Andreas Trumpp keynote lecture at the International PhD students meeting in Milan

As dandelions represent a problem for the gardener who wants to keep the garden clean and neat, so are dormant cancer stem cells, which are able to give rise to metastasis, for the management of oncological patients. With this insightful parallelism, Andreas Trumpp (Heidelberg Institute for Stem Cell Technology) started off his keynote lecture at the international PhD students meeting organised by the students of the IFOM-IEO campus for the PhD students of the Cancer Research UK institutes and the Netherlands Cancer Institute (Milan, May 19-21 2010)

There are indeed efficient and fast ways to get rid of the dandelions in one's garden, for example, the lawn-mower. But what happens is that after a few days the dandelions come back, stronger and more numerous. A similar scenario is played by chemotherapy, as a fast and efficient (the latter being true only in some cases) strategy to get rid of cancer cells, but not as an effective way to get rid of the cancer itself, as the patients experience a relapse when cancer stem cells (CSCs) strike back.

The problem of dormant CSCs is particularly acute in breast cancer, where it is too often the case that there are relapses well after the 5-year period after which a person is conventionally considered to be 'cured'. Therefore, new strategies are needed to identify dormant CSCs, and to literally 'eradicate' them.

Years have passed since the seminal paper by Weissman and colleagues in 2001 on the identification of leukemic stem cells¹, which paved the way for a fruitful line of research on CSCs. In this ten-year period, several subsets of CSCs have been identified, or at least their existence has been hypothesised: circulating tumor cells (CTC), metastatic initiating cells (MICS), disseminated tumour cells (DTC), with some of these subsets partially overlapping. While there are many questions that would be extremely interesting to pose from a biological point of view, from a clinical point of view the most relevant ones are just a few: which of these CSCs are able to give rise to metastasis? How can we identify and target them? And why are CSCs resistant to chemotherapy? How can we overcome this resistance?

In order to answer these questions and to unravel the mechanism of CSC resistance to chemotherapy, Trumpp and coauthors chose adult hematopoietic stem cells (HSCs) as a working model^2,3. Most recently, as described in a review which also got the cover of Nature Reviews Immunology, the group by Trumpp developed a 'model' for dormant homeostatic HSCs and their dynamic behaviour in response to injury⁴. The hypothesis is that stem cells (both normal adult stem cells such as HSCs, and CSCs) are resistant to chemotherapy for different reasons: they are dormant and they are physically located in a protective environment (such as the trabecular niche in the bone marrow where HSCs are located) which is difficult for a drug to penetrate.

What efficient strategies could there be to wake up dormant stem cells? One approach pursued by Trumpp et al has been interferon-alfa (IFN-α). IFN-α has been widely used in several clinical trials in the '90s, alone or in combination with chemotherapeutic agents, to treat patients affected with chronic myeloid leukemia (CML). These treatments induced partial or complete cytogenetic responses associated with significantly prolonged survival in a subset of patients (10–15% longer survival times), but the mechanisms underlying the response were not unravelled, the side-effects were important and the compliance of the patients difficult. Eventually, in 2001, IFN-α was superseded by new targeted treatments such as Imatinib/Gleevec in the treatment of CML.

In their model for dormant homeostatic HSCs, which Trumpp and colleagues think can also be applied to dormant leukemic stem cells (LSCs), IFN-α seems to be able to 'wake up' dormant HSCs and to trigger their exit from the G0 state. But how it does it is still not completely clear, even if it has been shown that IFN-α is able to induce STAT-1, Sca-1, and CD69. If it is confirmed in vivo that IFN-α can trigger the exit of dormant stem cells, and therefore render them sensitive to chemotherapy according to Trumpp's hypothesis, then strategies to trigger activation of endogenous IFN-α should be pursued.

The idea is that IFN-α priming might be a novel way to eliminate CSCs which are resistant to chemotherapy and targeted therapy, such as imatinib. Indeed, despite the impressive clinical responses observed with imatinib, there is still work to be done in the treatment of CML, as imatinib discontinuation results in high relapse rates, probably owing exactly to therapy-resistant LSC. Recognising that CML is a disease of the hematopoietic stem cell, first and foremost, carries great importance in how we design future investigations⁵. Going in this direction is the interesting link between IFN-α and imatinib hypothesized by Trumpp and coauthors.

Assuming that the dormant state of LSCs is the main reason for their drug resistance in patients, Trumpp and coauthors propose a two-step therapy model towards a long-term cure. Dormant LSCs would first be activated, leading to their exit from the niche, followed by treatment with imatinib. This in turn should lead to sensitisation and thus elimination of the now cycling LSCs⁶. Whether IFN-α is also efficient in activating and sensitising dormant LSCs to imatinib in patients with CML remains to be shown. The hints supporting the hypothesis is a case report where six patients who have been switched from IFN-α to imatinib did not relapse⁷.

While the hypothesis is intriguing, a few words of caution need to be aired on this possible second wave of 'fame' for IFN-α as a therapy in cancer. The hype surrounding its effects in the remissions of tumours was really astonishing some 10-15 years ago, but it apparently ended in a dead-end street. The mechanisms underlying IFN-α effects have not been unravelled, and this is the risk that is also being run today. What seems sure is that IFN-α has pleiotropic effects, and that is why it is our innate response to viruses! What about other cells being activated by IFN-α? It could also be reasonably hypothesised that IFN-α could trigger initiation of the metastatic process, not only reactivation of dormant stem cells. The sequential treatment hypothesised by Trumpp and coauthors seems promising in theory, but the arguments supporting it in practice seem still a bit tenuous.

Anyway, there are reasons for optimism, and places for postdoc positions in Trumpp's group at the Heidelberg Institute for Stem Cell Technology, as Trumpp made a point to stress at the end of his talk, in front of an audience of about 120 current PhD students, possibly 120 future candidates!

References

1. Reya T, Morrison SJ, Clarke MF, et al. Stem cells, cancer, and cancer stem cells. Nature 2001;414(6859):105-11.

2. Wilson A, Laurenti E, Oser G, et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 2008;(6):1118-29.

3. Laurenti E, Varnum-Finney B, Wilson A, et al. Hematopoietic stem cell function and survival depend on c-Myc and N-Myc activity. Cell Stem Cell 2008;3(6):611-24.

4. Trumpp A, Essers M, Wilson A. Awakening dormant haematopoietic stem cells. Nat Rev Immunol. 2010;10(3):201-9.

5. Kujawski LA, Talpaz M. The role of interferon-alpha in the treatment of chronic myeloid leukemia. Cytokine Growth Factor Rev 2007;18(5-6):459-71.

6. Essers MAG, Offner S, Blanco-Bose WE, et al. IFNa activates dormant haematopoietic stem cells in vivo. Nature 2009;458, 904-908.

7. Rousselot P, Huguet F, Rea D, et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood 2007;109(1):58-60.