysis. Human papillomavirus (HPV) status and cell morphology were also determined.
Eighty-five of the 122 cell lines had unique genetic profiles. HPV-16 DNA was detected in 2 cell lines. These 85 cell lines included cell lines from the major head and neck primary tumor sites, and close examination shows a wide range of in vitro phenotypes.
This panel of 85 genomically validated head and neck cell lines represents a valuable resource for the head and neck cancer research community that can help advance understanding of the disease by providing a standard reference for cell lines that can be used for biological as well as preclinical studies.
Clinical Cancer Research 08/2011; 17(23):7248-64. · 7.74 Impact Factor
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Anna E Arthur,
Sonia A Duffy,
Ann Arbor,
Gloria I Sanchez,
Stephen B Gruber,
Jeffrey E Terrell,
James R Hebert,
Emily Light,
Carol R Bradford,
Nisha J D Silva, Thomas E Carey
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ABSTRACT: No studies have investigated dietary differences between head and neck squamous cell carcinoma
(HNSCC) patients with human papillomavirus (HPV)-positive tumors and patients with HPV-negative
tumors. This study was designed to investigate the relationship between diet and HPV
status in HNSCC patients. Cases of HNSCC were recruited from 2 clinical centers participating in
the University of Michigan Head and Neck Specialized Program of Research Excellence
(SPORE). HPV tissue genotyping was performed, and epidemiological and dietary data collected.
Multivariable logistic regression tested whether pretreatment consumption of 12 selected
micronutrients was significantly associated with HPV-positive status in 143 patients newly
diagnosed with cancer of the oral cavity or pharynx. After controlling for age, sex, body mass
index, tumor site, cancer stage, problem drinking, smoking, and energy intake, significant and
positive associations were observed between vitamin A, vitamin E, iron, β-carotene, and folate
intake and HPV-positive status (Ptrend < 0.05), suggesting that diet may be a factor in the
improved prognosis documented in those with HPV-positive HNSCC. Dietary differences by HPV
status should be considered in prognostic studies to better understand the influence of diet on
HNSCC survival.
Nutrition and Cancer 06/2011; 63(5):734-742. · 2.78 Impact Factor
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Anna E Arthur,
Sonia A Duffy,
Gloria I Sanchez,
Stephen B Gruber,
Jeffrey E Terrell,
James R Hebert,
Emily Light,
Carol R Bradford,
Nisha J D'Silva, Thomas E Carey,
Gregory T Wolf,
Karen E Peterson,
Laura S Rozek
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[hide abstract]
ABSTRACT: No studies have investigated dietary differences between head and neck squamous cell carcinoma (HNSCC) patients with human papillomavirus (HPV)-positive tumors and patients with HPV-negative tumors. This study was designed to investigate the relationship between diet and HPV status in HNSCC patients. Cases of HNSCC were recruited from 2 clinical centers participating in the University of Michigan Head and Neck Specialized Program of Research Excellence (SPORE). HPV tissue genotyping was performed, and epidemiological and dietary data collected. Multivariable logistic regression tested whether pretreatment consumption of 12 selected micronutrients was significantly associated with HPV-positive status in 143 patients newly diagnosed with cancer of the oral cavity or pharynx. After controlling for age, sex, body mass index, tumor site, cancer stage, problem drinking, smoking, and energy intake, significant and positive associations were observed between vitamin A, vitamin E, iron, β-carotene, and folate intake and HPV-positive status (P(trend) < 0.05), suggesting that diet may be a factor in the improved prognosis documented in those with HPV-positive HNSCC. Dietary differences by HPV status should be considered in prognostic studies to better understand the influence of diet on HNSCC survival.
Nutrition and Cancer 06/2011; 63(5):734-42. · 2.78 Impact Factor
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ABSTRACT: Oncogenic human papillomaviruses (HPV) are associated with nearly all cervical cancers and are increasingly important in the etiology of oropharyngeal tumors. HPV-associated head and neck squamous cell carcinomas (HNSCC) have distinct risk profiles and appreciate a prognostic advantage compared to HPV-negative HNSCC. Promoter hypermethylation is widely recognized as a mechanism in the progression of HNSCC, but the extent to which this mechanism is consistent between HPV(+) and HPV(-) tumors is unknown. To investigate the epigenetic regulation of gene expression in HPV-induced and carcinogen-induced cancers, we examined genome-wide DNA methylation and gene expression in HPV(+) and HPV(-) SCC cell lines. We used two platforms: the Illumina Infinium Methylation BeadArray and tiling arrays, and confirmed illustrative examples with pyrosequencing and quantitative PCR. These analyses indicate that HPV(+) cell lines have higher DNA methylation in genic and LINE-1 regions than HPV(-) cell lines. Differentially methylated loci between HPV(+) and HPV(-) cell lines significantly correlated with HPV-typed HNSCC primary tumor DNA methylation levels. Novel findings include higher promoter methylation of polycomb repressive complex 2 target genes in HPV(+) cells compared to HPV(-) cells and increased expression of DNMT3A in HPV(+) cells. Additionally, CDKN2A and KRT8 were identified as interaction hubs among genes with higher methylation and lower expression in HPV(-) cells. Conversely, RUNX2, IRS-1 and CCNA1 were major hubs with higher methylation and lower expression in HPV(+) cells. Distinct HPV(+) and HPV(-) epigenetic profiles should provide clues to novel targets for development of individualized therapeutic strategies.
