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Following cardiovascular diseases, cancer
represents the second mostcommon cause of death in the western world. In 2008
the world healthorganization (WHO) estimated 12,7 million new cancer cases, of
thosecases 7.6 million people die of cancer. Cancer is a heterogeneous class
of diseases, which arises from normal cells giving rise to a malignant
neoplastic cell with uncontrolled growth and spread throughout thebody. Most
cancers form solid tumors like carcinomas, sarcomas, germcell tumors,
blastomas or lymphomas, however some cancer arise from the cells of the blood
and bone marrow like leukemias. </>
Currently individual types of therapy are
available for the different subgroups of cancers. The main pillars of cancer
therapy are based on surgery, chemotherapy including targeted and
immunotherapy, and radiotherapy. These therapies are combined to achieve the
optimal outcome, however not every patient can be cured and many cancers are
either diagnosed already too late, or they can find escape mechanisms from the
currently used treatments. </>
In the last decades cancer research has
vastly expanded our knowledge of the disease. Initially, research was focused
on the malignant cell itself, however, this view did not take into account that
a variety of mesenchymal and immune cell types as well as extracellular matrix
surround and interact with the neoplastic cells. During the progression of
cancer, this surrounding microenvironment develops into an activated state
through continuous communication, and thereby creates a supportive surrounding
that promotes cancer initiation and growth, and eventually the progress to a
fatal disease. Interestingly this interaction with the tumor microenvironment
does not only occur in solid tumors, but also in leukemias. This thesis was
focused on the role of the receptor tyrosine kinase-ligands PlGF and Gas6 in
the microenvironment of solid tumors and leukemias. </>
In the first part of this work we discovered
that bone marrow derived Gas6 promoted tumor growth and metastasis in different
experimental cancer models via the Axl receptor. Already previously the tumor
growth promoting and transforming properties of the tyrosine kinase receptor
Axl, belonging to the TAMR (Tyro3, Axl and Mer receptor) family, were well
recognized, however little was known about Gas6 in tumor biology. In this study
we found that tumor-infiltrating leukocytes are educated by the tumor
microenvironment to produce elevated levels of Gas6 and this upregulation took
particularly place in macrophages. Elevated levels of Gas6 lead to tumor cell
proliferation bothin vitro</> and in vivo</>. Consistent with these finding,
the reduced tumor growth in Gas6-/- mice could be rescued by the
transplantation of wild-type bone marrow. Vice versa transplantation of Gas6-/-
bone marrow into wild-type mice mimicked the impaired tumor growth in Gas6-/-
mice. Mechanistically we found that tumor cells educated infiltrating
leukocytes to upregulated Gas6 by expressing IL-10 and M-CSF leading to a
positive amplification loop in the tumor. </>
In thesecond part of this work we found that
PlGF plays a role in chronic myeloid leukemia. We discovered that the
angiogenic factor PlGF is upregulated in the bone marrow plasma and peripheral
blood of both CML mice as well as human CML patients. Also here the leukemia
cells do not produce PlGF autonomously, but CML cells induce bone marrow
stromal cells to upregulate PlGF in a NF-κB dependent manner. PlGF not only
promoted CML cell proliferation and metabolism in a Bcr-Abl1</> independent pathway, but also stimulated bone
marrow angiogenesis and fibrosis. Treatment of leukemicmice with an anti-PlGF
antibody prolonged survival in both imatinib-sensitive as well as in resistant
CML mice. CML models in PlGF-/- mice reconfirmed this. Interestingly
this beneficial effect of anti-PlGFtreatment acted additive to imatinib
treatment, arguing for a Bcr-Abl1</>
independent mechanism. </>
In summary we found that Gas6 and PlGF are stromal derived factor
supporting tumor progression in solid tumors andleukemias respectively. Based
on our results, both might represent interesting novel microenvironmental
targets for cancer therapy</>
Following cardiovascular diseases, cancer
represents the second most common cause of death in the western world. In 2008
the worldhealth organization (WHO) estimated 12,7 million new cancer cases, of
those cases 7.6 million people die of cancer. Cancer is a heterogeneous class
of diseases, which arises from normal cells giving rise to a malignant
neoplastic cell with uncontrolled growth and spread throughout the body. Most
cancers form solid tumors like carcinomas, sarcomas, germ cell tumors,
blastomas or lymphomas, however some cancer arise from the cells of the blood
and bone marrow like leukemias.
