Contents
Nerve Growth Factor Receptors and Signaling
in Breast Cancer Pp.463-470
Laurent
Dolle, Eric Adriaenssens, Ikram El Yazidi-Belkoura, Xuefen Le Bourhis, Victor
Nurcombe and Hubert Hondermarck
Heparin Affin Regulatory Peptide: A New
Target for Tumour Therapy?
Pp.471-482
E.
Papadimitriou, A. Polykratis, M. Hatziapostolou, A. Parthymou, C. Polytarchou
and C. Mikelis
Estrogen Receptors as Targets for Drug
Development for Breast Cancer, Osteoporosis and Cardiovascular Diseases Pp.483-499
Thresia
Thomas, Michael A. Gallo and T.J. Thomas
Two-Domain Vascular Disruptive Agents in
Cancer Therapy Pp.501-509
Stanislaw
Szala
The Relationship Between Oncogene Expression
and Clinical Outcome in Endometrial Carcinoma Pp.511-520
Noriyuki
Takai, Tami Ueda, Masakazu Nishida, Kaei Nasu and Isao Miyakawa
TSC-22 (TGF-β Stimulated Clone-22): A
Novel Molecular Target for Differentiation-Inducing Therapy in Salivary Gland
Cancer Pp.521-529
H. Kawamata, T. Fujimori and Y. Imai
Mammaglobin-Based Strategies for Treatment of
Breast Cancer Pp.531-542
Peter
S. Goedegebuure, Mark A. Watson, Carsten T. Viehl and Timothy P. Fleming
[Back to top] Nerve
Growth Factor Receptors and Signaling in Breast Cancer
Laurent Dolle, Eric Adriaenssens, Ikram El Yazidi-Belkoura, Xuefen Le Bourhis, Victor Nurcombe and Hubert Hondermarck
Nerve growth
factor (NGF) has long been known for its effects on neuronal cell survival and
differentiation. This prototypical neurotrophic factor stimulates neurons
through two distinct classes of membrane receptors: the TrkA tyrosine kinase
receptor, and the tumor necrosis factor receptor family member p75NTR,
also known as the common neurotrophin receptor. Somewhat surprisingly, there is
a growing body of evidence indicating that NGF is also a major stimulator of
breast cancer cell growth. Both the survival and proliferation of breast cancer
cells are strongly stimulated by NGF, mediated by TrkA and p75NTR
respectively, utilising signaling pathways similar to those described for
neurons. In addition, although NGF is produced by breast cancer cells, it is
not in normal breast epithelial cells, giving rise to an autocrine stimulation
of tumor growth. Therefore, NGF receptors and signaling are thus looking
increasingly promising as potential drug targets for breast cancer.
[Back to top] Heparin Affin Regulatory Peptide: A New
Target for Tumour Therapy?
E.
Papadimitriou, A. Polykratis, M. Hatziapostolou, A. Parthymou, C. Polytarchou
and C. Mikelis
Heparin affin
regulatory peptide (HARP), also known as pleiotrophin or heparin-binding
growth-associated molecule, is an 18-kDa growth factor that has a high affinity
for heparin. It constitutes with midkine and retinoic acid heparin-binding
protein, a family of structurally related heparin-binding growth factors. A
growing body of evidence indicates that HARP is involved in the control of
cellular proliferation, migration and differentiation and plays a significant
role in tumor growth and angiogenesis. HARP has a well described role in
physiological as well as tumor angiogenesis, and is detected in various
carcinomas, such as human breast and prostate cancer, neuroblastomas, gliomas,
benign meningiomas, small cell lung cancer and mammary tumors, exhibiting a
proto-oncogene function. It is also constitutively expressed in tumour cell
lines and is involved in tumour growth and metastasis. Therefore, HARP appears
to be a potential new target for the treatment or/and diagnosis of several
types of cancer.
