Influência de um ambiente hiperglicêmico na geração de inflamação e o papel desse fator no desenvolvimento do melanoma murino B16F10-NEX2
Data
2023
Autores
Freitas, Larissa Almeida de 
Orientadores
Rodrigues, Elaine Guadelupe
Tipo
Dissertação de mestrado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Diversos estudos epidemiológicos têm demonstrado uma forte correlação entre a ocorrência de diabetes e o risco aumentado para o desenvolvimento de diferentes tipos de câncer. Vários mecanismos biológicos associando essas duas doenças tem sido proposto, sendo a hiperglicemia um dos potenciais mediadores que as associam. Estudo anterior do nosso grupo mostrou uma correlação positiva entre a hiperglicemia e o maior desenvolvimento do melanoma subcutâneo B16F10-Nex2 in vivo, sendo este efeito dependente da maior concentração de macrófagos e secreção de óxido nítrico (NO) por estas células no microambiente tumoral. Diante disso, este trabalho propõe avaliar a influência da inflamação, no microambiente tumoral e sistemicamente, para o maior desenvolvimento do melanoma subcutâneo B16F10-Nex2 em animais com hiperglicemia sistêmica. Também investigamos in vitro como um ambiente tumoral hiperglicêmico modula o fenótipo de macrófagos derivados de progenitores de medula óssea (BMDMs), para avaliar como essas células são influenciadas localmente. Células tumorais B16F10-Nex2 foram inoculadas subcutaneamente em animais normo ou hiperglicêmicos, cuja hiperglicemia foi previamente induzida pela administração intraperitoneal de estreptozotocina (STZ). Os tumores foram coletados após 16 dias, e observou-se um aumento no número de macrófagos e linfócitos T reguladores intratumorais, associado a um aumento na concentração de IL-10, nos tumores dos animais hiperglicêmicos comparativamente aos animais normoglicêmicos. A análise sistêmica de marcadores inflamatórios mostrou uma menor concentração de IFN- nos linfonodos dos animais hiperglicêmicos, mas concentrações semelhantes de IFN- e IL-10 nos baços dos animais normo e hiperglicêmicos. Macrófagos derivados de progenitores de medula óssea estimulados com homogenatos de tumores isolados de animais hiperglicêmicos produziram menores concentrações de NO, o que sugere que no microambiente tumoral desses animais há um predomínio de uma resposta Th2. Nossos resultados sugerem que a hiperglicemia induz a formação de um ambiente anti-inflamatório que pode estar envolvido no maior desenvolvimento tumoral observado em condições de hiperglicemia.
Several epidemiological studies have demonstrated a strong correlation between the occurrence of diabetes and the increased risk of developing different types of cancer. Several biological mechanisms associating these two diseases have been proposed, and hyperglycemia is one of the potential mediators for this association. A previous study conducted by our group showed a positive correlation between hyperglycemia and increased development of B16F10-Nex2 subcutaneous melanoma in vivo, an effect dependent on the increased number of macrophages and nitric oxide (NO) secretion by these cells in the tumor microenvironment. Therefore, this work proposes to evaluate the influence of inflammation mediators, in the tumor microenvironment and also systemically, on the increased development of B16F10-Nex2 subcutaneous melanoma observed in hyperglycemic animals. We also investigated in vitro how a hyperglycemic tumor environment modulates the phenotype of bone marrow progenitor-derived macrophages (BMDMs), to assess how these cells are influenced locally. B16F10-Nex2 tumor cells were inoculated subcutaneously in normoglycemic or hyperglycemic animals, whose hyperglycemia was previously induced by intraperitoneal administration of streptozotocin (STZ). Tumors were collected after 16 days, and an increased number of intratumoral macrophages and regulatory T lymphocytes was observed, associated with an increased concentration of IL-10, in the tumors of hyperglycemic animals compared to normoglycemic animals. Systemic analysis of inflammatory markers showed a lower concentration of IFN-γ in the lymph nodes of hyperglycemic animals, but similar concentrations of IFN-γ and IL-10 in the spleens of normoglycemic and hyperglycemic animals. Macrophages derived from bone marrow progenitors stimulated with hyperglycemic animals tumor homogenates produced lower concentrations of NO, which suggests a predominance of a Th2 response in the tumor microenvironment of these animals. Our results suggest that hyperglycemia induces the formation of an anti-inflammatory environment that may be involved in the increased tumor development observed under hyperglycemic conditions.
Several epidemiological studies have demonstrated a strong correlation between the occurrence of diabetes and the increased risk of developing different types of cancer. Several biological mechanisms associating these two diseases have been proposed, and hyperglycemia is one of the potential mediators for this association. A previous study conducted by our group showed a positive correlation between hyperglycemia and increased development of B16F10-Nex2 subcutaneous melanoma in vivo, an effect dependent on the increased number of macrophages and nitric oxide (NO) secretion by these cells in the tumor microenvironment. Therefore, this work proposes to evaluate the influence of inflammation mediators, in the tumor microenvironment and also systemically, on the increased development of B16F10-Nex2 subcutaneous melanoma observed in hyperglycemic animals. We also investigated in vitro how a hyperglycemic tumor environment modulates the phenotype of bone marrow progenitor-derived macrophages (BMDMs), to assess how these cells are influenced locally. B16F10-Nex2 tumor cells were inoculated subcutaneously in normoglycemic or hyperglycemic animals, whose hyperglycemia was previously induced by intraperitoneal administration of streptozotocin (STZ). Tumors were collected after 16 days, and an increased number of intratumoral macrophages and regulatory T lymphocytes was observed, associated with an increased concentration of IL-10, in the tumors of hyperglycemic animals compared to normoglycemic animals. Systemic analysis of inflammatory markers showed a lower concentration of IFN-γ in the lymph nodes of hyperglycemic animals, but similar concentrations of IFN-γ and IL-10 in the spleens of normoglycemic and hyperglycemic animals. Macrophages derived from bone marrow progenitors stimulated with hyperglycemic animals tumor homogenates produced lower concentrations of NO, which suggests a predominance of a Th2 response in the tumor microenvironment of these animals. Our results suggest that hyperglycemia induces the formation of an anti-inflammatory environment that may be involved in the increased tumor development observed under hyperglycemic conditions.