RESUMEN
The extracellular matrix proteoglycan decorin is well-known for its oncosuppressive activity. Here, decorin expression was examined in human vulva carcinoma tissue samples and in primary and commercial cell lines representing this malignant disease. Furthermore, the effect of adenovirus-mediated decorin cDNA (Ad-DCN) transduction on the viability, proliferation, and the expression and activity of the epidermal growth factor receptor (ErbB/HER) family members of the cell lines were investigated. Using in situ hybridization and immunohistochemistry for decorin, it was demonstrated that malignant cells in human vulva carcinoma tissues lack decorin expression. This result was true independently on tumor stage, grade or human papillomavirus status. RT-qPCR analyses showed that the human vulva carcinoma cell lines used in this study were also negative for decorin expression. Transduction of the cell lines with Ad-DCN caused a marked reduction in cell viability, while the proliferation of the cells was not affected. Experiments examining potential mechanisms behind the oncosuppressive effect of Ad-DCN transduction revealed that ErbB2/HER2 expression and activity in carcinoma cells were markedly downregulated. In conclusion, the results of this study showed that human vulva carcinoma cells lack decorin expression, and that Ad-DCN transduction of these cells induces oncosuppressive activity in part via downregulation of ErbB2/HER2.
Asunto(s)
Decorina/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias de los Genitales Femeninos/genética , Transducción Genética , Vulva/patología , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , ADN Complementario/genética , Receptores ErbB/genética , Femenino , Neoplasias de los Genitales Femeninos/metabolismo , Neoplasias de los Genitales Femeninos/patología , Humanos , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/genética , Proteína Sequestosoma-1/metabolismoRESUMEN
An increasing amount of evidence indicates that a small extracellular chondroitin/dermatan sulfate proteoglycan, decorin, is indirectly involved in angiogenesis. Given that angiogenesis is a sine qua non for tumor growth and progression, we attempted to examine whether human malignant vascular tumors differ from human benign vascular tumors in terms of their decorin expression and synthesis. CD31 immunostaining demonstrated that the human malignant vascular tumors Kaposi's sarcoma and angiosarcoma were filled with capillary-like structures, whereas in benign cavernous and capillary hemangiomas, blood vessels were not as abundantly present. By utilizing in situ hybridization and immunocytochemical assays for decorin, we showed that there was no detectable decorin mRNA expression or immunoreactivity within the tumor mass in the Kaposi's sarcoma or angiosarcoma group. Instead, decorin was expressed in the connective tissue stroma lining the sarcoma tissue. In contrast to sarcomas, in hemangiomas, decorin mRNA expression and immunoreactivity were observed also within the tumor mass, particularly in the connective tissue stroma surrounding the clusters of intratumoral blood vessels. Finally, distribution of type I collagen was found to be similar to that of decorin in these tumor tissues. Our findings can be explained with different states of angiogenesis in dissimilar growths. In sarcomas, angiogenesis is extremely powerful, whereas in hemangiomas, angiogenesis has ceased. Thus, decorin is likely to possess a suppressive effect on human tumor angiogenesis in vivo, as previously described by studies using different experimental models. Decorin certainly provides a usable biomarker for distinguishing between benign and malignant vascular tumors in patients.
Asunto(s)
Proteínas de la Matriz Extracelular/biosíntesis , Hemangioma Capilar/metabolismo , Hemangioma Cavernoso/metabolismo , Hemangiosarcoma/metabolismo , Proteoglicanos/biosíntesis , Sarcoma de Kaposi/metabolismo , Neoplasias Cutáneas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/genética , Colágeno Tipo I/metabolismo , Decorina , Receptores ErbB/metabolismo , Proteínas de la Matriz Extracelular/genética , Femenino , Hemangioma Capilar/irrigación sanguínea , Hemangioma Cavernoso/irrigación sanguínea , Hemangiosarcoma/irrigación sanguínea , Humanos , Inmunohistoquímica , Hibridación in Situ , Masculino , Persona de Mediana Edad , Proteoglicanos/genética , ARN Mensajero/biosíntesis , Sarcoma de Kaposi/irrigación sanguínea , Neoplasias Cutáneas/irrigación sanguíneaRESUMEN
Decorin is generally recognized as a tumor suppressing molecule. Nevertheless, although decorin has been shown to be differentially expressed in malignant tissues, it has often remained unclear whether, in addition to non-malignant stromal cells, cancer cells also express it. Here, we first used two publicly available databases to analyze the current information about decorin expression and immunoreactivity in normal and malignant human colorectal tissue samples. The analyses demonstrated that decorin expression and immunoreactivity may vary in cancer cells of human colorectal tissues. Therefore, we next examined decorin expression in normal, premalignant and malignant human colorectal tissues in more detail using both in situ hybridization and immunohistochemistry for decorin. Our results invariably demonstrate that malignant cells within human colorectal cancer tissues are devoid of both decorin mRNA and immunoreactivity. Identical results were obtained for cells of neuroendocrine tumors of human colon. Using RT-qPCR, we showed that human colon cancer cell lines are also decorin negative, in accordance with the above in vivo results. Finally, we demonstrate that decorin transduction of human colon cancer cell lines causes a significant reduction in their colony forming capability. Thus, strategies to develop decorin-based adjuvant therapies for human colorectal malignancies are highly rational.