Epigenetics: official journal of the DNA Methylation Society 06/2011; 6(6):777-87. · 4.58 Impact Factor
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Waleed M Abuzeid,
Samantha Davis,
Alice L Tang,
Lindsay Saunders,
J Chadwick Brenner,
Jiayuh Lin,
James R Fuchs,
Emily Light,
Carol R Bradford,
Mark E P Prince, Thomas E Carey
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ABSTRACT: To determine whether a novel small molecule inhibitor derived from curcumin (FLLL32) that targets signal transducer and activator of transcription (STAT) 3 would induce cytotoxic effects in STAT3-dependent head and neck squamous cell cancer (HNSCC) cells and would sensitize tumors to cisplatin.
Basic science. Two HNSCC cell lines, UM-SCC-29 and UM-SCC-74B, were characterized for cisplatin [cis-diammineplatinum(II) dichloride] sensitivity. Baseline expression of STAT3 and other apoptosis proteins was determined. The FLLL32 50% inhibitory concentration (IC(50)) dose was determined for each cell line, and the effect of FLLL32 treatment on the expression of phosphorylated STAT3 and other key proteins was elucidated. The antitumor efficacy of cisplatin, FLLL32, and combination treatment was measured. The proportion of apoptotic cells after cisplatin, FLLL32, or combination therapy was determined.
The UM-SCC-29 cell line is cisplatin resistant, and the UM-SCC-74B cell line is cisplatin sensitive. Both cell lines express STAT3, phosphorylated STAT3 (pSTAT3), and key apoptotic proteins. FLLL32 downregulates the active form of STAT3, pSTAT3, in HNSCC cells and induces a potent antitumor effect. FLLL32, alone or with cisplatin, increases the proportion of apoptotic cells. FLLL32 sensitized cisplatin-resistant cancer cells, achieving an equivalent tumor kill with a 4-fold lower dose of cisplatin.
FLLL32 monotherapy induces a potent antitumor effect and sensitizes cancer cells to cisplatin, permitting an equivalent or improved antitumor effect at lower doses of cisplatin. Our results suggest that FLLL32 acts by inhibiting STAT3 phosphorylation, reduced survival signaling, increased susceptibility to apoptosis, and sensitization to cisplatin.
Archives of otolaryngology--head & neck surgery 05/2011; 137(5):499-507. · 1.92 Impact Factor
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ABSTRACT: The cancer stem cell (CSC) theory concludes that a subpopulation of cancer cells, the cancer stem cells, can self-renew and are responsible for tumor growth. Previous studies have identified cells able to efflux Hoechst 33342 dye as the side population (SP). SP cells and CSCs share many characteristics, suggesting the SP isolated from malignant tumors contains CSCs.
Experimental Study.
The SP was isolated from a head and neck cancer cell line and analyzed for CSC-like characteristics.
The SP demonstrated the ability to reproduce both SP and non-side population (NSP) cells from as few as one cell. The SP had lower expression of active β-catenin and more resistance to 5-fluorouracil; the SP also demonstrated greater expression of Bmi-1 (4.3-fold) and ABCG2 (1.4-fold). SP cells were able to produce tumors in an animal model, whereas NSP were not. SPs were identified in two primary human tumors.
This work adds to the evidence that the SP in head and neck cancer represents cells with CSC properties and provides a method by which CSCs can be isolated and studied.
The Laryngoscope 03/2011; 121(3):527-33. · 1.75 Impact Factor
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Mark H. Tabor MD,
Matthew R. Clay BSc,
John H. Owen BSc,
Carol R. Bradford MD, Thomas E. Carey PhD,
Gregory T. Wolf MD,
Mark E. Prince MD,
Mark H. Tabor,
Matthew R. Clay,
John H. Owen,
Carol R. Bradford,
Thomas E. Carey,
Gregory T. Wolf,
Mark E. Prince
[show abstract]
[hide abstract]
ABSTRACT: Objectives/Hypothesis:The cancer stem cell (CSC) theory concludes that a subpopulation of cancer cells, the cancer stem cells, can self-renew and are responsible for tumor growth. Previous studies have identified cells able to efflux Hoechst 33342 dye as the side population (SP). SP cells and CSCs share many characteristics, suggesting the SP isolated from malignant tumors contains CSCs.Study Design:Experimental Study.Methods:The SP was isolated from a head and neck cancer cell line and analyzed for CSC-like characteristics.Results:The SP demonstrated the ability to reproduce both SP and non-side population (NSP) cells from as few as one cell. The SP had lower expression of active β-catenin and more resistance to 5-fluorouracil; the SP also demonstrated greater expression of Bmi-1 (4.3-fold) and ABCG2 (1.4-fold). SP cells were able to produce tumors in an animal model, whereas NSP were not. SPs were identified in two primary human tumors.Conclusions:This work adds to the evidence that the SP in head and neck cancer represents cells with CSC properties and provides a method by which CSCs can be isolated and studied. Laryngoscope, 2011
The Laryngoscope 02/2011; 121(3):527 - 533. · 1.75 Impact Factor
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ABSTRACT: to design in vitro and in vivo models of metastasis to study the behavior of cancer stem cells (CSCs) in head and neck squamous cell carcinoma (HNSCC).
