McCormick Place- Chicago, IL,
March 31st- April 4th 2012- was flocked with scientists across the world for
the Annual American Association for Cancer Research (AACR) meeting. As with
each year, the meeting featured endless plenary presentations, symposiums, as
well as poster sessions and exhibitions that covered exciting advancements and
technologies in the global effort to end cancer. Much like Chicago's beautiful
cityscape with the harmonious mixture of old and new buildings, this year's
AACR meeting can be described as a harmonious mixture of new and old research
concepts. A new "buzz" in this year's AACR meeting is about cancer
stem cells and their role in tumor initiation.

Cancer stem cells (CSCs) were
first discovered in lymphomas in the late 1970s, followed by a wave of
"cancer stem cell discoveries" in leukemia (1997), and in solid
tumors such as glioma, breast cancers, and others [1]. With CSCs emerging in
many primary cancers, the AACR annual meeting this year had included a number
of symposia and meet-the-expert sessions focused on CSCs.

So, what exactly are cancer stem
cells? According to the Cell 2012 Timeline Review Article [1], researchers have
often used their increasing understanding of normal stem cell biology as a
conceptual mold to define CSCs in cancer biology. Similar to normal stem cells
that are classically defined by their ability to regenerate the tissue in which
they reside, it was thought that isolated CSCs can (re)-initiate the parental
tumor from which they originate. Much like normal tissue that consists of only
a small population of regenerative stem cells, it was also thought that tumors
consist of only a small population of "tumor-generative" CSCs. The
"tumor-generative" CSC model is very compelling, and appears to hold
true at least in human acute myeloid leukemia (AML) in which a small population
of leukemia stem cells can regenerate the entire cellular spectrum of the
cancer in mouse xenograft models.

Reflecting this popular CSC
concept in the Cell 2012 Timeline Review Article, the tumor-generative CSC
theory is well supported by the most renowned stem cell experts at the AACR
2012 meeting including: Dr. Michael F.
Clarke from the Stanford Institute for Stem Cell and Regenerative Medicine,
and Dr. Charles J. Sherr from the
Howard Hughes Medical Institute. According to Dr. Clarke, cancer stem cells are
defined by their capacity to continuously self-renew, a property that often
defines the "stemness" of hematopoietic stem cells. Likewise, Dr.
Sherr highlighted compelling evidence that the stem cell phenotype is
associated with "en bloc" silencing of cell cycle inhibitor genes.
Sherr further ended his seminar by concluding that the stem cell state, which
is defined by unimpeded cell cycle progression, is crucial to support tumor
growth and progression. 

But not all researchers think the
same way about CSCs. According to the Cell 2012 Timeline Article, CSCs from
solid tumors often show alarming inconsistencies in their tumor-initiating
capacity and their cell-surface marker expression. While these inconsistencies
brewed skepticism in the concept of CSCs, researchers reasoned that these may
be caused by the variation in techniques and cancer stem cell type/sources from
which data had been collected. Alternatively, there is a possibility that such
inconsistencies could also be caused by heterogeneous mutations or epigenetic
alterations of CSCs in culture- a very likely possibility due to the inherent
chromosome/epigenetic instability of the remarkably volatile population of
CSCs. This concept was supported by one of the speakers at the AACR 2012
conference, Dr. Ravindra Majeti,
Associate Professor at the Stanford School of Medicine. Using a series of
clonal genomic analyses from patient high-grade B cell lymphoblastic leukemia
samples, Majeti revealed compelling "clonal" evidence in his recent Sci Transl Med 2012 publication
suggesting that CSCs are produced by a series of stochastic mutations that
survive the selective pressures from the host environment, and become part of
the cancer

Therefore the CSCs may not
necessarily be defined as tumor initiating cells, but can also be an
"accidental" phenotype that so happens to be favorable for the tumor.
The question remains is whether all CSCs follow the conceptual mold of normal
stem cells and regenerate the tumor in which they reside? Or whether the CSC
phenotype actually has other functions in the tumor?

Overall, the AACR 2012 meeting
leaves us with the concept that although CSCs are cells that are defined by
their ability to self-renewal, this definition is not completely rigid. Rather,
CSCs may also be these lucky "stem cell" clones that are naturally
selected in the tumor to drive cancer progression. Indeed, further questions as
to whether CSCs might play other unappreciated roles in orchestrating tumor
progression may be interesting avenues to pursue.

References:

1. Nguyen, L. V.; Vanner, R.;
Dirks, P.; Eaves, C. J., Nat Rev Cancer 12, (2), 133-43.