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1.
Cancer Prev Res (Phila) ; 2(4): 385-93, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19336725

RESUMO

Despite numerous advances, the 5-year survival rate for head and neck squamous cell cancer (HNSCC) has remained largely unchanged. This poor outcome is due to several variables, including the development of multiple primary tumors. Therefore, it is essential to supplement early detection with preventive strategies. Using the 4-nitroquinoline 1-oxide (4-NQO) mouse model, we sought to define an appropriate dose and duration of administration that would predict the histologic timeline of HNSCC progression. Additionally, we sought to determine the timing of the onset of the angiogenic phenotype. Finally, using ABT-510 as a proof-of-principle drug, we tested the hypothesis that inhibitors of angiogenesis can slow/delay the development of HNSCC. We determined that 8 weeks of 100 microg/mL 4-NQO in the drinking water was the optimal dosage and duration to cause a sufficient incidence of hyperkeratoses, dysplasias, and HNSCC over a period of 32 weeks with minimal morbidity and mortality. Increased microvessel density and vascular endothelial growth factor expression in hyperkeratotic lesions provided evidence that the initiation of the angiogenic phenotype occurred before the development of dysplasia. Importantly, ABT-510 significantly decreased the overall incidence of HNSCC from 37.3% to 20.3% (P = 0.021) as well as the combined incidence of dysplasia and HNSCC from 82.7% to 50.6% (P < 0.001). These findings suggest that our refinement of the 4-NQO model allows for the investigation of the histologic, molecular, and biological alterations that occur during the premalignant phase of HNSCC. In addition, these data support the hypothesis that inhibitors of angiogenesis may be promising chemopreventive agents.


Assuntos
Inibidores da Angiogênese/farmacologia , Carcinoma de Células Escamosas/prevenção & controle , Modelos Animais de Doenças , Neoplasias Bucais/prevenção & controle , Oligopeptídeos/farmacologia , 4-Nitroquinolina-1-Óxido/toxicidade , Animais , Carcinógenos/toxicidade , Carcinoma de Células Escamosas/induzido quimicamente , Carcinoma de Células Escamosas/patologia , Imuno-Histoquímica , Antígeno Ki-67/biossíntese , Antígeno Ki-67/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos CBA , Microvasos/efeitos dos fármacos , Neoplasias Bucais/induzido quimicamente , Neoplasias Bucais/patologia , Neovascularização Patológica/tratamento farmacológico , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/tratamento farmacológico , Lesões Pré-Cancerosas/patologia , Fator A de Crescimento do Endotélio Vascular/biossíntese , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos
2.
Cancer Res ; 69(1): 65-74, 2009 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-19117988

RESUMO

Protein kinase Calpha (PKCalpha) has been implicated in cancer, but the mechanism is largely unknown. Here, we show that PKCalpha promotes head and neck squamous cell carcinoma (SCCHN) by a feed-forward network leading to cell cycle deregulation. PKCalpha inhibitors decrease proliferation in SCCHN cell lines and xenografted tumors. PKCalpha inhibition or depletion in tumor cells decreases DNA synthesis by suppressing extracellular signal-regulated kinase phosphorylation and cyclin E synthesis. Additionally, PKCalpha down-regulates miR-15a, a microRNA that directly inhibits protein synthesis of cyclin E, as well as other cell cycle regulators. Furthermore, both PKCalpha and cyclin E protein expression are increased in primary tumors, and PKCalpha inversely correlates with miR-15a expression in primary tumors. Finally, PKCalpha is associated with poor prognosis in SCCHN. These results identify PKCalpha as a key regulator of SCCHN tumor cell growth by a mechanism involving activation of mitogen-activated protein kinase, an initiator of the cell cycle, and suppression of miR-15a, an inhibitor of DNA synthesis. Although the specific components may be different, this type of feed-forward loop network, consisting of a stimulus that activates a positive signal and removes a negative brake, is likely to be a general one that enables induction of DNA synthesis by a variety of growth or oncogenic stimuli.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/patologia , MicroRNAs/metabolismo , Proteína Quinase C-alfa/metabolismo , Animais , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/genética , Ciclo Celular/genética , Ciclo Celular/fisiologia , Proteínas de Ciclo Celular/biossíntese , Proteínas de Ciclo Celular/genética , Processos de Crescimento Celular/fisiologia , Ciclina E/biossíntese , DNA de Neoplasias/biossíntese , Feminino , Expressão Gênica , Neoplasias de Cabeça e Pescoço/enzimologia , Neoplasias de Cabeça e Pescoço/genética , Humanos , Camundongos , Camundongos Nus , MicroRNAs/genética , Mucosa Bucal/citologia , Mucosa Bucal/enzimologia , Mucosa Bucal/metabolismo , Proteína Quinase C-alfa/antagonistas & inibidores , Proteína Quinase C-alfa/biossíntese , Proteína Quinase C-alfa/genética , Transdução de Sinais
3.
J Oral Pathol Med ; 37(3): 166-76, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18251941

