Treatment may sometimes fuel cancer's spread - a compound called TGF-beta may be one of the causes

Transforming growth factor beta (TGF-beta) is a ubiquitous cytokine
that plays a critical role in numerous pathways regulating cellular
and tissue homeostasis. TGF-beta signaling pathway is an essential
regulator of cellular processes, including proliferation,
differentiation, migration, and cell survival. TGF-beta has numerous
and often opposing cellular effects, as a tumor promoter and a tumor
suppressor, and as an inhibitor and stimulator of cellular
proliferation, apoptosis, and angiogenesis. The mechanisms by which
TGF-beta can promote late stages of tumor progression represent
testable molecular targets for novel interventions, For example,
inhibition of TGF-beta signaling results in decreased metastasis of
mammary tumors by impairing invasion, migration, and cellular
survival.

Now researchers at Vanderbilt University in Tennessee have found that
in mice chemotherapy drug doxorubicin or radiation both raised levels
of TGF-beta, which in turn helped breast cancer tumors spread to the
lung. When the mice were treated with an antibody that suppresses
TGF-beta, the spread stopped. Here's the news report about their
study:

Treatment may fuel cancer's spread, study finds
April 6, 2007
<http://www.asco.org/portal/site/ASCO/menuitem.d773f70619f767fd506fe310ee37a01d/?vgnextoid=4cca201eb61a7010VgnVCM100000ed730ad1RCRD&reuterview=detail_view&reutersid=6326>
<http://tinyurl.com/yrq9g5>

"WASHINGTON (Reuters) - Treating cancer with surgery,
chemotherapy or radiation may sometimes cause tumors to spread
and U.S. researchers said on Thursday they may have nailed down
one of the causes -- a compound called TGF-beta.

Tests in mice show that using the chemotherapy drug doxorubicin
or radiation both raised levels of TGF-beta, which in turn
helped breast cancer tumors spread to the lung.

But using an antibody to block TGF-beta stopped the process,
Dr. Carlos Arteaga and colleagues at Vanderbilt University in
Tennessee reported.

Developing drugs that block TGF-beta might help prevent cancer
from recurring, Arteaga's team reports in the May issue of the
Journal of Clinical Investigation.

"The repopulation and progression of tumors after anti-cancer
therapy is a well-recognized phenomenon," the researchers
wrote. "It has been shown to occur following radiotherapy,
chemotherapy, and surgery."

Cancer experts have wondered if the so-called primary tumor --
the first and biggest tumor -- might somehow suppress the
growth of other tumors, and that removing or destroying the
first tumor might allow other, undetectable, tumors to then
grow.

TGF-beta, which is involved in both the growth and suppression
of tumors, may hold part of the answer, Arteaga's team said.

When mice infected with human breast cancer cells were treated
with radiation or doxorubicin, they had higher levels of TGF-
beta in their blood. They also had more tiny tumor cells in
their blood, and these cells metastasized, or spread, to the
lungs.

When the mice were treated with an antibody that suppresses
TGF-beta, the spread stopped. And this spreading process did
not occur at all in mice bred to lack the TGF-beta protein.

"We wondered then if TGF-beta induced by anti-cancer therapies
can serve as a survival signal for tumor cells, thus allowing
them to withstand therapy and later recur," Arteaga said in a
statement.

His team is now testing TGF-beta levels in the blood of breast
cancer patients.

"We'll be looking to see in what proportion of patients the
serum and tumor TGF-beta goes up, and whether the increase
correlates with the inability of the therapy to eliminate the
cancer in the breast," Arteaga said.

Higher levels of TGF-beta after treatment may be a way to
predict which patients are likely to have their cancer come
back after treatment, Arteaga said.

His team is also testing drugs that interfere with TGF-beta to
see if they improve survival.

"It probably isn't just TGF-beta that is having this effect,"
Arteaga said. Many other compounds, including some immune
system signaling chemicals, are also associated with tumor
spread and growth.

"TGF-beta may be just the tip of the iceberg," Arteaga said."

