Identification of vitronectin as an extrinsic inducer of cancer stem cell differentiation and tumor formation.
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.
Hurt
Elaine M
EM
Cancer Stem Cell Section, Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA. hurte@ncifcrf.gov
Chan
King
K
Serrat
Maria Ana Duhagon
MA
Thomas
Suneetha B
SB
Veenstra
Timothy D
TD
Farrar
William L
WL
D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism / Q000494:pharmacology; D001943:Breast Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D002277:Carcinoma / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism*; D002853:Chromatography, Liquid; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000187:drug effects / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D009369:Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D019913:Nuclear Localization Signals / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D019096:Vitronectin / Q000378:metabolism* / Q000494:pharmacology; D051176:beta Catenin / Q000187:drug effects / Q000378:metabolism
D015415:Biomarkers; D001798:Blood Proteins; D039302:Integrin alphaVbeta3; D019913:Nuclear Localization Signals; D019096:Vitronectin; D051176:beta Catenin