Portal de Periódicos da CAPES

Stem Cells for Lung Cancer?

2005; Cell Press; Volume: 121; Issue: 6 Linguagem: Inglês

10.1016/j.cell.2005.06.004

1097-4172

Anton Berns,

Renal and related cancers

Stem cells are believed to be crucial players in tumor development. There is much interest in identifying those compartments that harbor stem cells involved in lung cancer, given the high incidence and recurrence rate of this disease. In this issue of Cell, Kim and colleagues describe a niche in the bronchioalveolar duct junction of adult mouse lung that harbors stem cells from which adenocarcinomas are likely to arise (Kim et al., 2005Kim C.F.B. Jackson E.L. Woolfenden A.E. Lawrence S. Babar I. Vogel S. Crowley D. Bronson R.T. Jacks T. Cell. 2005; 121 (this issue): 823-835Abstract Full Text Full Text PDF PubMed Scopus (1717) Google Scholar). They enriched, propagated, and differentiated these stem cells in vitro and found that they were activated by the oncogenic protein K-ras. This study provides exciting insights into how the stem cell compartment operates during both normal lung-tissue homeostasis and the development of lung cancer. The new work offers perspectives on possible therapeutic interventions to combat lung cancer. Stem cells are believed to be crucial players in tumor development. There is much interest in identifying those compartments that harbor stem cells involved in lung cancer, given the high incidence and recurrence rate of this disease. In this issue of Cell, Kim and colleagues describe a niche in the bronchioalveolar duct junction of adult mouse lung that harbors stem cells from which adenocarcinomas are likely to arise (Kim et al., 2005Kim C.F.B. Jackson E.L. Woolfenden A.E. Lawrence S. Babar I. Vogel S. Crowley D. Bronson R.T. Jacks T. Cell. 2005; 121 (this issue): 823-835Abstract Full Text Full Text PDF PubMed Scopus (1717) Google Scholar). They enriched, propagated, and differentiated these stem cells in vitro and found that they were activated by the oncogenic protein K-ras. This study provides exciting insights into how the stem cell compartment operates during both normal lung-tissue homeostasis and the development of lung cancer. The new work offers perspectives on possible therapeutic interventions to combat lung cancer. A key characteristic of stem cells is their capacity for self-renewal. A normal cell must have the capacity to self-renew in order to acquire a sufficient number of mutations to enable transformation into a cancer cell. The accumulation of deleterious mutations takes place only in cells that already have the capacity for self-renewal or that acquire this property early in the tumorigenic process. Examples of both these situations have been reported recently in tumors of the hematopoietic system (Bonnet and Dick, 1997Bonnet D. Dick J.E. Nat. Med. 1997; 3: 730-737Crossref PubMed Scopus (5126) Google Scholar, Jamieson et al., 2004Jamieson C.H. Weissman I.L. Passegue E. Cancer Cell. 2004; 6: 531-533Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). Usually, a subset of cells in a tumor exhibit this self-renewal capacity and regenerate the tumor when serially grafted into recipient animals; in contrast, other, often more differentiated, tumor cells lack this capacity. Cells with tumor regenerating capacity have been called "cancer stem cells" (CSCs; Pardal et al., 2003Pardal R. Clarke M.F. Morrison S.J. Nat. Rev. Cancer. 2003; 3: 895-902Crossref PubMed Scopus (1293) Google Scholar). The importance of CSCs in tumorigenesis has been demonstrated for several tumor types. An important criterion of CSCs is that they enable serial propagation of tumors that retain the often diverse marker profile of the primary tumor (Singh et al., 2004Singh S.K. Hawkins C. Clarke I.D. Squire J.A. Bayani J. Hide T. Henkelman R.M. Cusimano M.D. Dirks P.B. Nature. 2004; 432: 396-401Crossref PubMed Scopus (5678) Google Scholar). If CSCs are the driving force of tumor formation, then therapeutic interventions that target the main tumor mass but not the CSCs are bound to fail or, at best, leave the patient at risk of cancer recurrence. Lung cancer is a good example of this conundrum. This disease is responsible for 30% of all cancer deaths worldwide and cure rates are disappointingly low due to drug-refractory recurrent disease. As tumors are usually detected late in disease progression, we lack insight into the early stages of tumorigenesis and knowledge about the target cells in which the deleterious mutations accumulate. This insight has to come from animal models that closely mimic the human disease. In the rodent lung, there are several stem cell niches that are key in maintaining the epithelial layers of lung tissue (Giangreco et al., 2002Giangreco A. Reynolds S.D. Stripp B.R. Am. J. Pathol. 