Interferon-Alpha Decreases Cancer Stem Cell Properties and Modulates Exosomes in Malignant Melanoma

被引：2

作者：

Garcia-Ortega, Maria Belen ^{[1
,2
,3
,4
]}

Aparicio, Ernesto ^{[1
,2
,3
,5
]}

Grinan-Lison, Carmen ^{[1
,2
,3
,6
,7
]}

Jimenez, Gema ^{[1
,2
,3
,8
]}

Lopez-Ruiz, Elena ^{[2
,3
,9
]}

Palacios, Jose Luis ^{[1
,3
]}

Ruiz-Alcala, Gloria ^{[1
,2
,3
]}

Alba, Cristina ^{[4
]}

Martinez, Antonio ^{[10
]}

Boulaiz, Houria ^{[1
,2
,3
,8
]}

Peran, Macarena ^{[1
,2
,3
,9
]}

Hackenberg, Michael ^{[1
,2
,3
,5
]}

Braganca, Jose ^{[11
,12
,13
]}

Calado, Sofia M. ^{[11
,12
,13
]}

Marchal, Juan A. ^{[1
,2
,3
,8
]}

Garcia, Maria Angel ^{[1
,2
,3
,14
]}

机构：

[1] Univ Granada, Biopathol & Regenerat Med Inst IBIMER, Ctr Biomed Res, Granada 18016, Spain

[2] Inst Invest Biosanit Granada Ibs GRANADA, Granada 18012, Spain

[3] Univ Granada, Excellence Res Unit Modelling Nat MNat, Granada 18071, Spain

[4] Virgen Nieves Univ Hosp, Dept Oncol, Granada 18014, Spain

[5] Univ Granada, Dept Genet, Granada 18100, Spain

[6] Univ Granada, Fac Pharm, Dept Biochem & Mol Biol 2, Granada 18011, Spain

[7] Univ Granada Andalusian Reg Govt, GENYO Ctr Genom & Oncol Res Pfizer, Granada 18016, Spain

[8] Univ Granada, Fac Med, Dept Human Anat & Embryol, Granada 18016, Spain

[9] Univ Jaen, Dept Hlth Sci, Campus Lagunillas SN, Jaen 23071, Spain

[10] Virgen Nieves Univ Hosp, Dept Dermatol, Granada 18014, Spain

[11] Univ Algarve, Algarve Biomed Ctr Res Inst ABC RI, P-8005139 Faro, Portugal

[12] Univ Algarve, Fac Med & Ciencias Biomed, P-8005139 Faro, Portugal

[13] Champalimaud Ctr Unknown, Champalimaud Res Program, P-1400038 Lisbon, Portugal

[14] Univ Granada, Fac Med, Dept Mol Biol & Biochem & Immunol 3, Granada 18016, Spain

来源：

CANCERS | 2023年 / 15卷 / 14期

关键词：

interferon-& alpha; malignant melanoma; cancer stem cells; exosomes; metabolomics; biomarkers; SIDE POPULATION; GUIDELINE; TARGET;

D O I：

10.3390/cancers15143666

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Malignant melanoma spreads to other organs and is resistant in part due to the presence of cancer stem cell subpopulations (CSCs). To combat these aggressive subpopulations, different therapies are being studied. Our study aimed to evaluate the anti-tumor effect of interferon-alpha (IFN-a) treatments on melanoma CSCs and explore potential biomarkers. We found that even low doses of IFN-a reduced CSC formation and stemness properties, and led to a significant decrease in the ability to form tumors in mice xenotransplants. IFN-a also modulated the expression of genes and microRNAs involved in several cancer processes and the metabolomics of released exosomes. Our data suggest further investigations of new dose and combination approaches with IFN-a in malignant melanoma.Malignant melanoma (MM) can spread to other organs and is resistant in part due to the presence of cancer stem cell subpopulations (CSCs). While a controversial high dose of interferon-alpha (IFN-a) has been used to treat non-metastatic high-risk melanoma, it comes with undesirable side effects. In this study, we evaluated the effect of low and high doses of IFN-a on CSCs by analyzing ALDH activity, side population and specific surface markers in established and patient-derived primary cell lines. We also assessed the clonogenicity, migration and tumor initiation capacities of IFN-a treated CSCs. Additionally, we investigated genomic modulations related to stemness properties using microRNA sequencing and microarrays. The effect of IFN-a on CSCs-derived exosomes was also analyzed using NanoSight and liquid chromatography (LC-HRMS)-based metabolomic analysis, among others. Our results showed that even low doses of IFN-a reduced CSC formation and stemness properties, and led to a significant decrease in the ability to form tumors in mice xenotransplants. IFN-a also modulated the expression of genes and microRNAs involved in several cancer processes and metabolomics of released exosomes. Our work suggests the utility of low doses of interferon, combined with the analysis of metabolic biomarkers, as a potential clinical approach against the aggressiveness of CSCs in melanoma.

引用

页数：21