Abstract
Cancer stem cells (CSCs), a rare subset of cancer cells, are well known for their self-renewing capacity. CSCs play a critical role in therapeutic failure and are responsible for poor prognosis in leukemia and various solid tumors. However, it is still unclear how CSCs initiate carcinogenesis and evade the immune response. In humans, the melanoma initiating cells (MICs) are recognized as the CSCs in melanomas, and were verified to possess CSC potentials. The enzymatic system, aldehyde dehydrogenase (ALDH) is considered to be a specific marker for CSCs in several tumors. The expression of ALDH in MICs may be closely correlated with phenotypic heterogeneity, melanoma-genesis, metastasis, and drug resistance. The ALDH+ CSCs/MICs not only serve as an indicator for therapeutic efficacy, but have also become a target for the treat of melanoma. In this review, we initially introduce the multiple capacities of MICs in melanoma. Then, we summarize in vivo and in vitro studies that illustrate the relationship between ALDH and MICs. Furthermore, understanding of chemotherapy resistance in melanoma relies on ALDH+ MICs. Finally, we review studies that focus on melanoma immunotherapies, rendering ALDH a potential marker to evaluate the efficacy of anti-neoplastic therapies or an adjuvant anti-melanoma target.
Similar content being viewed by others
References
The Cancer Genome Atlas Network (2015) Genomic classification of cutaneous melanoma. Cell 161:1681–1696
Tsao H, Chin L, Garraway LA et al (2012) Melanoma: from mutations to medicine. Genes Dev 26:1131–1155
Kiuru M, Busam KJ (2017) The NF1 gene in tumor syndromes and melanoma. Lab Investig 97:146–157
Villani V, Sabbatino F, Ferrone CR et al (2015) Melanoma initiating cells: where do we stand? Melanoma Manag 2:109–114
Vasiliou V, Nebert DW (2005) Analysis and update of the human aldehyde dehydrogenase (ALDH) gene family. Hum Genomics 2:138–143
Vassalli G (2019) Aldehyde dehydrogenases: not just markers, but functional regulators of stem cells. Stem Cells Int.https://doi.org/10.1155/2019/3904645
Jackson B, Brocker C, Thompson DC et al (2011) Update on the aldehyde dehydrogenase gene (ALDH) superfamily. Hum Genomics 5:283–303
Sládek NE (2003) Human aldehyde dehydrogenases: potential pathological, pharmacological, and toxicological impact. J Biochem Mol Toxicol 17:7–23
Na HK, Lee JY (2017) Molecular basis of alcohol-related gastric and colon cancer. Int J Mol Sci 18:1116
Castelli G, Pelosi E, Testa U (2017) Liver cancer: molecular characterization, clonal evolution and cancer. Stem Cells Cancers 9:127
Bourguignon LYW, Christine E, Marisa S (2017) Activation of matrix hyaluronan-mediated CD44 signaling, epigenetic regulation and chemoresistance in head and neck cancer stem cells. Int J Mol Sci 18:1849
Suresh R, Ali S, Ahmad A et al (2015) The role of cancer stem cells in recurrent and drug-resistant lung cancer. Adv Exp Med Biol 890:57–74
Yan S, Wu G (2017) Could ALDH2*2 be the reason for low incidence and mortality of ovarian cancer for East Asia women? Oncotarget 9(15):12503–12512
Corominas-Faja B, Oliveras-Ferraros C, Cuyàs E (2013) Stem cell-like ALDH(bright) cellular states in EGFR-mutant non-small cell lung cancer: a novel mechanism of acquired resistance to erlotinib targetable with the natural polyphenol silibinin. Cell Cycle 12:3390–3404
Uomori T, Horimoto Y, Mogushi K et al (2017) Relationship between alcohol metabolism and chemotherapy-induced emetic events in breast cancer patients. Breast Cancer 24:702–707
Samson JM, Ravindran Menon D, Smith DE et al (2019) Clinical implications of ALDH1A1 and ALDH1A3 mRNA expression in melanoma subtypes. Chem Biol Interact 314:108822