Currently individual types of therapy are
available for the different subgroups of cancers. The main pillars of cancer
therapy are based on surgery, chemotherapy including targeted and
immunotherapy, and radiotherapy. These therapies are combined to achieve the
optimal outcome, however not every patient can be cured and many cancers are
either diagnosed already too late, or they can find escape mechanisms from the
currently used treatments.
In the last decades cancer research has
vastly expanded our knowledge of the disease. Initially, research was focused
on the malignant cell itself, however, this view did not take into account that
a variety of mesenchymal and immune cell types as well as extracellular matrix
surround and interactwith the neoplastic cells. During the progression of
cancer, this surrounding microenvironment develops into an activated state
through continuous communication, and thereby creates a supportive surrounding
that promotes cancer initiation and growth, and eventually the progressto a
fatal disease. Interestingly this interaction with the tumor microenvironment
does not only occur in solid tumors, but also in leukemias. This thesis was
focused on the role of the receptor tyrosine kinase-ligands PlGF and Gas6 in
the microenvironment of solid tumors and leukemias.
In the first part of this work we discovered
that bone marrow derived Gas6 promoted tumor growth and metastasis in different
experimental cancer models via the Axl receptor. Already previously the tumor
growth promoting and transforming properties of the tyrosine kinase receptor
Axl, belonging to the TAMR (Tyro3, Axl andMer receptor) family, were well
recognized, however little was knownabout Gas6 in tumor biology. In this study
we found that tumor-infiltrating leukocytes are educated by the tumor
microenvironment to produce elevated levels of Gas6 and this upregulation took
particularly place in macrophages. Elevated levels of Gas6 lead to tumor cell
proliferation both in vitro and in vivo. Consistent with these finding,
the reduced tumor growth in Gas6-/- mice could be rescued by the
transplantation of wild-type bone marrow. Vice versa transplantation of Gas6-/-
bone marrow into wild-type mice mimicked the impaired tumor growth in Gas6-/-
mice. Mechanistically we found that tumor cells educated infiltrating
leukocytes to upregulated Gas6 by expressing IL-10 and M-CSF leading to a
positive amplification loop in the tumor.
In the second part of this work we found that
PlGF plays a role inchronic myeloid leukemia. We discovered that the
angiogenic factor PlGF is upregulated in the bone marrow plasma and peripheral
blood of both CML mice as well as human CML patients. Also here the leukemia
cells do not produce PlGF autonomously, but CML cells induce bone marrow
stromal cells to upregulate PlGF in a NF-κB dependent manner. PlGF not only
promoted CML cell proliferation and metabolism in a Bcr-Abl1 independent pathway, but also stimulated bone
marrow angiogenesis and fibrosis. Treatment of leukemic mice with an anti-PlGF
antibody prolonged survival in both imatinib-sensitive as well as in resistant
CML mice. CML models in PlGF-/- mice reconfirmed this. Interestingly
this beneficial effect of anti-PlGF treatment acted additive to imatinib
treatment, arguing for a Bcr-Abl1
independent mechanism.
In summary we found that Gas6 and PlGF are
stromal derivedfactor supporting tumor progression in solid tumors and
leukemias respectively. Based on our results, both might represent interesting
novel microenvironmental targets for cancer therapy.