The study is

Biswas S, Guix M, Rinehart C, Dugger TC, Chytil A, Moses HL, Freeman
ML, Arteaga CL.
Inhibition of TGF-beta with neutralizing antibodies prevents
radiation-induced acceleration of metastatic cancer progression.
J Clin Invest. 2007 Apr 5; [Epub ahead of print]
PMID: 17415413 [PubMed - as supplied by publisher]
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17415413<
<http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17415413>
<http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1838926&blobtype=pdf>
(free full text downloadable PDF file)

Abstract:

"We investigated whether TGF-beta induced by anticancer
therapies accelerates tumor progression. Using the MMTV/PyVmT
transgenic model of metastatic breast cancer, we show that
administration of ionizing radiation or doxorubicin caused
increased circulating levels of TGF-beta1 as well as increased
circulating tumor cells and lung metastases. These effects were
abrogated by administration of a neutralizing pan-TGF-beta
antibody. Circulating polyomavirus middle T antigen-expressing
tumor cells did not grow ex vivo in the presence of the TGF-
beta antibody, suggesting autocrine TGF-beta is a survival
signal in these cells. Radiation failed to enhance lung
metastases in mice bearing tumors that lack the type II TGF-
beta receptor, suggesting that the increase in metastases was
due, at least in part, to a direct effect of TGF-beta on the
cancer cells. These data implicate TGF-beta induced by
anticancer therapy as a prometastatic signal in tumor cells and
provide a rationale for the simultaneous use of these therapies
in combination with TGF-beta inhibitors"


Selections from earlier TGF-beta research:

Fleisch MC, Maxwell CA, Barcellos-Hoff MH.
The pleiotropic roles of transforming growth factor beta in
homeostasis and carcinogenesis of endocrine organs.
Endocr Relat Cancer. 2006 Jun;13(2):379-400. Review.
PMID: 16728569 [PubMed - indexed for MEDLINE]
<http://erc.endocrinology-journals.org/cgi/content/full/13/2/379>

Ëxcerpts:

"Transforming growth factor beta (TGF-beta) is a ubiquitous
cytokine that plays a critical role in numerous pathways
regulating cellular and tissue homeostasis. TGF-beta is
regulated by hormones and is a primary mediator of hormone
response in uterus, prostate and mammary glands. This review
will address the role of TGF-beta in regulating hormone-
dependent proliferation and morphogenesis. The subversion of
TGF-beta regulation during the processes of carcinogenesis,
with particular emphasis on its effects on genetic stability
and epithelial to mesenchymal transition, will also be
examined. An understanding of the multiple and complex
mechanisms of TGF-beta regulation of epithelial function, and
the ultimate loss of TGF-beta function during carcinogenesis,
will be critical in the design of novel therapeutic
interventions for endocrine-related cancers.

[...]

Considering the pleiotropic effects of TGF-beta, the timing and
duration of inhibition is likely to be critical to the ultimate
benefit. There may be scenarios in which TGF-beta inhibition in
conjunction with cancer therapy is beneficial. The most
developed experimental evidence is that from radiotherapy,
where there is a clear benefit in experimental normal tissue
toxicity models for blocking TGF-beta.

[...]

The 25-year history of TGF-beta has been productive and
informative as to fundamental growth control by extracellular
factors and the loss of such regulation during cancer
progression. TGF-beta has confounded, perplexed and rewarded
researchers who have struggled to understand its complex
biology. The relatively recent appreciation of its role in
modulating response to hormones offers a new perspective on its
potential application to the treatment of endocrine-related
cancers."

Dong M, Blobe GC.
Role of transforming growth factor-beta in hematologic malignancies.
Blood. 2006 Jun 15;107(12):4589-96. Epub 2006 Feb 16. Review.
PMID: 16484590 [PubMed - indexed for MEDLINE]
<http://bloodjournal.hematologylibrary.org/cgi/content/abstract/107/12/4589>

Abstract:

"The transforming growth factor-beta (TGF-beta) signaling
pathway is an essential regulator of cellular processes,
including proliferation, differentiation, migration, and cell
survival. During hematopoiesis, the TGF-beta signaling pathway
is a potent negative regulator of proliferation while
stimulating differentiation and apoptosis when appropriate. In
hematologic malignancies, including leukemias,
myeloproliferative disorders, lymphomas, and multiple myeloma,
resistance to these homeostatic effects of TGF-beta develops.
Mechanisms for this resistance include mutation or deletion of
members of the TGF-beta signaling pathway and disruption of the
pathway by oncoproteins. These alterations define a tumor
suppressor role for the TGF-beta pathway in human hematologic
malignancies. On the other hand, elevated levels of TGF-beta
can promote myelofibrosis and the pathogenesis of some
hematologic malignancies through their effects on the stroma
and immune system. Advances in the TGF-beta signaling field
should enable targeting of the TGF-beta signaling pathway for
the treatment of hematologic malignancies."