Amann PM, Hofmann C, Freudenberger M et al (2012) Expression and activity of alcohol and aldehyde dehydrogenases in melanoma cells and in melanocytes. J Cell Biochem 113:792–299
Brinckerhoff CE (2017) Cancer stem cells (CSCs) in melanoma. J Cell Physiol 232:2674–2678
Quintana E, Shackleton M, Sabel MS et al (2008) Efficient tumour formation by single human melanoma cells. Nature 456:593–598
Shultz LD, Lyons BL, Burzenski LM et al (2005) Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2Rγnull mice engrafted with mobilized human hemopoietic stem cells. J Immunol 174:6477–6489
Marzagalli M, Raimondi M, Fontana F et al (2019) Cellular and molecular biology of cancer stem cells in melanoma: possible therapeutic implications. Semin Cancer Biol 59:221–235
Schmidt P, Kopecky C, Hombach A et al (2011) Eradication of melanomas by targeted elimination of a minor subset of tumor cells. Proc Natl Acad Sci USA 108:2474–2479
Schlaak M, Schmidt P, Bangard C et al (2012) Regression of metastatic melanoma in a patient by antibody targeting of cancer stem cells. Oncotarget 3:22–30
Gonçalves JM, Silva CAB, Rivero ERC et al (2019) Inhibition of cancer stem cells promoted by pimozide. Cli Exp Pharmacol Physiol 46:116–125
Ma I, Allan AL (2011) The role of human aldehyde dehydrogenase in normal and cancer stem cells. Stem Cell Rev 7:292–306
Ginestier C, Hur M, Charafe-Jauffret E (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1:555–567
Jiang F (2009) Aldehyde dehydrogenase 1 is a tumor stem cell-associated marker in lung cancer. Mol Cancer Res 7:330–338
Xu X, Chai S, Wang P et al (2015) Aldehyde dehydrogenases and cancer stem cells. Cancer Lett 369:50–57
Prasmickaite L, Engesaeter B, Skrbo N, Hellenes T et al (2010) Aldehyde dehydrogenase (ALDH) activity does not select for cells with enhanced aggressive properties in malignant melanoma. PLoS ONE 5:e10731
Yang J, Price MA, Li GY et al (2009) Melanoma proteoglycan modifies gene expression to stimulate tumor cell motility, growth, and epithelial-to-mesenchymal transition. Cancer Res 69:7538–7547
Boonyaratanakornkit JB, Yue L, Strachan LR et al (2010) Selection of tumorigenic melanoma cells using ALDH. J Investig Dermatol 130:2799–2808
Ohmura-Kakutani H, Akiyama K, Maishi N et al (2014) Identification of tumor endothelial cells with high aldehyde dehydrogenase activity and a highly angiogenic phenotype. PLoS ONE 9:e113910
Wilson-Robles HM, Daly M, Pfent C et al (2015) Identification and evaluation of putative tumour-initiating cells in canine malignant melanoma cell lines. Vet Comp Oncol 13:60–69
Luo Y, Dallaglio K, Chen Y et al (2012) ALDH1A isozymes are markers of human melanoma stem cells and potential therapeutic targets. Stem Cells 30:2100–2113
Wilson MA, Schuchter LM (2016) Chemotherapy for melanoma. Cancer Treat Res 167:209–229
Flaherty KT, Hodi FS, Fisher DE (2012) From genes to drugs: targeted strategies for melanoma. Nat Rev Cancer 12:349–361
Chapman PB, Hauschild A, Robert C et al (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507–2516
Li S, Wu X, Chen P et al (2018) Interferon-α versus interleukin-2 in Chinese patients with malignant melanoma: a randomized, controlled, trial. Anticancer Drugs 30:402–409
Simon A, Kourie HR, Kerger J (2017) Is there still a role for cytotoxic chemotherapy after targeted therapy and immunotherapy in metastatic melanoma? a case report and literature review. Chin J Cancer 36:10
Heppner GH (1984) Tumor heterogeneity. Cancer Res 44:2259–2265
Ahn A, Chatterjee A, Eccles MR (2017) The slow cycling phenotype: a growing problem for treatment resistance in melanoma. Mol Cancer Ther 16:1002–1009
Caswell DR, Swanton C (2017) The role of tumour heterogeneity and clonal cooperativity in metastasis, immune evasion and clinical outcome. BMC Med 15:133
