AACR 2010: 'Inglourious Basterds' and the clinical relevance of dormant tumour cells

22 Apr 2010


"If one makes a movie on WW II changing how it ended, that does not change the outcome of WW II". With these words George W. Sledge (Division of Hematology / Oncology School of Medicine, Indiana University) started off his talk, which concluded the very excellent session of tumour metastasis and microenvironment the last plenary session of AACR 101st meeting.

Sledge did not explicitly quote the last movie by Quentin Tarantino, 'Inglourious Basterds' (2009), but the reference was quite obvious (at least to me, but I may be biased).

What George Sledge meant, in the context of tumour metastasis, is that from a clinical point of view what occurs before diagnosis may be irrelevant, even if it can still be interesting from a biological perspective. What is most relevant for the patients is how to treat current primary tumours and metastasis -if we are able- and how to impede the formation of new metastases. One particular acute problem observed in the clinic is the one represented by dormant metastasis in breast cancer oestrogen positive receptor patients. In these subset of patients, relapse often occurs well after the traditional 5 year limit after which a person is conventionally declared 'cured', and is due to dormant tumour cells, which we are currently unable to tackle.

So the following question arises: Which dormant cells should we attack? In approaching dormant cells, we could have two different goals: dormancy maintenance (i.e. preventing progression from micro- to overt metastasis) vs dormancy eradication (i.e. killing micrometastasis). But, in order to be able to attack dormant cells, we need to be able to detect them.

Very powerful imaging techniques to detect even single dormant cells have previously been described by John Condeelis (Professor & Co-Chair of Anatomy & Structural Biology, Albert Einstein Medical College, New York), another of session's speakers. Condeelis' team works at developing imaging techniques to visualize the first steps of the metastatic cascade ( the invasion / intravasation steps ) in vivo. Using multiphoton confocal systems they are able to describe in detail the sort of 'mating dance' that takes place between macrophages and tumour cells at blood vessels (Kedrin et al, Nat Methods 2008; Gligorijevic et al, JoVe 2009), and to detect to at least 40 cells in depth and up to 100 cells in diameter.

Another exciting approach mentioned by Condeelis to image tumour cells in vivo, 'SPIONS', was recently described in a paper by Branca and collaborators (Branca RT et al, PNAS 2010). This approach combines nanotechnology and molecular imaging -in the form of magnetic resonance (MR)- for the detection of micrometastasis in the lung. Supermagnetic iron oxide nanoparticles (SPIONS) are a particularly promising class of MR contrast agents. Branca and coauthors have expanded on this mechanism by using SPIONS functionalized with luteinizing hormone- releasing hormone (LHRH) to selectively target breast cancers that have metastasized to the lung. Then, on the basis of the example of SPION uptake in the right cranial mediastinal lymph node of mice injected with human breast adenocarcinoma cells, Branca and collaborators suggested that cancer lesions smaller than 300 μm in diameter are detectable and, with further optimization, even single cancer cells may become so. And, as a wide variety of SPION agents have already been demonstrated to be safe for clinical use and approved by the US Food and Drug Administration, the LHRH-SPIONs could be administered to human subjects under an investigational new drug protocol.

However, being able to detect cancer cells alone is not enough. Branca and co-authors are aware of this and in the discussion of their paper rightly point out that "although much work remains to understand the potential clinical role of the imaging method described here, its value must eventually derive from very high specificity combined with high detection sensitivity". But, as Sledge rightly stressed in his talk, not even very high specificity and sensitivity alone may be clinically relevant. Indeed, as metastatization is a very inefficient process, many dormant tumour cells will not progress. "Detection is not a good thing if we cannot decide which cells are dangerous", Sledge said, adding, "even if single-cell molecular imaging detection can be exciting from a biological point of view, we -as clinicians- still have to ask ourselves what we are going to do with that information. Is that cluster of tumour cells going to metastasize, or not? Can we leave them as they are, or do we need to attack them?"

Another related clinical problem is the following: detection is not a good thing by itself (even if we are able to identify which cells are dangerous), if we are not able to tackle the dangerous cells. Therefore, the take-home message should be that, even though molecular imaging techniques hold a great potential in the field of tumour metastastic and cancer therapeutics, we need to be cautious in terms of excitement and in the way we use them.

A second parallel with 'Inglourious Basterds' may be arising here. The movie by Tarantino was criticised by some since, by depicting a fictional ending to World War II, it could in theory mislead young people into thinking that the war ended in a different way from reality.

But, as the fact that Tarantino (or anybody else,) directed a movie in which he changed the end does not change reality, so it is not the responsibility of the director to educate young generations on how history unravelled itself. And so, we cannot expect from molecular imaging techniques to tell us which cells are dangerous and will be able to metastasize and which will not.

It remains our responsibility to use the techniques together keeping in mind their limits, as it remains our responsibility to enjoy a movie while retaining the knowledge that it is a fictional world.