Elliott RL, Blobe GC.
Role of transforming growth factor Beta in human cancer.
J Clin Oncol. 2005 Mar 20;23(9):2078-93. Review.
PMID: 15774796 [PubMed - indexed for MEDLINE]
<http://jco.ascopubs.org/cgi/content/full/23/9/2078>

Excerpts:

"Transforming growth factor beta (TGF-beta) is a ubiquitous and
essential regulator of cellular and physiologic processes
including proliferation, differentiation, migration, cell
survival, angiogenesis, and immunosurveillance. Alterations in
the TGF-beta signaling pathway, including mutation or deletion
of members of the signaling pathway and resistance to TGF-beta-
mediated inhibition of proliferation are frequently observed in
human cancers. Although these alterations define a tumor
suppressor role for the TGF-beta pathway in human cancer, TGF-
beta also mediates tumor-promoting effects, either through
differential effects on tumor and stromal cells or through a
fundamental alteration in the TGF-beta responsiveness of the
tumor cells themselves. TGF-beta and members of the TGF-beta
signaling pathway are being evaluated as prognostic or
predictive markers for cancer patients. Ongoing advances in
understanding the TGF-beta signaling pathway will enable
targeting of this pathway for the chemoprevention and treatment
of human cancers.

[...]

In human cancers, TGF-beta promotes tumorigenesis through both
decreased TGF-beta signaling during early tumorigenesis and
increased TGF-beta signaling in advanced, progressive disease.
In addition, TGF-beta has complex and often opposing context-
specific effects on its cellular targets, mediating these
cellular effects through several TGF-beta-specific pathways and
through cross-talk with other signaling pathways. Finally, the
TGF-beta signaling pathway has a complex role in other human
diseases including cardiovascular disease and fibrotic
disease.64 Although each of these factors represents a
fundamental challenge to targeting the TGF-beta pathway,
numerous preclinical strategies have been tried with an
encouraging degree of success.

In clinical scenarios involving decreased TGF-beta activity,
attempts to restore or increase TGF-beta signaling could be
used as a chemoprevention strategy, as a postsurgical adjuvant
therapy, or as a therapy for early-stage disease. Indeed, the
effects of the chemopreventive agents tamoxifen and retinoids
may be mediated through their ability to increase serum TGF-
beta concentrations.203,204 Increased understanding of TGF-beta
ligand activation and the generation of agents that could
increase activation may also lead to potential chemoprevention
agents.

Many human cancers become resistant to the antiproliferative
effects of TGF-beta through decreased receptor expression (as
opposed to mutation or deletion of the receptor). In these
cases, increasing expression of the receptors may be a
reasonable therapeutic target.

[...]

Application of targeted therapies to block elevated TGF-beta
signaling in advanced and metastatic cancers may initially be
used in humans to block specific tumor-promoting effects of
TGF-beta including proangiogenic and immunosuppressive
functions in vivo. With regard to the proangiogenic effects of
TGF-beta, because the expression of the endothelial-specific
TGF-beta receptor endoglin is upregulated during tumor-induced
angiogenesis, antiendoglin antibodies coupled to toxins and
radionuclides have been used to selectively target the tumor
vasculature in animal models with marked success.219

Given that the TGF-beta signaling pathway has a defined role in
tumor-induced immunosuppression,107 inhibitors of this pathway
may be used to improve natural immunosurveillance of tumor
cells or to enhance the effectiveness of active or passive
immunotherapy strategies. Indeed, many of the aforementioned
strategies to block the TGF-beta signaling pathway have been
demonstrated to improve the ability of the immune system to
destroy tumors in animal models. For example, neutralizing
antibodies to TGF-beta combined with IL-2 therapy to stimulate
the immune system were able to decrease the number of
metastases in a murine B16 melanoma model,220 whereas
vaccinating with resected cancer cells containing antisense to
TGF-beta1 ligand (to decrease TGF-beta1 production)
successfully increased the ability of these vaccines to
eradicate cancer cells.221 More recently, blockade of the TGF-
beta signaling pathway specifically in CD4+ and CD8+ T cells
through expression of dominant negative TbetaRII has been shown
to increase the ability of these T cells to produce specific
anticancer cell (thymoma and melanoma) cytotoxic responses and
to eradicate these cancer cells in vivo.222 Taken together,
these studies provide proof of principle that targeting the
TGF-beta signaling pathway represents a viable method for
improving immunotherapy strategies for human cancers.