Shi H, Hugo W, Kong X et al (2014) Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov 4:80–93
Menon DR, Das S, Krepler C et al (2014) A stress-induced early innate response causes multidrug tolerance in melanoma. Oncogene 34:4448–4459
Busse A, Keilholz U (2011) Role of TGF-β in melanoma. Curr Pharm Biotechnol 12:2165–2175
Cantelli G, Orgaz JL, Rodríguez-Hernández I et al (2015) TGF-β-induced transcription sustains amoeboid melanoma migration and dissemination. Curr Biol 25:2899–2914
Spender LC, Ferguson GJ, Liu S et al (2016) Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells. Oncotarget 7:81995–82012
Li S, Song Y, Quach C et al (2019) Transcriptional regulation of autophagy-lysosomal function in BRAF-driven melanoma progression and chemoresistance. Nat Commun 10:1693
Teng Y, Wang X, Wang Y et al (2010) Wnt/β-catenin signaling regulates cancer stem cells in lung cancer A549 cells. Biochem Biophys Res Commun 392:373–379
Xue G, Romano E, Massi D et al (2016) Wnt/β-catenin signaling in melanoma: preclinical rationale and novel therapeutic insights. Cancer Treat Rev 49:1–12
Lu H, Liu S, Zhang G et al (2017) PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas. Nature 550:133–136
Suleymanova N, Crudden C, Worrall C et al (2017) Enhanced response of melanoma cells to MEK inhibitors following unbiased IGF-1R down-regulation. Oncotarget 8:82256–82267
Cheli Y, Guiliano S, Botton T et al (2011) Mitf is the key molecular switch between mouse or human melanoma initiating cells and their differentiated progeny. Oncogene 30:2307–2318
Müller J, Krijgsman O, Tsoi J (2013) Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma. Nat Commun 5:5712
Sun C, Wang L, Huang S et al (2014) Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature 508:118–122
Zhao D, Mo Y, Li MT et al (2014) NOTCH-induced aldehyde dehydrogenase 1A1 deacetylation promotes breast cancer stem cells. J Clin Investig 124:5453–5465
Chen YJ, Sims-Mourtada J, Izzo J et al (2007) Targeting the hedgehog pathway to mitigate treatment resistance. Cell Cycle 6:1826–1830
Januchowski R, Wojtowicz K, Zabel M (2013) The role of aldehyde dehydrogenase (ALDH) in cancer drug resistance. Biomed Pharmacother 67:669–680
Tomonori T, Koji M, Kenzo S et al (2009) Association of breast cancer stem cells identified by aldehyde dehydrogenase 1 expression with resistance to sequential Paclitaxel and epirubicin-based chemotherapy for breast cancers. Clin Cancer Res 15:4234–4241
Croker AK, Allan AL (2012) Inhibition of aldehyde dehydrogenase (ALDH) activity reduces chemotherapy and radiation resistance of stem-like ALDH hi CD44+ human breast cancer cells. Breast Cancer Res Treat 133:75–87
Moreb JS, Maccow C, Schweder M et al (2000) Expression of antisense RNA to aldehyde dehydrogenase class-1 sensitizes tumor cells to 4-hydroperoxycyclophosphamide in vitro. J Pharmacol Exp Ther 293:390–396
Sun QL, Sha HF, Yang XH et al (2011) Comparative proteomic analysis of paclitaxel sensitive A549 lung adenocarcinoma cell line and its resistant counterpart A549-Taxol. J Cancer Res Clin Oncol 137:521–532
Landen CN, Goodman B, Katre AA et al (2010) Targeting aldehyde dehydrogenase cancer stem cells in ovarian cancer. Mol Cancer Ther 9:3186–3199
Januchowski R, Wojtowicz K, Sterzyńska K et al (2016) Inhibition of ALDH1A1 activity decreases expression of drug transporters and reduces chemotherapy resistance in ovarian cancer cell lines. Int J Biochem Cell Biol 78:248–259
Kozłowska A, Mackiewicz J, Mackiewicz A (2013) Therapeutic gene modified cell based cancer vaccines. Gene 525:200–207
Murphy GF, Wilson BJ, Girouard SD et al (2014) Stem cells and targeted approaches to melanoma cure. Mol Aspects Med 39:33–49
