Activation of the HGF/c-Met axis in the tumor microenvironment: A multispecies model.
J Theor Biol
; 439: 86-99, 2018 02 14.
Article
em En
| MEDLINE
| ID: mdl-29203124
ABSTRACT
The tumor microenvironment is an integral component in promoting tumor development. Cancer-associated fibroblasts (CAFs), which reside in the tumor stroma, produce Hepatocyte Growth Factor (HGF), an important trigger for invasive and metastatic tumor behavior. HGF contributes to a pro-tumorigenic environment by activating its cognate receptor, c-Met, on tumor cells. Tumor cells, in turn, secrete growth factors that upregulate HGF production in CAFs, thereby establishing a dynamic tumor-host signaling program. Using a spatiotemporal multispecies model of tumor growth, we investigate how the development and spread of a tumor is impacted by the initiation of a dynamic interaction between tumor-derived growth factors and CAF-derived HGF. We show that establishment of such an interaction results in increased tumor growth and morphological instability, the latter due in part to increased cell species heterogeneity at the tumor-host boundary. Invasive behavior is further increased if the tumor lowers responsiveness to paracrine pro-differentiation signals, which is a hallmark of neoplastic development. By modeling anti-HGF and anti-c-Met therapy, we show how disruption of the HGF/c-Met axis can reduce tumor invasiveness and growth, thereby providing theoretical evidence that targeting tumor-microenvironment interactions is a promising avenue for therapeutic development.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fator de Crescimento de Hepatócito
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Comunicação Parácrina
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Proteínas Proto-Oncogênicas c-met
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Microambiente Tumoral
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Modelos Biológicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article