The effects of ALK5 inhibition and simultaneous inhibition or activation of HIF-1α in melanoma tumor growth and angiogenesis.
Tumour Biol
; 45(1): 111-126, 2023.
Article
in En
| MEDLINE
| ID: mdl-37927290
ABSTRACT
BACKGROUND:
Hypoxia is the most common signature of the tumor microenvironment that drives tumorigenesis through the complex crosstalk of a family of transcription factors called hypoxia-inducible factors (HIFs), with other intercellular signaling networks. Hypoxia increases transforming growth factor-beta (TGF-ß) expression. TGF-ß and HIF-1α play critical roles in several malignancies and their interactions in melanoma progression remain unknown. Therefore, the aim of this study was to assess the impact of inhibiting activin receptor-like kinase-5 (ALK5), a TGF-ß receptor, on the response to HIF-1α activation or inhibition in melanoma tumor progression. MATERIALS ANDMETHODS:
Tumors were induced in C57BL/6J mice by subcutaneous inoculation with B16F10 melanoma cells. Mice were divided into HIF-1α inhibitor, ALK5 inhibitor (1âmg/kg) and HIF-1α inhibitor (100âmg/kg), ALK5 inhibitor, HIF-1α activator (1000âmg/kg), HIF-1α activator and ALK5 inhibitor, and control groups to receive inhibitors and activators through intraperitoneal injection. The expression of E-cadherin was evaluated by RT-qPCR. Vessel density and platelet-derived growth factor receptor beta (PDGFR)-ß+ cells around the vessels were investigated using immunohistochemistry.RESULTS:
The groups receiving HIF-1α inhibitor and activator showed lower and higher tumor growth compared to the control group, respectively. E-cadherin expression decreased in all groups compared to the control group, illustrating the dual function of E-cadherin in the tumor microenvironment. Vascular density was reduced in the groups given HIF-1α inhibitor, ALK5 inhibitor, and ALK5 and HIF-1α inhibitor simultaneously. The percentage of PDGFR-ß+ cells was reduced in the presence of HIF-1α inhibitor, ALK5 inhibitor, HIF-1α and ALK5 inhibitors, and upon simultaneous treatment with HIF-1α activator and ALK5 inhibitor.CONCLUSION:
Despite increased expression and interaction between TGF-ß and HIF-1α pathways in some cancers, in melanoma, inhibition of either pathway alone may have a stronger effect on tumor inhibition than simultaneous inhibition of both pathways. The synergistic effects may be context-dependent and should be further evaluated in different cancer types.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Melanoma
Limits:
Animals
/
Humans
Language:
En
Journal:
Tumour Biol
Journal subject:
NEOPLASIAS
Year:
2023
Document type:
Article
Affiliation country:
Iran