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 lesions.
in vitro, CD44(high) cells were more motile but not more invasive than CD44(low) cells. In vivo, 8 of 17 mice injected with CD44(high) cells and 0 of 17 mice injected with CD44(low) cells developed lung lesions. Two of the lesions arose from CSCs from a primary tumor and 6 from CSCs from HNSCC cell lines.
in vitro, CSCs do not have an increased ability to invade through basement membrane, but they migrate more efficiently through a porous barrier. In contrast, CSCs efficiently formed lung lesions in vivo, whereas non-CSCs did not give rise to any distant disease. This phenomenon could be due to the enhanced migratory capacity of CSCs, which may be more important than basement membrane degradation in vivo.
Archives of otolaryngology--head & neck surgery 12/2010; 136(12):1260-6. · 1.92 Impact Factor
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Derrick Wansom,
Emily Light,
Frank Worden,
Mark Prince,
Susan Urba,
Douglas B Chepeha,
Kitrina Cordell,
Avraham Eisbruch,
Jeremy Taylor,
Nisha D'Silva,
Jeffrey Moyer,
Carol R Bradford,
David Kurnit,
Bhavna Kumar, Thomas E Carey,
Gregory T Wolf
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ABSTRACT: to determine whether the favorable outcome associated with human papillomavirus (HPV) 16-positive oropharyngeal cancer is related to a patient's adaptive immunity.
academic medical center.
forty-seven of 66 previously untreated patients (6 of 20 patients with stage III and 41 of 46 with stage IV cancer) in a prospective clinical trial of chemoradiotherapy.
all patients were treated with a single course of neoadjuvant chemotherapy followed by either surgery (for nonresponders) or chemoradiotherapy.
pretreatment levels (percentages and absolute counts) of CD3, CD4, CD8, natural killer, and B cells and overall white blood cell counts were measured by flow cytometry. Correlations of subsets with HPV-16 status, tumor subsite, cancer stage, T class, N class, smoking status, performance status, sex, response to chemoradiotherapy, p53 mutation type, epidermal growth factor receptor expression, and disease-specific and overall survival were determined.
after a median follow-up of 6.6 years, improved survival was associated with an elevated percentage of CD8 cells (P = .04), a low CD4:CD8 ratio (P = .01), low epidermal growth factor receptor expression (P = .002), and HPV status (P = .02). The percentage of CD8 cells was significantly higher (P = .04) and the CD4:CD8 ratio was significantly lower (P = .02) in HPV-16-positive patients. A higher percentage of CD8 cells was associated with response to induction chemotherapy (P = .02) and complete tumor response after chemoradiotherapy (P = .045).
these findings confirm previous correlations of outcome with circulating CD8 cell levels and support the conjecture that improved adaptive immunity may play a role in the favorable prognosis of patients with HPV-16-positive cancers.
Archives of otolaryngology--head & neck surgery 12/2010; 136(12):1267-73. · 1.92 Impact Factor
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ABSTRACT: In accord with the cancer stem cell (CSC) theory, only a small subset of cancer cells are capable of forming tumors. We previously reported that CD44 isolates tumorigenic cells from head and neck squamous cell cancer (HNSCC). Recent studies indicate that aldehyde dehydrogenase (ALDH) activity may represent a more specific marker of CSCs.
Six primary HNSCCs were collected. Cells with high and low ALDH activity (ALDH(high)/ALDH(low)) were isolated. ALDH(high) and ALDH(low) populations were implanted into NOD/SCID mice and monitored for tumor development.
ALDH(high) cells represented a small percentage of the tumor cells (1% to 7.8%). ALDH(high) cells formed tumors from as few as 500 cells in 24/45 implantations, whereas only 3/37 implantations of ALDH(low) cells formed tumors.
ALDH(high) cells comprise a subpopulation cells in HNSCCs that are tumorigenic and capable of producing tumors at very low numbers. This finding indicates that ALDH activity on its own is a highly selective marker for CSCs in HNSCC.
Head & Neck 09/2010; 32(9):1195-201. · 2.40 Impact Factor
