Modulation of peritumoral fibroblasts with a membrane-tethered tissue inhibitor of metalloproteinase (TIMP) for the elimination of cancer cells.
Invest New Drugs
; 40(1): 198-208, 2022 02.
Article
en En
| MEDLINE
| ID: mdl-34519970
ABSTRACT
BACKGROUND:
Peritumoral fibroblasts are key components of the tumor microenvironment. Through remodeling of the extracellular matrix (ECM) and secretion of pro-tumorigenic cytokines, peritumoral fibroblasts foster an immunosuppressive milieu conducive to tumor cell proliferation. In this study, we investigated if peritumoral fibroblasts could be therapeutically engineered to elicit an anti-cancer response by abolishing the proteolytic activities of membrane-bound metalloproteinases involved in ECM modulation.METHODS:
A high affinity, glycosylphosphatidylinositol (GPI)-anchored Tissue Inhibitor of Metalloproteinase (TIMP) named "T1PrαTACE" was created for dual inhibition of MT1-MMP and TACE. T1PrαTACE was expressed in fibroblasts and its effects on cancer cell proliferation investigated in 3D co-culture models.RESULTS:
T1PrαTACE abrogated the activities of MT1-MMP and TACE in host fibroblasts. As a GPI protein, T1PrαTACE could spontaneously detach from the plasma membrane of the fibroblast to co-localize with MT1-MMP and TACE on neighboring cancer cells. In a 3D co-culture model, T1PrαTACE promoted adherence between the cancer cells and surrounding fibroblasts, which led to an attenuation in tumor development.CONCLUSION:
Peritumoral fibroblasts can be modulated with the TIMP for the elimination of cancer cells. As a novel anti-tumor strategy, our approach could potentially be used in combination with conventional chemo- and immunotherapies for a more effective cancer therapy.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Inhibidores Tisulares de Metaloproteinasas
/
Fibroblastos
/
Neoplasias
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Invest New Drugs
Año:
2022
Tipo del documento:
Article
País de afiliación:
China