Reprogramming energy metabolism and inducing angiogenesis: co-expression of monocarboxylate transporters with VEGF family members in cervical adenocarcinomas.

BACKGROUND: Deregulation of cellular energetic metabolism was recently pointed out as a hallmark of cancer cells. This deregulation involves a metabolic reprogramming that leads to a high production of lactate. Lactate efflux, besides contributing for the glycolytic flux, also acts in the extracellular matrix, contributing for cancer malignancy, by, among other effects, induction of angiogenesis. However, studies on the interplay between cancer metabolism and angiogenesis are scarce. Therefore, the aim of the present study was to evaluate the metabolic and vascular molecular profiles of cervical adenocarcinomas, their co-expression, and their relation to the clinical and pathological behavior. METHODS: The immunohistochemical expression of metabolism-related proteins (MCT1, MCT4, CD147, GLUT1 and CAIX) as well as VEGF family members (VEGF-A, VEGF-C, VEGF-D, VEGFR-1, VEGFR-2 and VEGFR-3) was assessed in a series of 232 cervical adenocarcinomas. The co-expression among proteins was assessed and the expression profiles were associated with patients' clinicopathological parameters. RESULTS: Among the metabolism-related proteins, MCT4 and CAIX were the most frequently expressed in cervical adenocarcinomas while CD147 was the less frequently expressed protein. Overall, VEGF family members showed a strong and extended expression with VEGF-C and VEGFR-2 as the most frequently expressed and VEGFR-1 as the less expressed member. Co-expression of MCT isoforms with VEGF family members was demonstrated. Finally, MCT4 was associated with parametrial invasion and HPV18 infection, CD147 and GLUT1 with distant metastasis, CAIX with tumor size and HPV18 infection, and VEGFR-1 with local and lymphnode metastasis. CONCLUSIONS: The results herein presented provide additional evidence for a crosstalk between deregulating cellular energetics and inducing angiogenesis. Also, the metabolic remodeling and angiogenic switch are relevant to cancer progression and aggressiveness in adenocarcinomas.

Molecular characterization of EGFR, PDGFRA and VEGFR2 in cervical adenosquamous carcinoma.

BACKGROUND: Adenosquamous carcinoma of the uterine cervix is an infrequent but aggressive subtype of cervical cancer. A better understanding of its biological behaviour is warranted to define more accurate prognosis and therapeutic targets. Currently, the blockage of receptor tyrosine kinase (RTKs) activity is an efficient therapeutic strategy for many different cancers. The objective of this study was to investigate EGFR, PDGFRA and VEGFR2 RTKs overexpression and activating gene mutations in a cohort of 30 adenosquamous carcinomas of the uterine cervix. METHODS: EGFR, PDGFRA and VEGFR2 immunohistochemistry was performed in all samples, followed by DNA isolation from the gross macroscopically dissection of the neoplastic area. Screening for EGFR (exons 18-21) and PDGFRA (exons 12, 14 and 18) mutations was done by PCR--single-strand conformational polymorphism (PCR-SSCP). RESULTS: Despite the presence of EGFR immunohistochemical positive reactions in 43% (13/30) of the samples, no EGFR activating mutations in the hotspot region (exons 18-21) were identified. A silent base substitution (CAG>CAA) in EGFR exon 20 at codon 787 (Q787Q) was found in 17 cases (56%). All PDGFRA immunohistochemical reactions were positive and consistently observed in the stromal component, staining fibroblasts and endothelial cells, as well as in the cytoplasm of malignant cells. No activating PDGFRA mutations were found, yet, several silent mutations were observed, such as a base substitution in exon 12 (CCA>CCG) at codon 567 (P567P) in 9 cases and in exon 18 (GTC>GTT) at codon 824 (V824V) in 4 cases. We also observed the presence of base substitutions in intron 14 (IVS14+3G>A and IVS14+49G>A) in two different cases, and in intron 18 (IVS18-50insA) in 4 cases. VEGFR2 positivity was observed in 22 of 30 cases (73.3%), and was significantly associated with lack of metastasis (p=0.038). CONCLUSION: This is the most extensive analysis of EGFR, PDGFRA and VEGFR2 in cervical adenosquamous carcinomas. Despite the absence of EGFR and PDGFRA activating mutations, the presence of overexpression of these three important therapeutic targets in a subset of cases may be important in predicting the sensitivity of adenosquamous carcinoma to specific anti-RTKs drugs.

KIT activation in uterine cervix adenosquamous carcinomas by KIT/SCF autocrine/paracrine stimulation loops.

