Targeting ALDH1 to decrease tumorigenicity, growth and metastasis of human melanoma

Yue, Lili; Huang, Zhiming; Fong, Stephen S.; Leong, Stanley P. L.; Jakowatz, James G.; Charruyer-Reinwald, Alex; Wei, Maria L.; Ghadially, Ruby

doi:10.1097/cmr.0000000000000144

Cited by 59 publications

(55 citation statements)

References 40 publications

(37 reference statements)

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“…A recent study has shown that siRNA-mediated knockdown of ALDH in melanoma cells inhibited in vivo tumor development and metastatic properties [64]. Mechanistically, the ALDH high melanoma cells have been shown to possess higher tumorigenic, invasive, and self-renewal capacities than ALDH low cells and thus, can serve as a potential therapeutic target [13, 62, 65]. These studies implicate high ALDH activity as a relevant biomarker for identifying melanoma CICs, and the significant inhibition of ALDH activity that we observed with Lunasin phenocopies the anti-melanoma/anti-CIC effects observed in cells silenced for ALDH.…”

Section: Discussionmentioning

confidence: 99%

Lunasin is a novel therapeutic agent for targeting melanoma cancer stem cells

et al. 2016

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Recent studies provide compelling evidence that melanoma is initiated and maintained by a small population of malignant cells called cancer-initiating cells (CICs) that exhibit stem-cell-like properties. Observations that CICs have a distinct biology when compared to that of the bulk tumor cells and, importantly, are resistant to chemotherapies and radiation, suggest that CICs are involved in invasion, metastasis, and ultimately relapse. Lunasin, a bioactive peptide present in soybean, has both chemopreventive activity and chemotherapeutic activity against multiple cancer types. In this study, we tested the potential of Lunasin to specifically target CICs in melanoma tumor cell populations. In vitro studies using human melanoma cell lines showed that Lunasin treatment decreased the size of a subpopulation of melanoma cells expressing the surrogate CIC marker, Aldehyde Dehydrogenase, concomitant with a reduction in the ability to form colonies in soft agar assays, and reduced tumor growth in mouse xenografts. Similarly, Lunasin inhibited colony formation by isolated melanoma CICs in soft agar and reduced oncosphere formation in vitro and substantially inhibited tumor growth in mouse xenografts. Mechanistic studies revealed that Lunasin treatment of isolated melanoma CICs induced expression of the melanocyte-associated differentiation markers Tyrosinase and Microphthalmia-associated Transcription Factor concomitant with reduced expression of the stemness factor NANOG. These findings document for the first time that Lunasin has significant therapeutic activity against melanoma by specifically targeting melanoma CICs, and inducing a more differentiated, non-CIC phenotype. Thus, Lunasin may represent a novel therapeutic option for both chemoresistant and advanced metastatic melanoma management.

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Section: Discussionmentioning

confidence: 99%

Lunasin is a novel therapeutic agent for targeting melanoma cancer stem cells

et al. 2016

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“…We and others have recently shown the ability of ALDH activity to select for melanoma CSC [10–12]. High ALDH levels protect melanoma cells from apoptosis while ALDH1 blockade prevents tumor relapse [10–13]. …”

Section: Introductionmentioning

confidence: 99%

Therapeutic potential of the metabolic modulator phenformin in targeting the stem cell compartment in melanoma

et al. 2016

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Melanoma is the most dangerous and treatment-resistant skin cancer. Tumor resistance and recurrence are due to the persistence in the patient of aggressive cells with stem cell features, the cancer stem cells (CSC). Recent evidences have shown that CSC display a distinct metabolic profile as compared to tumor bulk population: a promising anti-tumor strategy is therefore to target specific metabolic pathways driving CSC behavior. Biguanides (metformin and phenformin) are anti-diabetic drugs able to perturb cellular metabolism and displaying anti-cancer activity. However, their ability to target the CSC compartment in melanoma is not known. Here we show that phenformin, but not metformin, strongly reduces melanoma cell viability, growth and invasion in both 2D and 3D (spheroids) models. While phenformin decreases melanoma CSC markers expression and the levels of the pro-survival factor MITF, MITF overexpression fails to prevent phenformin effects. Phenformin significantly reduces cell viability in melanoma by targeting both CSC (ALDHhigh) and non-CSC cells and by significantly reducing the number of viable cells in ALDHhigh and ALDHlow-derived spheroids. Consistently, phenformin reduces melanoma cell viability and growth independently from SOX2 levels. Our results show that phenformin is able to affect both CSC and non-CSC melanoma cell viability and growth and suggests its potential use as anti-cancer therapy in melanoma.

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“…AHDL1A1 silencing led to cell cycle arrest, apoptosis, decreased cell viability in vitro and reduced tumorigenesis in vivo . 22 Abovementioned findings indicated that ALDH1 isoenzymes are also possible therapeutic targets for melanoma. At the same time, Lu et al 23 reported targeting murine MSC via dendritic-cell (DC) vaccination using DCs pulsed with ALDH bright cell lysates, which significantly inhibited tumor growth as compared with DCs pulsed with either ALDH dim or whole tumor lysates.…”

Section: Discussionmentioning

confidence: 99%

Whole cell melanoma vaccine genetically modified to stem cells like phenotype generates specific immune responses to ALDH1A1 and long-term survival in advanced melanoma patients

Kwiatkowska-Borowczyk

Czerwińska

Mackiewicz

et al. 2018

OncoImmunology

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Allogeneic whole cell gene modified therapeutic melanoma vaccine (AGI-101H) comprising of two melanoma cell lines transduced with cDNA encoding fusion protein composed of IL-6 linked with the soluble IL-6 receptor (sIL-6R), referred to as H6 was developed. H6 served as a molecular adjuvant, however, it has altered vaccine cells phenotype towards melanoma stem cells (MSC)-like with high activity of aldehyde dehydrogenase isoenzyme (ALDH1A1). AGI-101H was applied in advanced melanoma patients with non-resected and resected disease. In the adjuvant setting, it was combined with surgery in case of recurring metastases, which were surgically removed and vaccination continued. A significant fraction of AGI-101H treated melanoma patients is still alive (11–19 years). Out of 106 living patients, 39 were HLA-A2 positive and were the subject of the study. Immunization of melanoma patients resulted in the generation of cytotoxic CD8+ T cells specific for ALDH1A1, which were detected in circulation by HLA-A0201 MHC dextramers loaded with ALDH1A188-96(LLYKLADLI) peptide. Phenotypically they were central memory CD8+ T cells. Re-stimulation with ALDH1A188-96 ex vivo resulted in IFN-γ secretion and cells degranulation. Following each vaccine dose administration, the number of ALDH1A1-CD8+ T cells increased in circulation and returned to the previous level until next dose injection (one month). ALDH1A1-CD8+ T cells were also found, however in the lower number than in vaccinated patients, in the circulation of untreated melanoma with stage IV but were not found in stage II or III and healthy donors. Specific anti-ALDH1 antibodies were present in treated patients. Long-term survival suggests immuno-targeting of MSC in treated patients.

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Targeting ALDH1 to decrease tumorigenicity, growth and metastasis of human melanoma

Cited by 59 publications

References 40 publications

Lunasin is a novel therapeutic agent for targeting melanoma cancer stem cells

Lunasin is a novel therapeutic agent for targeting melanoma cancer stem cells

Therapeutic potential of the metabolic modulator phenformin in targeting the stem cell compartment in melanoma

Whole cell melanoma vaccine genetically modified to stem cells like phenotype generates specific immune responses to ALDH1A1 and long-term survival in advanced melanoma patients

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