Bmi1 is critical for lung tumorigenesis and bronchioalveolar stem cell expansion

Abstract

Understanding the pathways that control epithelial carcinogenesis is vital to the development of effective treatments. The Polycomb group family member Bmi1 is overexpressed in numerous epithelial tumors, but its role in their development has not been established. We now show a key role for Bmi1 in lung adenocarcinoma. Whereas lung development occurs normally in Bmi1-deficient mice, loss of Bmi1 decreases the number and progression of lung tumors at a very early point in an oncogenic K-ras-initiated mouse model of lung cancer. This correlates with a defect in the ability of Bmi1-deficient putative bronchiolalveolar stem cells (BASCs) to proliferate in response to the oncogenic stimulus. Notably, in the absence of oncogenic K-ras, Bmi1-deficient BASCs show impaired proliferation and self-renewal capacity in culture and after lung injury in vivo. Abrogated lung cancer development and BASC self-renewal occur partially in a p19 ARF -dependent manner. Our data suggest that Bmi1 deficiency suppresses tumor development by limiting the expansion potential of BASCs, the apparent lung cancer cells of origin. Because Bmi1 is elevated in additional tumor types, this suggests that Bmi1 plays a key role in regulating proliferation of both stem cells and tumor cells in diverse adult epithelial tissues.Arf ͉ Ink4a ͉ non-small-cell lung cancer ͉ p16

Bmi1 Promotes Hepatic Stem Cell Expansion and Tumorigenicity in Both Ink4a/Arf -Dependent and -Independent Manners in Mice†

“…11,12 Bmi1 is also essential for cancer stem cells as demonstrated in a mouse leukemia model as well as in a mouse lung tumor model generated by the expression of a mutant K-ras gene in bronchioalveolar stem cells. 5,26 In addition, we previously demonstrated that forced expression of Bmi1 promotes the self-renewal of hepatic stem/progenitor cells and contributes to malignant transformation. 3 All these findings highlight the important role of Bmi1 in both the development and maintenance of cancer stem cell systems.…”

Runx3 is required for the differentiation of lung epithelial cells and suppression of lung cancer

“…Polycomb group member Bmi1 is essential for the self-renewal and maintenance of BASCs and is, therefore, used as a BASC marker (Valk-Lingbeek et al, 2004;Dovey et al, 2008). Bmi1 is also known as a marker of various cancer cells (Bea et al, 2001;Vonlanthen et al, 2001;Dimri et al, 2002;Leung et al, 2004).…”

“…K-ras mutation-independent lung adenoma development in Runx3 þ /À mice K-ras mutations are found in most chemically induced mouse lung adenomas (Dovey et al, 2008) and in about 40% of human AAHs (Westra et al, 1996). To determine whether the adenomas in Runx3 þ /À mouse lungs carried K-Ras mutations, we sequenced the K-ras gene in 10 spontaneous and 10 urethane-induced lung adenomas from Runx3 þ /À mice.…”

“…Interestingly, a number of Runx3À/À bronchiolar epithelial cells contained markers for both alveolar epithelial cells (SP-B) and bronchiolar epithelial cells (CC10), but not another alveolar epithelial cell marker (SP-C). Most of the Runx3À/À bronchiolar epithelial cells also contained Bmi1, which is essential for the self-renewal of stem cells (Valk-Lingbeek et al, 2004;Dovey et al, 2008) and is known as a marker of various cancer cells (Bea et al, 2001;Vonlanthen et al, 2001;Dimri et al, 2002;Leung et al, 2004). The accumulation of the SP-B þ /CC10 þ /Bmi1 þ /SP-C -cells suggests that differentiation of the lung epithelial progenitor cells was impaired in the Runx3À/À bronchioli.…”

“…Therefore, downregulation of Runx3 may induce lung adenoma development by disturbing lineage-specific differentiation of lung epithelial cells and by promoting progression to adenocarcinoma by allowing oncogenic mutations. Bmi1 has been suggested to have a vital function in K-ras-dependent lung tumorigenesis, as shown by the dramatic decrease in tumor development induced by a lack of Bmi1 in an oncogenic K-ras G12D mouse model of lung cancer (Dovey et al, 2008). Therefore, downregulation of Runx3, which results in an increase in Bmi1 expression, may cooperate with K-ras G12D in the development of lung adenocarcinoma.…”