Huang, Sui

Kaipainen, Arja

Kieran, Mark W.

Panigrahy, Dipak

English

PubMed

Dipak Panigrahy

Arja Kaipainen

Mark W. Kieran

Sui Huang

Crossref

Hindawi Publishing Corporation
PPAR Research
Volume 2008, Article ID 350351, 2 pages
doi:10.1155/2008/350351
Editorial
PPARs: A Double-Edged Sword in Cancer Therapy?
Dipak Panigrahy,1, 2 Arja Kaipainen,3 Mark W. Kieran,1, 2 and Sui Huang4
1Vascular Biology Program, Children’s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
2Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
3Department of Biochemistry & Molecular Biology, University of Calgary, Calgary, AB, Canada T2N 4N1
4 Institute for Biocomplexity and Informatics, University of Calgary, Calgary, AB, Canada T2N 1N4
Correspondence should be addressed to Dipak Panigrahy, dipak.panigrahy@childrens.harvard.edu
Received 31 December 2008; Accepted 31 December 2008
Copyright © 2008 Dipak Panigrahy et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Welcome to this special issue of PPAR Research, PPARs:
A Double-Edged Sword in Cancer Therapy. Peroxisome
Proliferator-Activated Receptors (PPARs) are a family of
pleiotropic transcription factors that play central roles in
cell metabolism and regulation of inflammation. Cancer
is thought to be the uncontrolled clonal evolution and
expansion of a mutated cell [1]. What is the connection
between PPARs and cancer? The theme of this special issue
reflects the impressive confluence of two originally separate
streams of investigation: PPARs and cancer research. Despite
the multitude of points of intersection between PPARs and
neoplasia, and associated unresolved paradoxes, the link
between PPARs and tumors is not yet widely appreciated
among specialists in either field. However, over the past years,
investigators who cross these fields have unearthed a myriad
of remarkable connections.
In view of the multiple links between PPARs and cancer,
perhaps epitomizing the pleiotropy of the biological eﬀects of
PPARs, this special issue contains an unusually large number
of excellent contributions. This large volume may also reflect
the increasing recognition of PPARs as a key player in cancer.
To help guide the readers, we have organized the articles, in
a departure from tradition, not according to the subtypes
PPARα, δ/β and γ, but instead, broadly in Sections 1–
6. Section 1 contains reviews that oﬀer a comprehensive
overview on PPARs’ eﬀects in cancer and on the more
established role of PPARγ in cancer therapy. This is followed
by Sections 2, 3, and 4 which have articles that discuss the
following three key questions.
(i) Are PPARs friends or foes of tumors?
(ii) Do PPARs modulate tumor cell-autonomous or noncell
autonomous processes?
(iii) Are the cancer-related eﬀects of PPAR ligands mediated
by a PPAR-dependent or independent mechanism?
We close our special issue with Sections 5 and 6, which focus
on PPAR ligand-based cancer therapies and the molecular
mechanisms through which these ligands may act.
(1) We start with five reviews that provide the necessary
background on structure and physiology of PPARs with
an emphasis on their role in cancer. One of these reviews
focuses on PPARγ, which historically has been studied
most intensely in conjunction with cancer. Notably, the
therapeutic potential of PPARγ agonists has been evaluated
in clinical trials for liposarcoma and prostate cancer. In fact,
38 out of a total of 56 articles in this issue focus on PPARγ.
(2) We continue with the first key question: Do PPARs
promote or inhibit cancer? The opposite directions of
observed PPAR eﬀects on cancer—which gave this special
issue its title—cannot be addressed in a straightforward
manner. This is not because of ambiguous observations but
(what makes it interesting) because the observed eﬀects of
PPAR on tumors have been clear—cut and powerful in either
direction—either stimulating or suppressing tumors. That
PPARs act as a “double-edged sword” may not come as a
surprise to veterans of PPAR research who appreciate their
pleiotropic eﬀects. While PPARα was the first PPAR to be
associated with tumorigenesis, the emerging awareness of the
PPARγ-cancer connection is evidenced by the fact that 4 out
of 7 reviews in this issue focus on PPARγ.
(3) While much attention has been devoted to deter-
mining whether PPARs are friend or foe of tumors, our
second question is also of fundamental significance: Is
PPAR’s role in tumor growth mediated by cell autonomous
or by noncell autonomous mechanisms? From the perspective
2 PPAR Research
of PPAR investigators, this question may arise naturally
because PPARs regulate intracellular processes, including
