A Feedback Loop between Hypoxia and Matrix Stress Relaxation Increases Oxygen-Axis Migration and Metastasis in Sarcoma.
Cancer Res
; 79(8): 1981-1995, 2019 04 15.
Article
em En
| MEDLINE
| ID: mdl-30777851
ABSTRACT
Upregulation of collagen matrix crosslinking directly increases its ability to relieve stress under the constant strain imposed by solid tumor, a matrix property termed stress relaxation. However, it is unknown how rapid stress relaxation in response to increased strain impacts disease progression in a hypoxic environment. Previously, it has been demonstrated that hypoxia-induced expression of the crosslinker procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2), in sarcomas has resulted in increased lung metastasis. Here, we show that short stress relaxation times led to increased cell migration along a hypoxic gradient in 3D collagen matrices, and rapid stress relaxation upregulated PLOD2 expression via TGFß-SMAD2 signaling, forming a feedback loop between hypoxia and the matrix. Inhibition of this pathway led to a decrease in migration along the hypoxic gradients. In vivo, sarcoma primed in a hypoxic matrix with short stress relaxation time enhanced collagen fiber size and tumor density and increased lung metastasis. High expression of PLOD2 correlated with decreased overall survival in patients with sarcoma. Using a patient-derived sarcoma cell line, we developed a predictive platform for future personalized studies and therapeutics. Overall, these data show that the interplay between hypoxia and matrix stress relaxation amplifies PLOD2, which in turn accelerates sarcoma cell motility and metastasis. SIGNIFICANCE:
These findings demonstrate that mechanical (stress relaxation) and chemical (hypoxia) properties of the tumor microenvironment jointly accelerate sarcoma motility and metastasis via increased expression of collagen matrix crosslinker PLOD2.
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Base de dados:
MEDLINE
Assunto principal:
Oxigênio
/
Sarcoma
/
Regulação Neoplásica da Expressão Gênica
/
Movimento Celular
/
Matriz Extracelular
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Neoplasias Pulmonares
/
Hipóxia
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Cancer Res
Ano de publicação:
2019
Tipo de documento:
Article