Publicação
Unravel the role of hypoxia in the tumor microenvironment: a focus on macrophage-cancer cell interplay
| Resumo: | Cancer is a consequence not only of genetic aberrations but also of other elements of the surrounding hypoxic tumor microenvironment such as extracellular matrix components, fibroblasts, and immune cells, which affect cancer cells, modulating their activities and influencing tumor progression and therapy response. Despite this knowledge, underlying mechanisms governing these interactions are poorly understood, and their understanding can be translated into new or more efficient therapies. Macrophages are one of the most abundant cells in the tumor microenvironment and depending of the stimuli that they are subjected to, can either present a pro-inflammatory (M1) or anti-inflammatory (M2) phenotype. Although hypoxia and macrophages are independently associated with tumor progression, and macrophages are preferentially recruited to low oxygen areas, there is insufficient information about the influence of hypoxia on macrophage-cancer cell crosstalk, and on macrophage-mediated cancer cell invasion. Therefore, in order to understand how hypoxia can influence the crosstalk between tumor cells and macrophages a co-culture system with cancer cells and human macrophages, derived from healthy blood donors was established. Macrophages were cultured in monoculture or in indirect co-culture with CRC cell line (RKO) in normoxia (20% O2) or hypoxia (1% O2), enabling the collection of biological material to characterize both populations. Firstly, our experimental setup was validated regarding the response of cancer cells and macrophages to hypoxia. Our results suggest that hypoxia triggers a more pro-inflammatory phenotype on macrophages, along with alterations in macrophages function hallmarks: phagocytosis, antigen presenting capacities, and immune response regulation. Hypoxia and co cultures modulate macrophage expression of SIRP1α, CD47, MHC-II, and PD-L1. In addition, the characterization of RKO cells was also evaluated and revealed that hypoxia potentiates invasion, expression of EMT genes and expression of proteolytic genes. Our results demonstrate that hypoxia is a critical feature to have in consideration when studying the tumor microenvironment interactions. |
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| Autores principais: | Oliveira, Rosa Alexandra Costa |
| Assunto: | Tumor microenvironment Hypoxia Macrophages Colorectal cancer Cancer cell invasion Microambiente tumoral Hipoxia Macrófagos Cancro colorretal Invasão de células tumorais |
| Ano: | 2018 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | inglês |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | Cancer is a consequence not only of genetic aberrations but also of other elements of the surrounding hypoxic tumor microenvironment such as extracellular matrix components, fibroblasts, and immune cells, which affect cancer cells, modulating their activities and influencing tumor progression and therapy response. Despite this knowledge, underlying mechanisms governing these interactions are poorly understood, and their understanding can be translated into new or more efficient therapies. Macrophages are one of the most abundant cells in the tumor microenvironment and depending of the stimuli that they are subjected to, can either present a pro-inflammatory (M1) or anti-inflammatory (M2) phenotype. Although hypoxia and macrophages are independently associated with tumor progression, and macrophages are preferentially recruited to low oxygen areas, there is insufficient information about the influence of hypoxia on macrophage-cancer cell crosstalk, and on macrophage-mediated cancer cell invasion. Therefore, in order to understand how hypoxia can influence the crosstalk between tumor cells and macrophages a co-culture system with cancer cells and human macrophages, derived from healthy blood donors was established. Macrophages were cultured in monoculture or in indirect co-culture with CRC cell line (RKO) in normoxia (20% O2) or hypoxia (1% O2), enabling the collection of biological material to characterize both populations. Firstly, our experimental setup was validated regarding the response of cancer cells and macrophages to hypoxia. Our results suggest that hypoxia triggers a more pro-inflammatory phenotype on macrophages, along with alterations in macrophages function hallmarks: phagocytosis, antigen presenting capacities, and immune response regulation. Hypoxia and co cultures modulate macrophage expression of SIRP1α, CD47, MHC-II, and PD-L1. In addition, the characterization of RKO cells was also evaluated and revealed that hypoxia potentiates invasion, expression of EMT genes and expression of proteolytic genes. Our results demonstrate that hypoxia is a critical feature to have in consideration when studying the tumor microenvironment interactions. |
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