Induction of Human Epithelial Stem/Progenitor Expansion by FOXM1

Abstract

Stem cells are permanent residents of tissues and thought to be targets of cancer initiation. The frequent, and often early, upregulation of the FOXM1 transcription factor in the majority of human cancers suggests that it may participate in the initiation of human tumorigenesis. However, this hypothesis has not been tested. Herein, we show that targeting the ectopic expression of FOXM1 to the highly clonogenic cells of primary human keratinocytes with stem/progenitor cell properties, but not to differentiating cells, caused clonal expansion in vitro. We show, using a functional three-dimensional organotypic epithelial tissue regeneration system, that ectopic FOXM1 expression perturbed epithelial differentiation generating a hyperproliferative phenotype reminiscent of that seen in human epithelial hyperplasia. Furthermore, transcriptional expression analysis of a panel of 28 epithelial differentiation-specific genes reveals a role for FOXM1 in the suppression of epithelial differentiation. This study provides the first evidence that FOXM1 participates in an early oncogenic pathway that predisposes cells to tumorigenesis by expanding the stem/progenitor compartment and deregulating subsequent keratinocyte terminal differentiation. This finding reveals an important window of susceptibility to oncogenic signals in epithelial stem/progenitor cells prior to differentiation, and may provide a significant benefit to the design of cancer therapeutic interventions that target oncogenesis at its earliest incipient stage. Cancer Res; 70(22); 9515-26. ©2010 AACR.

Expansion of Hepatic Stem Cell Compartment Boosts Liver Regeneration

“…This result opens a new theoretical option for increasing the endogenous regenerative capacity of the liver. The amplification of stem/progenitor cell pool carries increased risk of tumor formation [29][30][31][32][33][34][35], although there are contradictory results as well [36]. Our results show that the DEN-AAF/CCl 4 model is as efficient a carcinogenesis model as the original Solt-Farber model and that the AAF/CCl 4 treatment is a powerful tumor promoter.…”

“…Thus, the increased number of stem cells does not indicate persistently higher tumor incidence. The recently revealed new results about the regulation of the stem cell compartment [31][32][33][34][35][36] may give us the tool to safely expand the pool of these cells in liver, which may result in clinically applicable increased regenerative capacity.…”

Analysis of Gene Expression Regulated by the ETV5 Transcription Factor in OV90 Ovarian Cancer Cells Identifies FOXM1 Overexpression in Ovarian Cancer

“…FOXM1 has been shown to be induced by increased oncogenic stress (28) and to counteract oxidative stress-induced premature senescence (51). A recent report has also hypothesized that FOXM1 may induce cancer initiation through stem/progenitor cell expansion (52). FOXM1 can also promote drug resistance to herceptin, paclitaxel (53), and cisplatin (54) in breast cancer cells.…”

Self-renewal and Differentiation of Muscle Satellite Cells Are Regulated by the Fas-associated Death Domain

“…FADD-D has been observed to inhibit the expression of FoxM1 (49). FoxM1 promotes the expansion and differentiation of several types of stem cells, suggesting a mechanism for how FADD phosphorylation regulates the fates of SCs (50,51). Additional experiments are required to determine whether FoxM1 is a downstream effector of FADD phosphorylation.…”