“We’re suggesting that the cancer stem cell model will be true in some cancers and not in others.”
Sean Morrison, University of Michigan, Ann Arbor

This week, everyone is talking about cancer stem cells (CSC), everywhere on the web. I wrote about this a half year ago and it has been finally materialized in the paper. Basically the main reason for a new boom is a Nature report from Sean Morrison’s lab which shows that cancer stem cell concept doesn’t apply for human melanoma.

NOG mice is a relatively new xeno-transplant model for studying human hematopoiesis, immunity and cancers, which basically made the whole story.

Scheme of experiments and some results (credit: Elsa Quintana, Mark Shackleton, 2008):

Previous assays used NOD/SCID mice, immunocompromised mice that still have functioning natural killer (NK) cells, immune-system cells that can destroy tumour cells. Morrison used more severely immunocompromised mice that lacked NK cells. When he used the standard assay, he found the frequency of melanoma tumorigenic cells was 1 in 837,000, consistent with previous reports for melanoma. With his new assay system, it was more than 1 in 4.

“I think the cancer stem-cell model will, in the end, hold up for some cancers,” Morrison said. “But other cancers, like melanoma, probably won’t follow a cancer stem-cell model at all. The field will have to be reassessed after more time is spent to optimize the methods used to detect cancer stem cells.”

Guys, now I think it’s time to start counting how many “Nature papers” NOG mice can make. Remember the article about leukemic stem cell engraftment in Nature Biotechnology, which looks like an advertisement of NOG model.

and one more citation:

“There are some people out there who look at the paper and say that this completely invalidates the cancer stem-cell field,” he says. “That’s an over-interpretation.” He argues that the evidence for cancer stem cells in certain cancers, such as leukaemia, is particularly convincing.

Honestly I’m not sure about the case of leukemias anymore and I told you why back in June.
The second part of the story is about Dominique Bonnet.

In June I wrote about her talk on ISSCR’2008:

The same xeno-model - NOG mice made Dominique Bonnet reconsider the leukemic stem cell concept, which was described for the first time in 1994-1997 by John Dick’s group on NOD/SCID mice. 10 years ago it was postulated that only human CD34+/CD38- cells from acute myelogenous leukemia (AML) samples initiate leukemia in immunocompromise mice, but not CD34+/CD38+. Now, using NOG model, Bonnet got leukemia either from CD34+/CD38- and CD34+/CD38+ cells and even in some cases AML was initiated only by CD34+/CD38+.

Now she explained in detail why she got that.

We report that anti-CD38 antibodies have a profound inhibitory effect on the engraftment of both normal and leukemic repopulating cells.

The finding that SL-ICs (SCID Leukemia Initialing Cells) were found in the CD34+CD38+ fraction from all 7 sorted AML samples is novel. The potent inhibitory effect of anti-CD38 antibody is the probable explanation why this was not seen in previous studies.

Only one thing they didn’t do is to test the self-renewal ability of CD34+/CD38+ cells in serial transplant assay.

This study, in complement to Morrison’s one, indicated that we have to be even more careful about models. Bonnet paper actually showed that if we can inhibit function of NK cells (for example by administration of anti-CD122) in a standard NOD/SCID/b2-microglobulin xeno-model or administrate cells intra-bone, we can get much better engraftment, comparable to NOGs.

So, mouse xeno-model, antibody by which cells were treated, site of transplantation and route of administration, matrix and microenviroment, recepient conditioning… - everything is important!
Why do we need to be very careful about it? Because a xeno-model has a translational potential which can bring us to therapeutic protocols and clinical success.

Also, as Morrison said, these studies do not invalidate the CSC hypothesis but they just show that not all of cancers fit in this hypothesis and the problem is more complex.

BTW, I’d like to congratulate NOG mice as the winner in the category of “the best engrafters ever!”

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read more:
Cancer stem cells, becoming common (Nature Reporst Stem Cells)
Melanoma in mice casts doubt on scarcity of cancer stem cells (Nature; 2008:456:553)
Cancer stem cells: Here, there, everywhere? (Commentary by Connie Eaves Nature; 2008:456:581)