Abstract
Accumulation of lactate in tumor has been linked to poor prognosis of oral squamous cell carcinoma (OSCC), but the underlying mechanism remained largely uncertain. Previous studies have suggested that presence of cancer stem cells (CSCs) closely correlated with cellular malignancy of OSCC. Here, using 3D organoid culture model, we investigated whether lactate promoted CSCs phenotype in primary OSCC cells. We generated organoids using fresh OSCC specimens and verified that organoids recapitulated histopathology and cellular heterogeneity of parental tumor. Organoids were then transfected with a Wnt reporter to visualize Wnt activity. The sphere forming assay demonstrated that high Wnt activity functionally designated CSCs population in OSCC cells. Further investigations indicated that lactate treatment promoted Wnt activity and increased the expression of CSCs (i.e. CD133+ cells) in organoids. Moreover, silencing monocarboxylate transporter 1 (MCT1), the prominent path for lactate uptake in human tumor with siRNA significantly impaired organoid forming capacity of OSCC cells. Together, our study demonstrated that lactate can promote CSCs phenotype of OSCC, and MCT1 may be a therapeutic target against OSCC growth.
Keywords:
cancer stem cells; lactate; monocarboxylate transporter 1; oral squamous cell carcinoma; organoid.
MeSH terms
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AC133 Antigen / genetics
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AC133 Antigen / metabolism
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Aged
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Axin Protein / genetics
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Axin Protein / metabolism
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Carcinoma, Squamous Cell / genetics*
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Carcinoma, Squamous Cell / metabolism
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Carcinoma, Squamous Cell / pathology
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Cell Proliferation / drug effects
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Female
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Gene Expression Regulation, Neoplastic*
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Genes, Reporter
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Humans
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Hyaluronan Receptors / genetics
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Hyaluronan Receptors / metabolism
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Lactic Acid / pharmacology*
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Male
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Middle Aged
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Monocarboxylic Acid Transporters / antagonists & inhibitors
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Monocarboxylic Acid Transporters / genetics*
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Monocarboxylic Acid Transporters / metabolism
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Mouth Neoplasms / genetics*
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Mouth Neoplasms / metabolism
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Mouth Neoplasms / pathology
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Nanog Homeobox Protein / genetics
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Nanog Homeobox Protein / metabolism
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Neoplastic Stem Cells / drug effects*
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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Octamer Transcription Factor-3 / genetics
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Octamer Transcription Factor-3 / metabolism
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Organoids / drug effects
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Organoids / metabolism
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Organoids / pathology
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Primary Cell Culture
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Spheroids, Cellular / drug effects
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Spheroids, Cellular / metabolism
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Spheroids, Cellular / pathology
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Symporters / antagonists & inhibitors
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Symporters / genetics*
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Symporters / metabolism
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Wnt Signaling Pathway / drug effects*
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Wnt Signaling Pathway / genetics
Substances
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AC133 Antigen
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AXIN2 protein, human
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Axin Protein
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CD44 protein, human
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Hyaluronan Receptors
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MYC protein, human
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Monocarboxylic Acid Transporters
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NANOG protein, human
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Nanog Homeobox Protein
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Octamer Transcription Factor-3
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POU5F1 protein, human
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PROM1 protein, human
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Proto-Oncogene Proteins c-myc
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RNA, Small Interfering
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Symporters
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monocarboxylate transport protein 1
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Green Fluorescent Proteins
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Lactic Acid