GROWTH FACTOR group
mexp : : de duve : : ucl
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Signal transduction by growth factor receptors in cancer Back to project overview
Activation of receptor tyrosine kinases, including PDGF and FGF receptors, is often associated with cancer development. Mechanims of activation can involve an autocrine loop (1), constitutively activating mutations (2), cytosolic hybrid kinases (3, 4) and overexpression (5). Genetic alterations in PDGF receptors have been found in several types of tumors (see Table below).
We are studying the signal transduction pathways activated by receptor tyrosine kinases in cancer cells, particularly in leukemias. We also noticed that cytosolic hybrid kinases escape degradation, which contributes to cell transformation.

Alterations of the PDGF receptors in cancer cells:
PDGFRA translocations fusion with BCR, ETV6, striatin, CDK5RAP2 or KIF5B chronic eosinophilic leukemia or

atypical chronic myeloid leukemia
PDGFRB translocations fusion with ETV6, or another partner (>14 described) chronic myelomonocytic leukemia (CMML,

associated with hypereosinophilia)

juvenile myelomonocytic leukemia (1 case)
CHIC2 deletion FIP1L1-PDGFRA fusion chronic eosinophilic leukemia (CEL, >50%)
PDGFRA mutations disrupts the activation loop or the inhibitory WW-like domain gastrointestinal stromal tumors (GIST, 5%)
PDGFRA amplification receptor over-expression glioblastoma (8-39%)

grade IV or recurrent glioma
PDGFRB amplification receptor over-expression choroid plexus carcinoma
PDGF-B tranlocation collagen I-PDGF-B fusion, driven by col1A1 promoter, results in massive production of mature PDGF-B dermatofibrosarcoma protuberans (100%)
autocrine loop aberrant expression of PDGF and PDGF receptors glioma, medulloblastoma
PDGF receptor activation in stromal cells angiogenesis, interstitial pressure many tumor types
Patients with leukemia, GIST and dermatofibrosarcoma who harbour one of these alterations may respond to imatinib mesylate and/or to other tyrosine kinase inhibitors. Resistance due to mutations have been described. Brain tumors are poorly sensitive to PDGF receptor inhibition.