2002; 161: 173-182Abstract Full Text Full Text PDF PubMed Scopus (414) Google Scholar, Hong et al., 2004Hong K.U. Reynolds S.D. Watkins S. Fuchs E. Stripp B.R. Am. J. Pathol. 2004; 164: 577-588Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar, Reynolds et al., 2000Reynolds S.D. Hong K.U. Giangreco A. Mango G.W. Guron C. Morimoto Y. Stripp B.R. Am. J. Physiol. Lung Cell. Mol. Physiol. 2000; 278: L1256-L1263PubMed Google Scholar). Progenitors of bronchiolar Clara cells (a type of epithelial cell found in the distal lung) are crucial for the renewal of bronchial, bronchiolar, and alveolar epithelia. This was demonstrated by ablating Clara cell progenitors in mouse lung using Gancyclovir treatment of transgenic mice expressing HSV-TK driven by a Clara cell-specific promoter (Reynolds et al., 2000Reynolds S.D. Hong K.U. Giangreco A. Mango G.W. Guron C. Morimoto Y. Stripp B.R. Am. J. Physiol. Lung Cell. Mol. Physiol. 2000; 278: L1256-L1263PubMed Google Scholar). This treatment abolished the capacity of lung to reconstitute the bronchiolar and alveolar epithelia, indicating that Clara cell progenitors are essential for the maintenance of these epithelia (Figure 1). In contrast, bronchial epithelium, including Clara cells, was reconstituted from a basal cell population expressing keratin 14, indicating that these basal cells can differentiate into Clara cells in the proximal airway epithelium (Hong et al., 2004Hong K.U. Reynolds S.D. Watkins S. Fuchs E. Stripp B.R. Am. J. Pathol. 2004; 164: 577-588Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar), but not in terminal bronchioles or alveoli. When mice are exposed to the lung-damaging agent naphthalene, a different scenario is observed. In this case, nearly all Clara cells lining the bronchial surface and terminal bronchioles are ablated. In two regions, however, cells expressing Clara specific markers survive. Surviving Clara cells were found in neuroepithelial bodies, structures that replenish both neuroendocrine cell and Clara cell populations (Reynolds et al., 2000Reynolds S.D. Hong K.U. Giangreco A. Mango G.W. Guron C. Morimoto Y. Stripp B.R. Am. J. Physiol. Lung Cell. Mol. Physiol. 2000; 278: L1256-L1263PubMed Google Scholar). However, given the limited location and frequency of neuroepithelial bodies, these structures are likely to be only minor players in terminal bronchiolar repair. Surviving Clara cells that express both Clara-specific and alveolar-specific markers were also found at the bronchioalveolar duct junction (Giangreco et al., 2002Giangreco A. Reynolds S.D. Stripp B.R. Am. J. Pathol. 2002; 161: 173-182Abstract Full Text Full Text PDF PubMed Scopus (414) Google Scholar). These regional-specific stem cells appear crucial for the regeneration of epithelial components (Clara cells and alveolar cells) of the terminal bronchioles and alveoli. The obvious question then is whether any of these stem cell niches are involved in lung cancer. This is the question that Kim et al., 2005Kim C.F.B. Jackson E.L. Woolfenden A.E. Lawrence S. Babar I. Vogel S. Crowley D. Bronson R.T. Jacks T. Cell. 2005; 121 (this issue): 823-835Abstract Full Text Full Text PDF PubMed Scopus (1717) Google Scholar address in this issue of Cell. These authors investigate in vitro and in vivo whether any of the cells at the bronchioalveolar duct junction exhibit features of stem cells. They discovered that cells at this junction carrying Clara cell and alveolar-cell markers appear refractory to naphthalene treatment and start to divide after naphthalene-induced damage, resulting in repair of damaged lung epithelial tissue. This suggests that these double-positive cells are precursors of both Clara cells and alveolar type I and type II cells. More importantly, these double-positive cells appear enriched in FACS-sorted Sca-1pos/CD34pos cell populations and show enhanced capacity for both self-renewal and differentiation in vitro. Upon plating in Matrigel, these double-positive cells give rise to both Clara cells and alveolar cells, indicating that they are indeed progenitors of both cell types. Thus, Kim and