Abstract
There is mounting evidence that tumors are initiated by a rare subset of cells called cancer stem cells (CSCs). CSCs are generally quiescent, self-renew, form tumors at low numbers, and give rise to the heterogeneous cell types found within a tumor. CSCs isolated from multiple tumor types differentiate both in vivo and in vitro when cultured in serum, yet the factors responsible for their differentiation have not yet been identified. Here we show that vitronectin is the component of human serum driving stem cell differentiation through an integrin alpha V beta 3-dependent mechanism. CSCs cultured on vitronectin result in downregulation of stem cell genes, modulation of differentiation markers, and loss of beta-catenin nuclear localization. Blocking integrin alpha V beta 3 inhibits differentiation and subsequently tumor formation. Thus, CSCs must be engaged by one or more extracellular signals to differentiate and initiate tumor formation, defining a new axis for future novel therapies aimed at both the extrinsic and intracellular pathways.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Biomarkers / analysis
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Biomarkers / metabolism
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Blood Proteins / metabolism
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Blood Proteins / pharmacology
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Breast Neoplasms / chemically induced
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Breast Neoplasms / metabolism
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Breast Neoplasms / physiopathology
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Carcinoma / chemically induced
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Carcinoma / metabolism
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Carcinoma / physiopathology
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Cell Differentiation / drug effects
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Cell Differentiation / genetics
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Cell Line, Tumor
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Cell Transformation, Neoplastic / drug effects
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Cell Transformation, Neoplastic / metabolism*
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Chromatography, Liquid
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Female
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / physiology
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Humans
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Integrin alphaVbeta3 / drug effects
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Integrin alphaVbeta3 / metabolism
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Male
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Mass Spectrometry
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Mice
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Neoplasms / chemically induced
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Neoplasms / metabolism*
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Neoplasms / physiopathology
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Neoplastic Stem Cells / drug effects
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Neoplastic Stem Cells / metabolism*
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Nuclear Localization Signals / drug effects
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Nuclear Localization Signals / metabolism
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Prostatic Neoplasms / chemically induced
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / physiopathology
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Vitronectin / metabolism*
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Vitronectin / pharmacology
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beta Catenin / drug effects
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beta Catenin / metabolism
Substances
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Biomarkers
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Blood Proteins
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Integrin alphaVbeta3
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Nuclear Localization Signals
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Vitronectin
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beta Catenin