This is re-blog from Stem Cell Assays
I was lucky to attend the 101th annual meeting American Association of Cancer Research in Washington DC. I was trying to attend all of the sessions that covered cancer stem cells topic. Now I’d like to share with you some of my notes and thoughts about it.
Rather than highlight some talks and posters in details I’d like to generalize the current status and directions – where the field of cancer stem cells stands right now and where it is moving.
Cancer stem cells (CSC) was one of the “highest yield topic” in AACR 2010. Nobody was trying to challenge the existence of CSC, so the concept now is generally accepted by researchers. Almost every speaker admitted that the field is full of controversies and uncertainty about definitions, markers and assays. Nevertheless, society and leaders in the field did not set up a workshop to clarify controversial issues as it was done back in 2006. We really need it again, I think.
Identification and markers of CSC
It was noted by many speakers that CSC can evolve and they are complex, and that the whole field still relies on surface markers for their identification. One of the exceptions was a great talk by Sean Morrison where he stressed that at least in some cancers (melanoma), CSC turn surface markers off and on all the time and that they are not associated with functional properties (tumorigeneity). Complimentary to him, Carla Kim reported that the phenotype of CSC is different in the same type of lung cancer induced by different oncogenes.
The idea of changing surface marker expression on CSC all the time is not new and was proposed almost 3 years ago in conferences. But since that we almost didn’t move. I went to a poster session and saw that most researchers simply sort cells out from the tumors by whatever marker and call them “cancer stem cell” right away. The top 3 “hottest” markers were:
Some researchers even didn’t check their functional properties because “it was described before”. But some of them who re-check sometimes find some interesting things – not all of markers label all CSC. And sure enough, Ching-Huai Ko compared directly isolated CSC (by 7 reported markers) from hepatocellular carcinoma cell lines and did not see any difference between marker-positive and marker-negative populations in terms of tumorigeneity and drug-resistance. But when functional method of enrichment and isolating CSC (serum-free culture of spheroids, hypoxic conditions and drug-resistance selection) was applied, they were able to see difference in tumorigeneity.
Interestingly, CSC markers were not always associate with chemoresistance. For example, in small lung cancer CD133+ and CD87+ cells are not sufficient as CSC markers but possess chemoresistance, unlike colorectal cancer, where chemoresistance ability resides in CD133- population.
It seems like functional (or metabolic) markers, such as ALDH are more significant than surface – CD133 or CD44. The power of ALDH marker in breast cancer for instance was pointed out by Max Wicha. Realizing this heterogeneity some researchers accurately call sorted populations “CSC-enriched”.
I’d like to refer to a groundbreaking moment in the field, which happened 2-3 years ago, when Sean Morrison postulated that we should be very, very careful about xenotransplantation assays for assessment of tumorigeneity of CSC. In particular he offered a few modifications of assays, such as NOG (NGS) mice instead of NOD/SCID and longer time of assessment. Again, I noticed that the field did not move since then. It is not commonly accepted yet! Almost all presenters assessed tumorigeneity in NOD/SCID mice with maybe 1-2 exclusions.
Many researchers presented work done only on cell lines, but not with patient samples. Based on data they got from cell lines, surface markers and functional assessment in NOD/SCID mice, they draw conclusions about CSC.
Nevertheless, speakers highlighted the weakness of current assays. Sean Morrison one more time noticed that (1) tumorigeneity is very much assay-dependent and (2) no xenotransplant assay recapitulates the immune response that occurs in some patients. Therefore, in order to mimic patient organism, CSC should be tested not only in immunocomromised conditions, but with mouse models of cancer transplanted into histocompatible recipients. Jeremy Rich indicated that cell lines fail to replicate original heterogeneity of tumors. But cell lines could be useful to unveil a mechanisms (Max Wicha).
I didn’t see lineage tracing analysis studies, even though their importance was indicated in previous 100th annual AACR meeting by John Dick. So, not a lot of movement or progress in terms of CSC assays and marker validation was made in my opinion. The good thing is that many potential therapeutic targets, especially signaling pathways, associated with CSC and/ or their niches, were proposed. You can look at it here and here.