OBJECTIVES: Uterine adenosquamous carcinoma (ASC) is an uncommon, yet, one of the most aggressive cervical cancer subtype. The successful treatment of some tumors, such as gastrointestinal stromal tumors (GISTs), by anti-KIT inhibitors fosters the study of this receptor tyrosine kinase in other malignancies. In the present study, we intended to molecularly characterize KIT in ASC. METHODS: In a series of 30 cases, we studied KIT (CD117), KIT phosphorylated/activated form, as well as KIT ligand, stem cell factor (SCF), by immunohistochemistry. We further screened for KIT hotspot mutations (exon 9, 11, 13 and 17) by PCR-SSCP and for KIT gene amplification by Quantitative real-time PCR in CD117 positive cases. RESULTS: We observed CD117 expression in approximately 13% of cases, with approximately 7% co-expressing SCF, which resulted in KIT phosphorylation/activation. No KIT activating mutations or gene amplification were found, despite the presence of 4q aneuploidy in one case. CONCLUSIONS: This is the first study assessing KIT activation and molecular alterations in a large series of rare ASC. Our findings showed the absence of KIT molecular alterations and suggested the presence of KIT activation in a small proportion of cases through KIT/SCF co-expression.

Correlaçäo citologia-colposcopia-conizaçäo nas displasias cervicais uterinas / Cytology colposcopy-conization correlation in uterine cervical dysplasias

Foram estudados 101 casos de conizaçäo do colo uterino no período de 1979 a 1981. Os exames citológico e colposcópico foram correlacionados com o exame histopatológico. Encontraram-se 11,8% de resultados falsos negativos e 4,9% de falsos positivos para a citologia vaginal. A colposcopia evidenciou concordância total com o exame histopatológico em 75,1% dos casos, sendo as lesöes leucoqueratóticas as mais freqüentes (58%) A complicaçäo mais freqüente da conizaçäo foi o sangramento vaginal (8,9%)

AvaliaçÝo da dissecçäo axilar na mastectomia radical modificada a Madden para o tratamento do câncer mamário / Evaluation of axillary dissection in Madden modified radical mastectomy for treatment of breast cancer

Com o objetivo de analisar o número de linfonodos dissecados, foram estudados 229 pacientes portadoras de câncer de mama, tratadas no Hospital Araújo Jorge entre 1979 e 1988. Destas, 175 foram submetidas à mastectomia radical clássica (MRC) e 54 à mastectomia radical modificada com preservaçäo de ambos os músculos peitorais (MRM). NÝo houve influência do estádio clínico nem do tratamento prévio sobre o procedimento cirúrgico, porém pacientes mais jovens foram submetidas mais freqüentemente à MRC. O número médio de linfonodos disecados foi maior na MRC que na MRM, 23 e 18 respectivamente. Ressecçäo de mais de 30 gânglios só foi obtida com a MRC, sendo esta diferença significativa (p < 0,001). Concluiu-se que a MRC possibilita uma melhor dissecaçäo axilar com retirada de maior número de linfonodos quando comparado à MRM com preservaçäo de ambos os peitorais.

Avaliaçäo da resposta do câncer de mama localmente avançado em pacientes submetidas à quimioterapia neoadjuvante / Evaluation of te response of locally advanced breast cancer in patients submitted to neoadjuvant chemotherapy

Este trabalho tem como objetivo avaliar a resposta do câncer de mama, estádio III, em pacientes submetidas à quimioterapia neoadjuvante, estudar os fatores relacionados à resposta e verificar a acurácia do exame físico como método de avaliaçäo da resposta do tumor à quimioterapia. Em um período de 6 anos, 71 pacientes com carcinoma de mama, E III, foram submetidas à quimioterapia neoadjuvante com o esquema FACV (ciclofosfamida 400 mg/m2, 5-fluorouracil 400 mg/m, doxorrubicina 10 mg/m2 e vincristina 1 mg/m2). Foram realizados 6 ciclos semanais antes da cirurgia e 11 ciclos quinzenais, após o tratamento cirúrgico. Na avaliaçäo clínica após o 6§ ciclo, houve reduçao completa do tumor em 9 por cento dos casos; reduçäo maior que 50 por cento em 59 por cento das pacientes e, em 32 por cento dos casos houve reduçäo menor que 50 por cento ou progressäo. Apenas o tamanho do tumor inicial esteve significativamente associado à resposta tumoral, sendo que tumores maiores mostraram-se mais responsivos. Dentre os 57 casos apontados como tendo tumor residual ao exame físico, 52 foram confirmados histologicamente. Dos 6 casos sem tumor ao exame físico, dois foram confirmados histologicamente. A acurácia total do exame clínico foi de 86 por cento, a sensibilidade de 93 por cento, a especificidade de 29 por cento, o valor preditivo positivo de 91 por cento e o valor preditivo negativo de 33 por cento. Concluiu-se que a quimioterapia neoadjuvante proporcionou boa reduçäo dos tumores, sendo que os maiores apresentaram uma melhor resposta. O exame físico apresenta baixa acurácia no estudo da resposta tumoral e, isoladamente, näo é um bom método de avaliaçäo.