Abstract
Emerging evidence suggests that some cancers contain a population of stem-like TICs (tumor-initiating cells) and eliminating TICs may offer a new strategy to develop successful anti-cancer therapies. As molecular mechanisms underlying the maintenance of the TIC pool are poorly understood, the development of TIC-specific therapeutics remains a major challenge. We first identified and characterized TICs and non-TICs isolated from a mouse breast cancer model. TICs displayed increased tumorigenic potential, self-renewal, heterogeneous differentiation, and bipotency. Gene expression analysis and immunostaining of TICs and non-TICs revealed that FGFR2 was preferentially expressed in TICs. Loss of FGFR2 impaired self-renewal of TICs, thus resulting in marked decreases in the TIC population and tumorigenic potential. Restoration of FGFR2 rescued the defects in TIC pool maintenance, bipotency, and breast tumor growth driven by FGFR2 knockdown. In addition, pharmacological inhibition of FGFR2 kinase activity led to a decrease in the TIC population which resulted in suppression of breast tumor growth. Moreover, human breast TICs isolated from patient tumor samples were found enriched in a FGFR2+ population that was sufficient to initiate tumor growth. Our data suggest that FGFR2 is essential in sustaining the breast TIC pool through promotion of self-renewal and maintenance of bipotent TICs, and raise the possibility of FGFR2 inhibition as a strategy for anti-cancer therapy by eradicating breast TICs.
Highlights
Stem cells may play an essential role in regenerative capacity, and in the development of cancer [1]
To understand the molecular mechanisms underlying tumor initiation and self-renewal, we first identified potential tumor-initiating cells (TICs) and non-TIC populations that were isolated from breast tumors of mammary tumor virus (MMTV)-PyMT transgenic mice
Given that many functional properties of normal stem cells are shared by TICs, we isolated and examined subpopulations from the breast tumors, based on expression of cell-surface markers CD29 and CD24, which were used to enrich for mouse normal mammary stem cells [21]
Summary
Stem cells may play an essential role in regenerative capacity, and in the development of cancer [1]. The notion that tumors are heterogeneous and that tumor cells share certain properties with normal stem cells led to the hypothesis that tumors may contain a subset of self-renewing, stem-like tumorigenic cells, TICs, which drive tumor initiation and growth. In this hypothesis, only the tumor initiating cells are capable of unlimited self-renewal, extensive proliferation, and give rise to heterogeneous progenies while differentiated progenies have a limited proliferative potential [3,4]. TICs have been proposed to be responsible for tumor recurrence Based on this view, therapeutic strategies for selectively eradicating tumorinitiating cells should lead to successful curative therapies for cancer. There is little evidence to support this concept, mainly due to the poor understanding of the molecular mechanisms underlying tumor initiation and the stem-like function of TICs
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