RESUMO
In cervical cancer, the epidermal growth factor receptor (EGFR) is overexpressed in 70-90% of the cases and has been associated with poor prognosis. EGFR-based therapy is currently being explored in cervical cancer. We investigated which EGFR ligand is primarily expressed in cervical cancer and which cell type functions as the major source of this ligand. We hypothesized that macrophages are the main source of EGFR ligands and that a paracrine loop between tumor cells and macrophages is responsible for ligand expression. mRNA expression analysis was performed on 32 cervical cancer cases to determine the expression of the EGFR ligands amphiregulin, ß-cellulin, epidermal growth factor (EGF), epiregulin, heparin-binding EGF-like growth factor (HBEGF) and transforming growth factor α (TGFα). Subsequently, protein expression was determined immunohistochemically on 36 additional cases. To assess whether macrophages are the major source of EGFR ligands, immunohistochemical double staining was performed on four representative tissue slides. Expression of the chemokines granulocyte-macrophage colony-stimulating factor (GM-CSF) and C-C motif ligand 2 (CCL2) was determined by mRNA in situ hybridization. Of the known EGFR ligands, HBEGF had the highest mRNA expression and HBEGF and EGFR protein expression were highly correlated. Tumor specimens with high EGFR expression showed higher numbers of macrophages, and higher expression of GM-CSF and CCL2, but only a small subset (9%) of macrophages was found to be HBEGF-positive. Strikingly, 78% of cervical cancer specimens were found to express HBEGF. Standardized assessment of staining intensity, using spectral imaging analysis, showed that HBEGF expression was higher in the tumor compartment than in the stromal compartment. These results suggest that HBEGF is an important EGFR ligand in cervical cancer and that cervical cancer cells are the predominant source of HBEGF. Therefore, we propose an autocrine EGFR stimulation model in cervical carcinomas.
Assuntos
Receptores ErbB/genética , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/genética , Neoplasias do Colo do Útero/genética , Anfirregulina/genética , Comunicação Autócrina/genética , Linhagem Celular Tumoral , Quimiocina CCL2/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Humanos , Ligantes , RNA Mensageiro , Transdução de Sinais/genética , Neoplasias do Colo do Útero/patologiaRESUMO
AIM: Human papillomavirus (HPV) is a risk factor for oropharyngeal squamous cell carcinoma (OPSCC), with an increasing incidence. The present study aimed to determine the changing incidence of HPV in patients with OPSCC in the period 1980-2009 and its influence on survival. PATIENTS AND METHODS: We randomly sampled 158 patients from a cohort of 828 patients with OPSCC stratified by decade (1980-1989, 1990-1999, 2000-2009). Formalin-fixed paraffin-embedded material was tested for HPV DNA by SPF-10 polymerase chain reaction (PCR) and immunohistochemically stained for p16 and p53. RESULTS: DNA from 146 patients was suitable for HPV detection. HPV DNA was detected in 13/47 (28%), 18/47 (38%), and 20/52 (38%) patients in the cohorts of 1980-1989, 1990-1999, and 2000-2009, respectively (p-value for trend=0.269). Lack of further increase during the most recent decade is inconsistent with the rising incidence and higher prevalence reported in other Western countries. Patients with HPV-positive OPSCC had a better survival in spite of higher tumor stage.
Assuntos
Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/virologia , Papillomavirus Humano 16/genética , Neoplasias Orofaríngeas/etiologia , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/complicações , Carcinoma de Células Escamosas/mortalidade , DNA Viral/genética , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Países Baixos , Neoplasias Orofaríngeas/mortalidade , Infecções por Papillomavirus/mortalidade , Infecções por Papillomavirus/virologia , Fatores de RiscoRESUMO
Human papillomavirus-induced usual-type vulvar intraepithelial neoplasia (uVIN) are infiltrated by immune cells but apparently not cleared. A potential explanation for this is an impaired T cell effector function by an immunesuppressive milieu, coinfiltrating regulatory T cells or the expression of coinhibitory molecules. Here, the role of these potential inhibitory mechanisms was evaluated by a detailed immunohistochemical analysis of T cell infiltration in the context of FoxP3, Tbet, indoleamine 2,3-dioxygenase, programmed cell death 1, T cell immunoglobulin mucin 3 (TIM3), natural killer cell lectin-like receptor A (NKG2A) and galectins-1, -3 and -9. Paraffin-embedded tissues of primary uVIN lesions (n=43), recurrent uVIN lesions (n=20), vulvar carcinoma (n=21) and healthy vulvar tissue (n=26) were studied. We show that the vulva constitutes an area intensely surveyed by CD8+, CD4+, Tbet+ and regulatory T cell populations, parts of which express the examined coinhibitory molecules. In uVIN especially, the number of regulatory T cells and TIM3+ T cells increased. The expression of the coinhibitory markers TIM3 and NKG2A probably reflected a higher degree of T cell activation as a dense infiltration with stromal CD8+TIM3+ T cells and CD3+NKG2A+ T cells was related to the absence of recurrences and/or a prolonged recurrence-free survival. A dense coinfiltrate with regulatory T cells was negatively associated with the time to recurrence, most dominantly when the stromal CD8+TIM3+ infiltration was limited. This notion was sustained in vulvar carcinoma's where the numbers of regulatory T cells progressively increased to outnumber coinfiltrating CD8+TIM3+ T cells and CD3+NKG2A+ T cells.