Tang L, Bergevoet SM, Gilissen C et al (2010) Hematopoietic stem cells exhibit a specific ABC transporter gene expression profile clearly distinct from other stem cells. BMC Pharmacol 10:12
Han L, Shi S, Gong T et al (2013) Cancer stem cells: therapeutic implications and perspectives in cancer therapy. Acta Pharm Sin B 3:65–75
Zheng L, Pan J (2018) The anti-malarial drug artesunate blocks wnt/β-catenin pathway and inhibits growth, migration and invasion of uveal melanoma cells. Curr Cancer Drug Targ 18:988–998
Kim IG, Kim SY, Choi SI et al (2014) Fibulin-3-mediated inhibition of epithelial-to-mesenchymal transition and self-renewal of ALDH+ lung cancer stem cells through IGF1R signaling. Oncogene 33:3908–3917
Jin N, Zhu X, Cheng F et al (2018) Disulfiram/copper targets stem cell-like ALDH+ population of multiple myeloma by inhibition of ALDH1A1 and Hedgehog pathway. J Cell Biochem 119:6882–6893
Yue L, Huang ZM, Fong S et al (2015) Targeting ALDH1 to decrease tumorigenicity, growth and metastasis of human melanoma. Melanoma Res 25:138–148
Ma YW, Liu YZ, Pan JX (2016) Verteporfin induces apoptosis and eliminates cancer stem-like cells in uveal melanoma in the absence of light activation. Am J Cancer Res 6:2816–2830
Zhu Y, Ye T, Yu X et al (2016) Nifuroxazide exerts potent anti-tumor and anti-metastasis activity in melanoma. Sci Rep 6:20253
Sarvi S, Crispin R, Lu Y et al (2018) ALDH1 bio-activates nifuroxazide to eradicate ALDHHigh melanoma-initiating cells. Cell Chem Biol 25:1456-1469.e6
Petrachi T, Romagnani A, Albini A et al (2017) Therapeutic potential of the metabolic modulator phenformin in targeting the stem cell compartment in melanoma. Oncotarget 8:6914–6928
Zhang B, Zhang J, Pan J (2017) Pristimerin effectively inhibits the malignant phenotypes of uveal melanoma cells by targeting NF-κB pathway. Int J Oncol 51:887–898
Liu S, Gao X, Zhang L et al (2018) A novel anti-cancer stem cells compound optimized from the natural symplostatin 4 scaffold inhibits Wnt/β-catenin signaling pathway. Eur J Med Chem 156:21–42
Li Q, Lu L, Tao H et al (2014) Generation of a novel dendritic-cell vaccine using melanoma and squamous cancer stem cells. J Vis Exp 83:e50561
Ning N, Pan Q, Zheng F et al (2012) Cancer stem cell vaccination confers significant antitumor immunity. Cancer Res 72:1853–1864
Badrinath N, Yoo SY (2019) Recent advances in cancer stem cell-targeted immunotherapy. Cancers 11:310
Dashti A, Ebrahimi M, Hadjati J et al (2016) Dendritic cell based immunotherapy using tumor stem cells mediates potent antitumor immune responses. Cancer Lett 374:175–185
Xu Q, Liu G, Yuan X et al (2009) Antigen-specific T-cell response from dendritic cell vaccination using cancer stem-like cell-associated antigens. Stem Cells 27:1734–1740
Lu Lin. Tao H, Chang AE et al (2015) Cancer stem cell vaccine inhibits metastases of primary tumors and induces humoral immune responses against cancer stem cells. Oncoimmunology 4:e990767
Hu Y, Lu L, Xia Y et al (2016) Therapeutic efficacy of cancer stem cell vaccines in the adjuvant setting. Cancer Res 76:4661–4672
Duraiswamy J. Kaluza KM. Freeman GJ et al ( (2013) Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res 73:3591–3603
Lee Y, Shin JH, Longmire M et al (2016) Cd44+ cells in head and neck squamous cell carcinoma suppress T-cell-mediated immunity by selective constitutive and inducible expression of PD-L1. Clin Cancer Res 22:3571–3581
Tamai K, Nakamura M, Mizuma M et al (2014) Suppressive expression of CD274 increases tumorigenesis and cancer stem cell phenotypes in cholangiocarcinoma. Cancer Sci 105:667–674
Zheng F, Dang J, Zha H et al (2017) PD-L1 promotes self-renewal and tumorigenicity of malignant melanoma initiating cells. Biomed Res Int 2017:1293201