</>
Project
Genetic and pharmacological studies of two growth factor receptor tyrosine kinase-ligands in cancer: Gas6 and PlGF
Following cardiovascular diseases, cancer
represents the second mostcommon cause of death in the western world. In 2008
the world healthorganization (WHO) estimated 12,7 million new cancer cases, of
thosecases 7.6 million people die of cancer. Cancer is a heterogeneous class
of diseases, which arises from normal cells giving rise to a malignant
neoplastic cell with uncontrolled growth and spread throughout thebody. Most
cancers form solid tumors like carcinomas, sarcomas, germcell tumors,
blastomas or lymphomas, however some cancer arise from the cells of the blood
and bone marrow like leukemias. </>
Currently individual types of therapy are
available for the different subgroups of cancers. The main pillars of cancer
therapy are based on surgery, chemotherapy including targeted and
immunotherapy, and radiotherapy. These therapies are combined to achieve the
optimal outcome, however not every patient can be cured and many cancers are
either diagnosed already too late, or they can find escape mechanisms from the
currently used treatments. </>
In the last decades cancer research has
vastly expanded our knowledge of the disease. Initially, research was focused
on the malignant cell itself, however, this view did not take into account that
a variety of mesenchymal and immune cell types as well as extracellular matrix
surround and interact with the neoplastic cells. During the progression of
cancer, this surrounding microenvironment develops into an activated state
through continuous communication, and thereby creates a supportive surrounding
that promotes cancer initiation and growth, and eventually the progress to a
fatal disease. Interestingly this interaction with the tumor microenvironment
does not only occur in solid tumors, but also in leukemias. This thesis was
focused on the role of the receptor tyrosine kinase-ligands PlGF and Gas6 in
the microenvironment of solid tumors and leukemias. </>
In the first part of this work we discovered
that bone marrow derived Gas6 promoted tumor growth and metastasis in different
experimental cancer models via the Axl receptor. Already previously the tumor
growth promoting and transforming properties of the tyrosine kinase receptor
Axl, belonging to the TAMR (Tyro3, Axl and Mer receptor) family, were well
recognized, however little was known about Gas6 in tumor biology. In this study
we found that tumor-infiltrating leukocytes are educated by the tumor
microenvironment to produce elevated levels of Gas6 and this upregulation took
particularly place in macrophages. Elevated levels of Gas6 lead to tumor cell
proliferation bothin vitro</> and in vivo</>. Consistent with these finding,
the reduced tumor growth in Gas6-/- mice could be rescued by the
transplantation of wild-type bone marrow. Vice versa transplantation of Gas6-/-
bone marrow into wild-type mice mimicked the impaired tumor growth in Gas6-/-
mice. Mechanistically we found that tumor cells educated infiltrating
leukocytes to upregulated Gas6 by expressing IL-10 and M-CSF leading to a
positive amplification loop in the tumor. </>
In thesecond part of this work we found that
PlGF plays a role in chronic myeloid leukemia. We discovered that the
angiogenic factor PlGF is upregulated in the bone marrow plasma and peripheral
blood of both CML mice as well as human CML patients. Also here the leukemia
cells do not produce PlGF autonomously, but CML cells induce bone marrow
stromal cells to upregulate PlGF in a NF-κB dependent manner. PlGF not only
promoted CML cell proliferation and metabolism in a Bcr-Abl1</> independent pathway, but also stimulated bone
marrow angiogenesis and fibrosis. Treatment of leukemicmice with an anti-PlGF
antibody prolonged survival in both imatinib-sensitive as well as in resistant
CML mice. CML models in PlGF-/- mice reconfirmed this. Interestingly
this beneficial effect of anti-PlGFtreatment acted additive to imatinib
treatment, arguing for a Bcr-Abl1</>
independent mechanism. </>
In summary we found that Gas6 and PlGF are stromal derived factor
supporting tumor progression in solid tumors andleukemias respectively. Based
on our results, both might represent interesting novel microenvironmental
targets for cancer therapy</>
Following cardiovascular diseases, cancer
represents the second most common cause of death in the western world. In 2008
the worldhealth organization (WHO) estimated 12,7 million new cancer cases, of
those cases 7.6 million people die of cancer. Cancer is a heterogeneous class
of diseases, which arises from normal cells giving rise to a malignant
neoplastic cell with uncontrolled growth and spread throughout the body. Most
cancers form solid tumors like carcinomas, sarcomas, germ cell tumors,
blastomas or lymphomas, however some cancer arise from the cells of the blood
and bone marrow like leukemias.
