Growth factors and their receptors are frequently activated by mutations in human cancer. Platelet-derived growth factor (PDGF)-B and its tyrosine kinase receptor, the PDGF β-receptor, have been implicated in autocrine transformation as well as paracrine stimulation of tumor growth. The availability of clinically useful antagonists motivates evaluation of PDGF inhibition in these diseases.In chronic myelomonocytic leukemia with t(5;12), parts of the transcription factor TEL and the PDGF β-receptor are fused, generating a constitutively signaling protein. Oligomerization and unique phosphorylation pattern of TEL-PDGFβR was demonstrated, as well as the transforming activity of TEL-PDGFβR, which was sensitive to PDGF β-receptor kinase inhibition.Dermatofibrosarcoma protuberans (DFSP) is characterized by a translocation involving the collagen Iα1 and PDGF B-chain genes. The COLIA1-PDGFB fusion protein was processed to mature PDGF-BB and transformed fibroblasts in culture. The PDGF antagonist STI571 inhibited growth of COLIA1-PDGFB transfected cells and primary DFSP cells in vitro and in vivo through induction of apoptosis.Paracrine effects of PDGF-DD, a ligand for the PDGF β-receptor, were evaluated in a murine model of malignant melanoma. PDGF-DD production accelerated tumor growth and altered the vascular morphology in experimental melanomas.A validated immunohistochemical procedure for PDGF β-receptor detection was established and applied to normal tissues and more…
Contents
I. Introduction
A. Growth factors in cancer
1. Autocrine growth factor dependency
2. Angiogenesis
3. Tumor stroma formation
B. Platelet-derived growth factor (PDGF)
1. The PDGF family of ligands and receptors
2. Signaling from PDGF receptors
3. Developmental and physiological roles of PDGF
4. PDGF in fibrotic disease
5. PDGF in malignant disease
6. PDGF antagonists
C. Chronic myelomonocytic leukemia
D. Dermatofibrosarcoma protuberans
II. Present investigation
A. Characterization of the chronic myelomonocytic leukemia associated
Tel-PDGFβR fusion protein (Paper I)
B. The dermatofibrosarcoma protuberans-associated collagen type Iα1/
PDGF B-chain fusion protein is processed to PDGF-BB and sustains
the growth of DFSP tumor cells (Paper II-III)
C. Enhanced tumor growth and angiogenesis by paracrine action of
PDGF-DD (Paper IV)
D. Stromal and perivascular expression of the PDGF β-receptor in normal andmalignant tissues (Paper V)
E. Anti-stromal tumor therapy by combination of STI571 and paclitaxel
(Paper VI)
III. Future perspectives
IV. Acknowledgements
V. References
Author: Sjoblom, Tobias
Source: Uppsala University Library
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