Hao C, Tian J, Liu H et al (2017) Efficacy and safety of anti-PD-1 and anti-PD-1 combined with anti-CTLA-4 immunotherapy to advanced melanoma: A systematic review and meta-analysis of randomized controlled trials. Medicine 96:e7325
Zhang B, Dang J, Ba D et al (2018) Potential function of CTLA-4 in the tumourigenic capacity of melanoma stem cells. Oncol Lett 16:6163–6170
Zheng F, Dang J, Zhang H et al (2018) Cancer stem cell vaccination with PD-L1 and CTLA-4 blockades enhances the eradication of melanoma stem cells in a mouse tumor model. J Immunother 41:361–368
Gammaitoni L, Giraudo L, Leuci V et al (2013) Effective activity of cytokine-induced killer cells against autologous metastatic melanoma including cells with stemness features. Clin Cancer Res 19:4347–4358
Hontscha C, Borck Y, Zhou H et al (2011) Clinical trials on CIK cells: first report of the international registry on CIK cells (IRCC). J Cancer Res Clin Oncol 137:305–310
Volonte A, Tomaso TD, Spinelli M et al (2014) Cancer-initiating cells from colorectal cancer patients escape from T cell-mediated immunosurveillance in vitro through membrane-bound IL-4. J Immunol 192:523–532
Schatton T, Frank MH (2009) Antitumor immunity and cancer stem cells. Ann N Y Acad of Sci 1176:154–169
Mukherjee N, Almeida A, Partyka KA et al (2016) Combining a GSI and BCL-2 inhibitor to overcome melanoma's resistance to current treatments. Oncotarget 7:84594–84607
Thomas LW, Lam C, Edwards SW (2010) Mcl-1; the molecular regulation of protein function. FEBS Lett 584:2981–2989
Mukherjee N, Lu Y, Alemeida A et al (2017) Use of a MCL-1 inhibitor alone to de-bulk melanoma and in combination to kill melanoma initiating cells. Oncotarget 8:46801–46817
Santini R, Vinci MC, Pandolfi S et al (2012) HEDGEHOG-GLI signaling drives self-renewal and tumorigenicity of human melanoma-initiating cells. Stem Cells 30:1808–1818
Santini R, Pietrobono S, Pandolfi S et al (2014) SOX2 regulates self-renewal and tumorigenicity of human melanoma-initiating cells. Oncogene 33:4697–4708
Miyabayashi T, Kagamu H, Koshio J et al (2011) Vaccination with CD133+ melanoma induces specific Th17 and Th1 cell-mediated antitumor reactivity against parental tumor. Cancer Immunol Immunother 60:1597–1608
Koshio J, Kagamu H, Nozaki K et al (2013) DEAD/H (Asp-Glu-Ala-Asp/His) box polipeptide 3, X-linked I san immunogenic target of cancer stem cells. Cancer Immunol Immunother 62:1619–1628
Nozaki K, Kagamu H, Shoji S et al (2014) DDX3X induces primary EGFR-TKI resistance based on intratumor heterogeneity in lung cancer cells harboring EGFR-activating mutations. PloS ONE 9:e111019
Shen H, Shi S, Zhang Z et al (2015) Coating solid lipid nanoparticles with hyaluronic acid enhances antitumor activity against melanoma stem-like cells. Theranostics 5:755–771
Wang Y, Liu M, Jin Y et al (2017) In vitro and in vivo anti-uveal melanoma activity of JSL-1, a novel HDAC inhibitor. Cancer Lett 400:47–60
Bazewicz CG, Dinavahi SS, Schell TD et al (2019) Aldehyde dehydrogenase in regulatory T cell development, immunity and cancer. Immunology 156:47–55
Acknowledgements
We are indebted to all individuals who participated in or helped with this research project.
Author information
Authors and Affiliations
Contributions
SZ contributed to study conception, literature search and original draft preparation. ZY contributed to study conception and paper revision. FQ contributed to supervision. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declares that they have no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Zhang, S., Yang, Z. & Qi, F. Aldehyde dehydrogenase-positive melanoma stem cells in tumorigenesis, drug resistance and anti-neoplastic immunotherapy. Mol Biol Rep 47, 1435–1443 (2020). https://doi.org/10.1007/s11033-019-05227-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-019-05227-2