Currently individual types of therapy are
available for the different subgroups of cancers. The main pillars of cancer
therapy are based on surgery, chemotherapy including targeted and
immunotherapy, and radiotherapy. These therapies are combined to achieve the
optimal outcome, however not every patient can be cured and many cancers are
either diagnosed already too late, or they can find escape mechanisms from the
currently used treatments.
In the last decades cancer research has
vastly expanded our knowledge of the disease. Initially, research was focused
on the malignant cell itself, however, this view did not take into account that
a variety of mesenchymal and immune cell types as well as extracellular matrix
surround and interactwith the neoplastic cells. During the progression of
cancer, this surrounding microenvironment develops into an activated state
through continuous communication, and thereby creates a supportive surrounding
that promotes cancer initiation and growth, and eventually the progressto a
fatal disease. Interestingly this interaction with the tumor microenvironment
does not only occur in solid tumors, but also in leukemias. This thesis was
focused on the role of the receptor tyrosine kinase-ligands PlGF and Gas6 in
the microenvironment of solid tumors and leukemias.
In the first part of this work we discovered
that bone marrow derived Gas6 promoted tumor growth and metastasis in different
experimental cancer models via the Axl receptor. Already previously the tumor
growth promoting and transforming properties of the tyrosine kinase receptor
Axl, belonging to the TAMR (Tyro3, Axl andMer receptor) family, were well
recognized, however little was knownabout Gas6 in tumor biology. In this study
we found that tumor-infiltrating leukocytes are educated by the tumor
microenvironment to produce elevated levels of Gas6 and this upregulation took
particularly place in macrophages. Elevated levels of Gas6 lead to tumor cell
proliferation both in vitro and in vivo. Consistent with these finding,
the reduced tumor growth in Gas6-/- mice could be rescued by the
transplantation of wild-type bone marrow. Vice versa transplantation of Gas6-/-
bone marrow into wild-type mice mimicked the impaired tumor growth in Gas6-/-
mice. Mechanistically we found that tumor cells educated infiltrating
leukocytes to upregulated Gas6 by expressing IL-10 and M-CSF leading to a
positive amplification loop in the tumor.
In the second part of this work we found that
PlGF plays a role inchronic myeloid leukemia. We discovered that the
angiogenic factor PlGF is upregulated in the bone marrow plasma and peripheral
blood of both CML mice as well as human CML patients. Also here the leukemia
cells do not produce PlGF autonomously, but CML cells induce bone marrow
stromal cells to upregulate PlGF in a NF-κB dependent manner. PlGF not only
promoted CML cell proliferation and metabolism in a Bcr-Abl1 independent pathway, but also stimulated bone
marrow angiogenesis and fibrosis. Treatment of leukemic mice with an anti-PlGF
antibody prolonged survival in both imatinib-sensitive as well as in resistant
CML mice. CML models in PlGF-/- mice reconfirmed this. Interestingly
this beneficial effect of anti-PlGF treatment acted additive to imatinib
treatment, arguing for a Bcr-Abl1
independent mechanism.
In summary we found that Gas6 and PlGF are
stromal derivedfactor supporting tumor progression in solid tumors and
leukemias respectively. Based on our results, both might represent interesting
novel microenvironmental targets for cancer therapy.
</>
Date:25 Feb 2010 → 15 Jun 2012
Keywords:Stromal cells, Growth arrest-specific gene 6 (Gas6), Leukemia, Placental growth factor (PIGF)
Disciplines:Genetics, Systems biology, Molecular and cell biology, Cardiac and vascular medicine, Biomarker discovery and evaluation, Drug discovery and development, Medicinal products, Pharmaceutics, Pharmacognosy and phytochemistry, Pharmacology, Pharmacotherapy, Toxicology and toxinology, Other pharmaceutical sciences
Project type:PhD project