[Back to top] Estrogen Receptors
as Targets for Drug Development for Breast Cancer, Osteoporosis and
Cardiovascular Diseases
Thresia
Thomas, Michael A. Gallo and T.J. Thomas
Estrogen receptors
(ERs) are proteins that mediate the action of estradiol and a series of natural
and synthetic chemicals that mimic the estradiol structure. Estrogenic action
was initially attributed to a single type of ER, now known as ERa, but ERb was
discovered in 1995. Tissue specific distribution and the intensity of
expression of these proteins determine the first response of tissues to
estrogenic compounds. Estrogens and ERs play a major role in the origin and
progression of breast cancer, and antiestrogens that block ER function are
useful for breast cancer prevention and treatment. Estrogen mimetics, however,
do not fall into distinct categories of agonists and antagonists, since their
action is regulated by tissue-specific expression of a number of auxiliary proteins
called coactivators or corepressors. In addition, small molecules such as
polyamines, fattyacids, and thioredoxin may modulate ER function. Estrogenic
functions encompass multiple organ systems, including the reproductive,
skeletal, cardiovascular, and nervous system. Estrogens are critical for bone
remodeling and mineralization so that estrogen replacement therapy is proven to
strengthen bone health in post-menopausal women. Ideally, selective blockade of
ER function in breast epithelial cells should be accompanied by growth support
on bone and cardiovascular systems. The details of estrogenic function in
different organs are to be fully realized, in order to better utilize selective
estrogen receptor modulators (SERMs) to fight not only breast cancer but also
osteoporosis and cardiovascular diseases. Current research on SERMs points
toward accomplishing this goal by exploiting ER as a versatile target against
multiple diseases.
[Back to top] Two-Domain Vascular Disruptive Agents in Cancer
Therapy
Stanislaw Szala
The two-domain
vascular drug constructs are selective anti-cancer agents capable of specific
targeting and subsequent elimination of endothelial cells lining tumor blood
vessels. The destruction of existing vasculature within tumor tissue causes
insufficient oxygenation of adjacent neoplastic cells and their necrotic death.
The recognition
(cognitive) domain of the vascular disruptive agents is responsible for
recognizing markers specific for endothelial cells. This domain can be formed
by variable regions of antibodies or by suitable ligands (such as those binding
various integrin or growth factor receptors). The effector domain, in turn, can
be constructed from proteins participating in blood clotting process, as well
as from toxins, cytokines, radioactive isotopes or pro-apoptotic factors.
This article
outlines issues important for constructing such two-domain vascular disruptive
agents and emphasizes the modularity of their assembly. Several pharmacokinetic
and pharmacodynamic properties of these novel agents are discussed. Compared to
known cytostatic substances exerting anti-angiogenic effects, such vascular
disruptive agents can be much more effective as cytotoxic agents, especially in
combination with proven anti-cancer drugs.
[Back to top] The Relationship Between Oncogene Expression
and Clinical Outcome in Endometrial Carcinoma
Noriyuki
Takai, Tami Ueda, Masakazu Nishida, Kaei Nasu and Isao Miyakawa
The mechanism of
oncogenesis is extremely complicated and controlled by various factors, most of
which are based on cell proliferation, tumor invasion, neovascularization, and
inhibition of apoptosis. We have investigated the relationship between thirty
three oncogenes expression and histopathological prognostic factors of
endometrial carcinomas, including clinical stage, histological grade, presence
of invasion to greater than one-half the myometrium, clinical outcome, and
survival rate.
Scoring on the
basis of the percentage of positive cells indicated that Plks, EphB4,
ephrin-B2, Id1, CaMKIV, c-Ets1, Elf-1, and survivin expression were
significantly associated with PCNA-labeling index, clinical stage, histological
grade, the presence of invasion to greater than one-half the myometrium, and
clinical outcome. Survival data were available for all patients, and univariate
Cox regression analysis showed that Plks, CaMKIV, Elf-1, and survivin
expression were significantly associated with poor prognosis.