RESUMO

With the identification of a number of novel markers having diagnostic, prognostic, and therapeutic significance, the application of tissue microarray (TMA) has become a valuable tool for validating candidate markers in cancer research. The TMA is a high-throughput technique, which allows large-scale analyses of hundreds of archival clinical tissue samples using the 'array' approach. This paper highlights briefly its robust technology, technical aspects of its construction, and the validity of the TMA results for oral pathology diagnostics by reviewing data from recent literature particularly with reference to head and neck cancer.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/patologia , Análise Serial de Tecidos , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/genética , Perfilação da Expressão Gênica , Neoplasias de Cabeça e Pescoço/química , Neoplasias de Cabeça e Pescoço/genética , Humanos , Estimativa de Kaplan-Meier , Modelos de Riscos Proporcionais , Transdução de Sinais
4.
Lab Invest ; 88(4): 342-53, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18283272

RESUMO

The literature contains numerous references describing heterogeneity for tumor phenotypes including cell proliferation, invasiveness, metastatic potential, and response to therapies. However, data regarding angiogenic heterogeneity are limited. In this study, we investigated the degree of intertumoral angiogenic heterogeneity present in head and neck squamous cell carcinomas (HNSCC). In addition, we investigated the biological relevance that this heterogeneity may have in the context of cytokine directed antiangiogenic therapy. Keratinocytes were harvested from HNSCC specimens using laser capture microdissection (LCM). Gene expression profiling of the RNA extracted from these specimens demonstrated variability in the expression of angiogenesis-related genes. Hierarchical clustering and principal component analyses (PCA) demonstrated the presence of unique patient clusters, suggesting that there may be two potentially distinct pathways by which HNSCC induce angiogenesis. Immunohistochemistry for VEGF, IL-8/CXCL8, HGF, and FGF-2, cytokines that play functional roles in HNSCC angiogenesis was performed on the original patient samples as well as a larger panel of normal, dysplastic and HNSCC specimens to validate the heterogeneous expression observed in the gene expression profiling studies. Finally, the therapeutic response of HNSCC tumor xenografts to anti-VEGF therapy was found to be dependent on the amount of VEGF produced by the tumor cells. These findings support the hypothesis of intertumoral angiogenic heterogeneity. They imply that there are differences with regard to the specific molecular mechanisms by which individual tumors within the same histological type induce angiogenesis. Moreover, they demonstrate the need for a more in-depth understanding of the variability of the angiogenic phenotype within a given type of neoplasm when designing cytokine targeted antiangiogenic therapies. Finally, they suggest that studies in conjunction with the ongoing clinical trials that explore the correlation between target expression and clinical outcome are warranted.


Assuntos
Proteínas Angiogênicas/metabolismo , Carcinoma de Células Escamosas/irrigação sanguínea , Neoplasias de Cabeça e Pescoço/irrigação sanguínea , Neovascularização Patológica/metabolismo , Proteínas Angiogênicas/genética , Anticorpos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/metabolismo , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Interleucina-8/genética , Interleucina-8/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/imunologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
5.
Cancer Res ; 66(12): 6296-303, 2006 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-16778206

