Moving Targets That Drive Cancer Progression
Mark Shackleton, M.D., Ph.D.
N Engl J Med 363:885-886 | August 26, 2010
Lying in the dark heart of each cancer cell are genetic mutations that confer malignant potential. However, within a tumor, this potential may not be revealed in all cells at all times. Roesch and colleagues1 recently highlighted the importance of nongenetic factors in regulating the malignant behavior of cancer cells — an observation that presents both challenges and opportunities for treating patients.
Pathologists know better than anyone that in many tumors not all cancer cells are the same. The basis for cancer-cell heterogeneity has intrigued cancer biologists because of the possibility that phenotypic differences may be indicative of functional differences in the capacity of cancer cells to propagate disease. Such a possibility would have profound implications for treatment because functionally distinct cancer cells may need to be targeted differently.
The best accepted explanation for cancer-cell heterogeneity is clonal evolution.2 This occurs when individual cancer cells acquire additional genetic mutations that alter not only their phenotype, but also their malignant potential, resulting in Darwinian-style selection of some clones during disease progression. Another explanation is the cancer stem-cell model,3 in which tumorigenic cells renew their own malignant potential as well as produce phenotypically distinct cancer cells that lose their malignant potential through stable epigenetic changes. A hallmark of both these models is the irreversibility of the molecular changes that result in phenotypic and functional differences between cells.
In view of the findings of Roesch et al., we must add another layer of complexity to our understanding of cancer-cell heterogeneity: the influence of reversible factors. These researchers identified subpopulations in melanoma cell lines that could be distinguished by different proliferation kinetics and by differences in the expression of JARID1B, an enzyme that regulates gene expression by removing methyl groups from a lysine residue in the histone 3 molecule. Although only a minority of cells in the melanoma sections that Roesch et al. examined expressed JARID1B, the inhibition of JARID1B expression in cell lines impaired serial tumor formation in xenotransplantation studies (Figure 1A). JARID1B was thus required to maintain tumorigenic activity in these cells. This finding not only supports the burgeoning body of literature implicating the modification of histone proteins in the regulation of tumorigenesis but also suggests a strategy for treating melanoma by inhibiting JARID1B function.
Figure 1
Cell Plasticity and Tumorigenesis.
The plot of this story thickened considerably, however, when Roesch and colleagues found that JARID1B expression was not stable; purified JARID1B? and JARID1B+ cells each produced tumors that contained JARID1B? and JARID1B+ cells (Figure 1B). JARID1B expression was therefore reversible, in contrast to the tumorigenic determinants that drive cancer progression in the clonal evolution and cancer stem-cell models. Although these findings need to be confirmed in noncultured melanoma cells, the data implicate cancer-cell plasticity as an additional determinant of intratumoral heterogeneity.
More important, this work indicates that key drivers of cancer progression may be moving targets that are not active in all cells at all times. This possibility has fundamental implications for the development of therapies targeting oncogenic mechanisms that are not simultaneously active in all cells. Like shooting ducks in a sideshow gallery, targeting only tumor-maintaining JARID1B+ cells would not cure patients if these cells were continually replenished, derived from persistent JARID1B? cells, after treatment. At a minimum, such therapies would need to be administered over the long term, raising concerns about their therapeutic index and the possibility that drug resistance could develop.
But what if cancer cells could be turned into sitting ducks by being forced to become susceptible to therapy? The use of histone deacetylase (HDAC) inhibitors could represent such an approach. Although HDAC inhibitors show anticancer activity as single agents, preclinical studies suggest that they are potently synergistic when combined with therapies that target specific components of the oncogenic machinery.4 For example, in cancer cell lines, HDAC inhibitors overcame drug resistance that was mediated by another histone demethylase of the JARID family, JARID1A.5 The modes of action of HDAC inhibitors are not yet fully understood but are likely to include the induction of an epigenetic state in cancer cells that renders them vulnerable to the effects of specific, card-carrying anticancer agents.
Because cancer cells arise and change as a result of genetic mutation, we must continue to identify and target the genetically determined mechanisms that confer malignant potential. However, the work of Roesch et al. underscores another means by which cancer cells can change during disease progression: epigenetically determined plasticity. As the complex biology of cancer cells is revealed, layer by layer, it becomes apparent that treatment approaches with similar complexity will be needed. Further studies of plasticity as a cause of phenotypic and functional heterogeneity among cancer cells are likely to turn this adaptive property of malignant disease into a therapeutic opportunity.
Disclosure forms provided by the author are available with the full text of this article at NEJM.org.
References
A Roesch, M Fukunaga-Kalabis, EC Schmidt, A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth.Cell2010;141:583-594
PC NowellThe clonal evolution of tumor cell populations.Science1976;194:23-28
T Reya, SJ Morrison, MF Clarke, IL WeissmanStem cells, cancer, and cancer stem cells.Nature2001;414:105-111
JE Bolden, MJ Peart, RW JohnstoneAnticancer activities of histone deacetylase inhibitors.Nat Rev Drug Discov2006;5:769-784
SV Sharma, DY Lee, B Li, A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations.Cell2010;141:69-80
Source Information
From the Melanoma Research Laboratory and Department of Hematology and Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne, and the Department of Pathology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville — both in Australia.
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