proliferation, apoptosis, and diﬀerentiation as well as inflam-
matory processes through the control of mediators in cell-
cell communication. In cancer biology this dualism has
deeper roots. It is the subject of a major paradigm shift that
has occurred over the past decade in cancer research. The
simple notion, unquestioned for decades, that cancer is a
cell-autonomous disease, driven by mutation and selection
for fast growing and increasingly malignant cell clones, has
yielded to the more encompassing view that cancer is also
a nonautonomous disease, requiring the support from the
“tissue microenvironment” in the “tumor bed”.
It took many years to overcome the picture of cancer
cell autonomy aﬀorded by cellular oncogenes. It began with
a simple idea that had far-reaching consequences. Judah
Folkman proposed in 1972, against all conventional wisdom,
that tumor growth required neovascularization, and that
such “tumor angiogenesis” was induced by soluble factors
produced by the tumor. We dedicate this special issue to
Dr. Folkman (1933–2008), our teacher and mentor, who has
opened the world’s eye to the tissue context of tumors. His
arduous uphill battle against the established paradigm of
cell-autonomous growth, although focused on angiogenesis,
has shined the first beam of light on the role of the host
microenvironment which was hidden in the shadow of the
quest for mutations that establish the oncogenic pathways in
the cancer cell. Dr. Folkman’s persistence paved the path to
the acceptance of the active role of nonneoplastic, “host” cells
in the tumor microenvironment. In this generalization of the
concept of tumor angiogenesis, it is now firmly established
that the tumor stroma is comprised a variety of cells that
are essential for tumor growth, including “tumor associated
fibroblasts”, various inflammatory cells, and the pericytes
around the tumor endothelium.
Much as cancer research was initially focused on the
tumor parenchyma, the first connection between PPARα
and tumorigenesis was also directed at understanding how
prolonged PPARα activation by its ligands induces hepa-
tocarcinogenesis in rodents by altering liver cell function
[2]. However, mirroring the development in tumor biology,
attention soon turned toward the eﬀects of PPAR on the
tumor microenvironment. In this issue, ten articles discuss
the modulation of the tumor stroma by PPARs. Five of these
reviews discuss their eﬀects on the tumor endothelium, while
the other five focus on the inflammatory compartment.
(4) The thirdmajor question addressed in this issue refers
to the tumor-inducing or inhibiting eﬀects of PPAR ligands:
are their activities on tumors mediated by their nominal
targets, the nuclear receptors, or do they act in a PPAR-
independent manner? This matter is complicated by the fact
that both PPAR agonists and antagonists can inhibit tumor
progression. Six reviews provide an overview of the use of
PPAR agonists and their “oﬀ-target” eﬀects in various cancer
therapies. We have also included one original research article
on how rosiglitazone inhibits both tumor and endothelial
cells via receptor dependent and independent mechanisms.
(5) The vast majority of PPAR research in the context of
cancer focuses on the use of ligands in anticancer therapies.
Thus, we dedicate the next section to articles that review
preclinical and clinical studies of the use of PPARα and
PPARγ ligands in a variety of cancer models, including
combinatorial therapy.
(6) The last section of this special issue contains arti-
cles that review the molecular mechanisms through which
PPARs, or their ligands, modulate tumor growth. There is
an additional original research article in this section on how
rosiglitazone inhibits tumor cell proliferation by interfering
with IGF-IR signaling.
We hope you will find these articles informative. Clearly,
much work lies ahead if we are to unravel the mysteries
behind the double edged-sword nature of PPARs. This
special issue describes the problem from many angles, and
in doing so it reveals the gaps in our knowledge. Thus, rather
than providing a unifying answer, it may hopefully inspire
you to further research.
Dipak Panigrahy
Arja Kapainen
Mark W. Kieran
Sui Huang
REFERENCES
[1] B. Vogelstein and K. W. Kinzler, “The multistep nature of
cancer,” Trends in Genetics, vol. 9, no. 4, pp. 138–141, 1993.
[2] J. M. Peters, R. C. Cattley, and F. J. Gonzalez, “Role of PPARα
in themechanism of action of the nongenotoxic carcinogen and
peroxisome proliferatorWy-14,643,”Carcinogenesis, vol. 18, no.
11, pp. 2029–2033, 1997.
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