Another potential strategy for blocking the TGF-beta signaling
pathway would be to specifically target defined pathways
mediating the immunosuppressive effects of TGF-beta using RNA-
mediated interference (RNAi) technology. RNAi is an
evolutionarily conserved process that produces small (21 to 23
nucleotide) interfering RNA molecules, which then result in
specific degradation of homologous RNA, downregulating the mRNA
and subsequently the resulting protein expression. RNAi is able
to specifically and potently abrogate expression of targeted
proteins in mammalian cells.223 Such an approach could be used
to engineer T cells for use in immunotherapy that are
specifically resistant to the immunosuppressive effects of TGF-
beta through stable expression of RNAi constructs. This
approach could initially be used to target members of the TGF-
beta pathway known to be necessary for T-cell function-TbetaRII
and Smad3. This approach has the advantages that it could be
applied to any component of the TGF-beta signaling pathway or
other pathways involved in immunosuppression, it could target
specific arms of these pathways (ie, the immunosuppressive
arm), it could be used to target more than one pathway
simultaneously, and it could be expressed in various components
of the immune system (T cells and APC) to modulate the TGF-beta
signaling pathway in numerous immunotherapy or vaccine
approaches.

[...]

Given that TGF-beta has numerous and often opposing cellular
effects, as a tumor promoter and a tumor suppressor, and as an
inhibitor and stimulator of cellular proliferation, apoptosis,
and angiogenesis, a major challenge remains in more precisely
defining TGF-beta signaling pathways, including specific
pathways involved in mediating the specific and context-
dependent effects of TGF-beta. Although Smad-mediated signaling
is well established as the predominant TGF-beta signaling
pathway, the significance of contributions by other signaling
pathways (ie, MAP kinase, Rho, and PI-3 kinase/Akt pathways)
and mechanisms for this signaling remain to be established.
Once these pathways and other potential signaling pathways
downstream of TGF-beta are defined, and the contributions of
these pathways to the specific cellular and context-dependent
effects of TGF-beta are established, more specific targeting of
this pathway will be possible. Concurrently, the ability to
define the alterations occurring in the TGF-beta signaling
pathways at a molecular level in an individual's tumor will
allow the matching of targeted therapies developed with these
alterations to make individualized cancer treatment a less
toxic and more effective reality."

Muraoka RS, Dumont N, Ritter CA, Dugger TC, Brantley DM, Chen J,
Easterly E, Roebuck LR, Ryan S, Gotwals PJ, Koteliansky V, Arteaga CL.
Blockade of TGF-beta inhibits mammary tumor cell viability, migration,
and metastases.
J Clin Invest. 2002 Jun;109(12):1551-9.
PMID: 12070302 [PubMed - indexed for MEDLINE]
<http://www.jci.org/cgi/content/full/109/12/1551>

Excerpts:

"TGF-betas are potent inhibitors of epithelial cell
proliferation. However, in established carcinomas,
autocrine/paracrine TGF-beta interactions can enhance tumor
cell viability and progression. Thus, we studied the effect of
a soluble Fc:TGF-beta type II receptor fusion protein
(Fc:TbetaRII) on transgenic and transplantable models of breast
cancer metastases. Systemic administration of Fc:TbetaRII did
not alter primary mammary tumor latency in MMTV-Polyomavirus
middle T antigen transgenic mice. However, Fc:TbetaRII
increased apoptosis in primary tumors, while reducing tumor
cell motility, intravasation, and lung metastases. These
effects correlated with inhibition of Akt activity and FKHRL1
phosphorylation. Fc:TbetaRII also inhibited metastases from
transplanted 4T1 and EMT-6 mammary tumors in syngeneic BALB/c
mice. Tumor microvessel density in a mouse dorsal skin window
chamber was unaffected by Fc:TbetaRII. Therefore, blockade of
TGF-beta signaling may reduce tumor cell viability and
migratory potential and represents a testable therapeutic
approach against metastatic carcinomas.

[...]

In summary, the mechanisms by which TGF-beta can promote late
stages of tumor progression represent testable molecular
targets for novel interventions like Fc:TbetaRII. Our results
suggest that inhibition of TGF-beta signaling results in
decreased metastasis of mammary tumors by impairing invasion,
migration, and cellular survival. The lack of any obvious
toxicity in mice treated with Fc:TbetaRII for 12 weeks suggests
that Fc:TbetaRII or other inhibitors of the TGF-beta signaling
pathway may prove to be powerful antimetastatic therapies."


--
Matti Narkia
.

Loading