coworkers call these cells bronchioalveolar stem cells (Kim et al., 2005Kim C.F.B. Jackson E.L. Woolfenden A.E. Lawrence S. Babar I. Vogel S. Crowley D. Bronson R.T. Jacks T. Cell. 2005; 121 (this issue): 823-835Abstract Full Text Full Text PDF PubMed Scopus (1717) Google Scholar; Figure 1). Expression of the oncogenic protein K-ras by these bronchioalveolar stem cells, either in vitro or in vivo (Jackson et al., 2001Jackson E.L. Willis N. Mercer K. Bronson R.T. Crowley D. Montoya R. Jacks T. Tuveson D.A. Genes Dev. 2001; 15: 3243-3248Crossref PubMed Scopus (1303) Google Scholar), boosted their proliferation. Such a response was not seen in cultured alveolar cells. This finding is in keeping with the observation that K-ras expression in lung tissue causes proliferation of only a small fraction of lung epithelial cells (Guerra et al., 2003Guerra C. Mijimolle N. Dhawahir A. Dubus P. Barradas M. Serrano M. Campuzano V. Barbacid M. Cancer Cell. 2003; 4: 111-120Abstract Full Text Full Text PDF PubMed Scopus (444) Google Scholar). Furthermore, when the AdenoCre construct was used to induce tumorigenesis in naphthalene-treated mice expressing K-ras conditionally, there was an increase in the number and size of tumors. Such tumors expressed the alveolar-specific SP-C marker, a predominant differentiation marker that was also frequently expressed by the double-positive bronchioalveolar stem cells after these cells were induced to express K-ras. This finding implicates these double-positive cells with their stem cell-like features in the transformation of normal lung epithelia into adenocarcinomas. As these lung stem cells are already endowed with the capacity for self-renewal, they are excellent candidates for the accumulation of deleterious mutations. The finding that larger tumors arise after naphthalene treatment points to the possibility that microenvironmental conditions may work synergistically with activated K-ras to promote tumorigenesis, in keeping with the classical initiation-promotion model of tumor formation. The Kim et al., 2005Kim C.F.B. Jackson E.L. Woolfenden A.E. Lawrence S. Babar I. Vogel S. Crowley D. Bronson R.T. Jacks T. Cell. 2005; 121 (this issue): 823-835Abstract Full Text Full Text PDF PubMed Scopus (1717) Google Scholar findings are an important advance as they provide us with a candidate target cell from which nonsmall cell lung cancers may arise. Furthermore, the development of in vitro methods to purify, propagate, and differentiate lung stem cells offers exciting opportunities for follow-up studies. Obviously, there are many questions still to be answered. For example, do these bronchioalveolar stem cells give rise to CSCs and, if so, which mutations are required to achieve this transformation? We eagerly await the results of serial grafting experiments with cells enriched for bronchioalveolar stem cell markers or with bronchioalveolar stem cells carrying different mutations introduced in vitro. Surprisingly, although bronchioalveolar stem cells from mouse lung can be propagated for many generations on feeder-cell layers in vitro, it has proved difficult to establish cell lines from adenocarcinomas induced in the same mice. The mouse model of lung tumorigenesis described by Kim et al., 2005Kim C.F.B. Jackson E.L. Woolfenden A.E. Lawrence S. Babar I. Vogel S. Crowley D. Bronson R.T. Jacks T. Cell. 2005; 121 (this issue): 823-835Abstract Full Text Full Text PDF PubMed Scopus (1717) Google Scholar provides us with a system that allows the study of how nonsmall cell lung cancers develop with high precision. Learning the Achilles heel of these stem cells might help us to design better intervention strategies for treating human lung cancer. This optimism is supported by the promising response to the drug Iressa of lung cancer patients, who carry activating mutations in the epidermal growth factor receptor (Paez et al., 2004Paez J.G. Janne P.A. Lee J.C. Tracy S. Greulich H. Gabriel S. Herman P. Kaye F.J. Lindeman N. Boggon T.J. et al.Science. 2004; 304: 1497-1500Crossref PubMed Scopus (8027) Google Scholar). The work of Kim and colleagues represents not only a leap forward in our understanding of lung tumorigenesis, it also heralds the arrival of a valuable mouse model for identifying those cells that should be the targets of therapeutic intervention. Some of the more notorious critics of mouse tumor models might start thinking about lowering their collective voices.