Our results
demonstrate that some oncogenes expression in endometrial carcinoma correlate
with the malignant potential of these tumors. Thus, in addition to being of
diagnostic value, modulation of these oncogenes activity in the tumors by
chemotherapeutic agents or gene therapy may prove to be of therapeutic value.
In this review, we
demonstrate the biologic behavior of seven novel molecules (Plks, Eph/ephrin,
Id family, CaMK, c-Ets1, Elf-1, and survivin) in the endometrial carcinoma.
[Back to top] TSC-22 (TGF-β Stimulated Clone-22): A
Novel Molecular Target for Differentiation-Inducing Therapy in Salivary Gland
Cancer
H.
Kawamata, T. Fujimori and Y. Imai
TSC-22
(Transforming growth factor-b stimulated
clone-22) was originally isolated as a TGF-b-inducible
gene in mouse osteoblastic cells. TSC-22 encodes a putative transcriptional
regulator containing a leucine zipper-like structure. Several
differentiation-inducing stimuli up-regulate the TSC-22 gene. Furthermore,
TSC-22 acts as an effector that integrates multiple extracellular signals
during embryogenesis of Drosophila and mouse. Separately, we identified TSC-22
cDNA as an anti-cancer drug (vesnarinone)-inducible gene in a human salivary
gland cancer cell line, TYS. Vesnarinone is known to have a
differentiation-inducing activity in several cell types. We showed that TSC-22
negatively regulated the growth of TYS cells, and that down-regulation of
TSC-22 played a major role in the salivary gland tumorigenesis. Subsequently,
we found that artificial overexpression of TSC-22 enhanced chemosensitivity and
radiation-sensitivity by inducing apoptosis in TYS cells. Recently, we isolated
TSC-22 genomic DNA and analyzed the transcriptional and post-transcriptional
regulation of the TSC-22 gene. Then, we confirmed by the luciferase reporter
assay that several differentiation-inducing stimuli directly activated the
promoter region of TSC-22 gene. Now we are investigating the chemical
compounds, which could enhance the transcription of the TSC-22 gene. Thus,
because TSC-22 is a key molecule for differentiation of several cells, it can
be used as a molecular target for cancer differentiation therapy in salivary
gland cancer.
[Back to top] Mammaglobin-Based Strategies for Treatment of
Breast Cancer
Peter
S. Goedegebuure, Mark A. Watson, Carsten T. Viehl and Timothy P. Fleming
Mammaglobin is a
gene that is expressed almost exclusively in the normal breast epithelium and
human breast cancer. It is a member of the secretoglobin gene family and forms
a heterodimer with lipophilin B. We have focused on the tissue-specificity of
mammaglobin as a potential mechanism for the specific killing of breast cancer
cells. By elucidating the promoter region of mammaglobin, we hope to utilize
this site as a method for turning on the apoptosis inducer gene, Bax, in breast
cancer cells. The Bax gene will only be expressed at levels necessary to induce
apoptosis in mammaglobin positive cells. This would include >80% of all
breast cancer cells and some normal breast epithelium. This type of targeted
killing could be conceptualized as a biochemical mastectomy; that is, genetic
ablation of breast tumor cells and perhaps non-malignant breast epithelium
while preserving the adipose and stromal components of the breast. Work is also
being done to address the binding specificity of the secreted mammaglobin
protein. There is early evidence that the mammaglobin heterodimer may in fact
bind to breast and breast cancer cells. If this finding is validated, this
creates the possibility that mammaglobin can be tagged with a radioisotope or a
toxin, so that binding of the tagged–mammaglobin complex results in the
specific killing of that breast cancer cell. Finally, mammaglobin is being
explored as a target for immune-based interventions. In vitro studies
have demonstrated that T cell-mediated immune responses can be induced against
mammaglobin-derived peptides expressed by MHC molecules on tumor cells and
antigen-presenting cells.
In summary,
mammaglobin displays several unique features that make it a promising target
for intervention.