the primary tumor, which suggests that
CLV dilation may have a far more central
role in the metastatic process than hith-
erto appreciated. Interestingly, Etodolac
also diminished metastatic burden in the
lung. These results suggest that a level
of control over the lymphatic and sys-
temic dissemination could potentially be
achieved by administration of relatively
safe anti-inflammatory agents.
This provocative study adds an impor-
tant dimension to the process that might
be viewed as vascular system ‘‘condi-
tioning’’ for cancer metastasis. While the
focus of the present study is on CLV dila-
tion, others observed lymphangiogenesis
within lymph nodes prior to their meta-
static colonization (Tobler and Detmar,
2006), a process that may be attributed
to remote influences of growth factors
or exosomes (Hood et al., 2011). Analo-
gous pre-metastatic niches were also
described at sites of blood borne metas-
tases (Kaplan et al., 2005).
located outside of a growing tumor is not
restricted to CLVs. Similar increases in
diameter are often observed in the case of
which is also apparent from some of the
images included in the study by Karnezis
et al., (2012). Although this is a commonly
logical process has thus far attracted
minimal attention (Yu and Rak, 2003). In
contrast to angiogenesis, which occurs at
the level of microscopic capillaries(Carme-
liet and Jain, 2011), formation of larger
tumor-feeding blood vessels may involve
such mechanisms as dilation, similar to
that occurring in CLVs, or circumferential
growth (‘‘tumor arteriogenesis’’) (Yu and
Rak, 2003). Whether such macroscopic
changes control tumor microenvironment,
growth, or hematogenous metastasis (by
analogy to CLVs) remains to be studied.
The novel and fascinating link between
CLV dilation and lymphatic metastasis
described by these authors raises several
important questions. For example, how
does CLV dilation promote metastasis? Is
this merely a wider conduit (‘‘plumbing’’)
effect, or does it involve more subtle regu-
latory mechanisms (e.g., tumor-LEC inter-
increase inprostaglandinlevelsis detected
indicative of impending lymphatic metas-
tasis in the clinic?How early inprogression
glandins occur, and how discrete, how
detectable, would this event be? What
systemic consequences may be associ-
ated with VEGF-D-induced increase in
prostaglandins in blood, e.g., for the
vascular system? What turns on lymphan-
giogenic growth factors in metastatic
cancers, and is there a link between onco-
genic pathways and CLV dilation?
logical blockade of the pathological CLV
dilation and metastasis could be achieved
with already available agents (VEGF/
VEGFR3/2 inhibitors and NSAIDs). How-
could interfere withthe lymph outflowfrom
the primary tumor mass leading to a build
up of interstitial fluid pressure (IFP)?
drug delivery and could result in vascular
compression, hypoxia, and perhaps in
hematogenous metastasis. It is unclear if
apeutic interference with CLV dilation.
Indeed, the work of Karnezis et al., (2012)
opens up several new lines of inquiry
and a new domain in the field of lymphan-
giogenesis and cancer progression.
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aSIRTing Control over Cancer Stem Cells
Takahiro Ito,1Bryan Zimdahl,1,2and Tannishtha Reya1,*
1Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA 92093, USA
2Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
Cancer stem cells lie at the root of chronic myelogenous leukemia (CML) and mediate its continued growth.
Li et al. identify SIRT1 as a new target for eliminating CML cancer stem cells.
Chronic myelogenous leukemia (CML) is
a cancer that begins in hematopoietic
stem cells. Triggered by the BCR-ABL
translocation (Melo and Barnes, 2007),
progression from a slow-growing chronic
mutationscan induce its
Cancer Cell 21, February 14, 2012 ª2012 Elsevier Inc.