The effects of ALK5 inhibition and simultaneous inhibition or activation of HIF-1α in melanoma tumor growth and angiogenesis.

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 AND METHODS: Tumors were induced in C57BL/6J mice by subcutaneous inoculation with B16F10 melanoma cells. Mice were divided into HIF-1α inhibitor, ALK5 inhibitor (1 mg/kg) and HIF-1α inhibitor (100 mg/kg), ALK5 inhibitor, HIF-1α activator (1000 mg/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.

A review on the role of tau and stathmin in gastric cancer metastasis.

Gastric cancer is resistant to chemotherapy, especially in the later stages. The prevalence of gastric cancer increases after the age of 40, and its peak is in the 7th decade of life. The proteins tau (tubulin associated unit) and stathmin are overexpressed in gastric cancer and contribute to the progression of the disease by increasing cancer cell proliferation, invasion, and inducing drug resistance. This review summarizes the current knowledge on the expression of tau protein and stathmin in gastric cancer and their roles in drug resistance. Medline and PubMed databases were searched from 1990 till February 2021 for the terms "tau protein", "stathmin", and "gastric cancer." Two reviewers screened all articles and assessed prognostic studies on the role of tau and stathmin proteins in gastric cancer progression. Collectively, studies reported that both proteins are expressed at different concentrations in gastric cancer and could be significant molecular biomarkers for prognosis. Both proteins could be good candidates for targeted therapy of gastric cancer and are associated with resistance to taxanes.