RESUMO

Protein kinase C (PKC) zeta has been implicated as a mediator of epidermal growth factor (EGF) receptor (EGFR) signaling in certain cell types. Because EGFR is ubiquitously expressed in squamous cell carcinomas of the head and neck (SCCHN) and plays a key role in tumor progression, we determined whether PKCzeta is required for tumor cell proliferation and viability. Examination of total and phosphorylated PKCzeta expression in normal oral mucosa, dysplasia, and carcinoma as well as SCCHN tumor cell lines revealed a significant increase in activated PKCzeta expression from normal to malignant tissue. PKCzeta activity is required for EGF-induced extracellular signal-regulated kinase (ERK) activation in both normal human adult epidermal keratinocytes and five of seven SCCHN cell lines. SCCHN cells express constitutively activated EGFR family receptors, and inhibition of either EGFR or mitogen-activated protein kinase (MAPK) activity suppressed DNA synthesis. Consistent with this observation, inhibition of PKCzeta using either kinase-dead PKCzeta mutant or peptide inhibitor suppressed autocrine and EGF-induced DNA synthesis. Finally, PKCzeta inhibition enhanced the effects of both MAPK/ERK kinase (U0126) and broad spectrum PKC inhibitor (chelerythrine chloride) and decreased cell proliferation in SCCHN cell lines. The results indicate that (a) PKCzeta is associated with SCCHN progression, (b) PKCzeta mediates EGF-stimulated MAPK activation in keratinocytes and SCCHN cell lines, (c) PKCzeta mediates EGFR and MAPK-dependent proliferation in SCCHN cell lines; and (d) PKCzeta inhibitors function additively with other inhibitors that target similar or complementary signaling pathways.


Assuntos
Carcinoma de Células Escamosas/enzimologia , Fator de Crescimento Epidérmico/metabolismo , Neoplasias de Cabeça e Pescoço/enzimologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteína Quinase C/metabolismo , Alcaloides , Sequência de Aminoácidos , Benzofenantridinas , Butadienos/farmacologia , Carcinoma de Células Escamosas/patologia , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/metabolismo , DNA de Neoplasias/biossíntese , Ativação Enzimática , Receptores ErbB/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Queratinócitos/enzimologia , Dados de Sequência Molecular , Mucosa Bucal/enzimologia , Mucosa Bucal/patologia , Neoplasias Bucais/enzimologia , Neoplasias Bucais/patologia , Nitrilas/farmacologia , Fenantridinas/farmacologia , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/biossíntese , Inibidores de Proteínas Quinases/farmacologia
6.
Clin Cancer Res ; 11(22): 8105-8, 2005 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-16299242

RESUMO

PURPOSE: Small-molecule tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) have shown modest yet reproducible response rates in patients with squamous cell carcinoma of the head and neck (SCCHN). Somatic mutations in EGFR have recently been shown to be predictive of a clinical response in patients with non-small cell lung cancer (NSCLC) treated with these inhibitors. The objective of this study was to determine if such mutations, or recently reported mutations in ERBB2, also underlie EGFR-TKI responsiveness in SCCHN patients. EXPERIMENTAL DESIGN: We sequenced the kinase domain of EGFR and exon 20 of ERBB2 in tumor specimens from eight responsive patients. In addition, mutational analysis was done on tumor specimens from nine gefitinib nonresponders and 65 unselected cases of SCCHN. RESULTS: None of eight TKI-responsive specimens had mutations within the kinase domain of EGFR. EGFR amplification was also not associated with drug responsiveness. However, a single responsive case had a somatic missense mutation within exon 20 of ERBB2. CONCLUSION: Our data indicate that unlike NSCLC, EGFR kinase mutations are rare in unselected cases of SCCHN within the United States and are not linked to gefitinib or erlotinib responses in SCCHN. Alternative mechanisms, including ERBB2 mutations, may underlie responsiveness in this tumor type.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Receptores ErbB/genética , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Mutação/genética , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-2/genética , Idoso , Antineoplásicos/uso terapêutico , Sequência de Bases , Carcinoma de Células Escamosas/genética , Análise Mutacional de DNA , Receptores ErbB/antagonistas & inibidores , Feminino , Gefitinibe , Neoplasias de Cabeça e Pescoço/genética , Humanos , Masculino , Pessoa de Meia-Idade , Quinazolinas/uso terapêutico , Resultado do Tratamento
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