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c-kit Is Expressed in Soft Tissue Sarcoma of Neuroectodermic
Origin and Its Ligand Prevents Apoptosis of Neoplastic Cells
Emanuela Ricotti,
Franca Fagioli,
Emanuela Garelli,
Claudia Linari,
Nicoletta Crescenzio,
Alberto L. Horenstein,
Paola Pistamiglio,
Sergio Vai,
Massimo Berger,
Luca Cordero diMontezemolo,
Enrico Madon, and
Giuseppe Basso
From the Department of Pediatrics and the Laboratory of Cell Biology,
Department of Genetics, Biology and Biochemistry, the University of
Turin, Torino, Italy.
During development, mice with mutations of stem cell factor (SCF) or
its receptor c-kit exhibit defects in melanogenesis, as well as
hematopoiesis and gonadogenesis. Consequently, accumulating evidence
suggests that the c-kit/SCF system plays a crucial role in all
of these processes and in tumors which derive from them. Especially in
neuroblastoma (infant tumors of neuroectoderm crest derivation such as
melanocytes) it would appear that an autocrine loop exists between
c-kit and SCF, and that the functional block of the
c-kit receptors with monoclonal antibodies (MoAbs) results in a
significant decrease in cellular proliferation. We studied the
expression and role of c-kit and SCF in cell lines of soft tissue sarcoma of neuroectodermic origin, such as Ewing's sarcoma (ES)
and peripheral neuro-ectodermal tumors (PNET). Using flow cytometry
with MoAb CD117 PE, c-kit expression was highlighted in all six
of the cell lines examined. This receptor was specifically and
functionally activated by SCF, as shown by the binding experiments and
the intracellular phosphotyrosine and immunoprecipitation studies that
were performed. Using reverse transcriptase polymerase chain reaction
analysis, five of the six cellular lines expressed the mRNA of SCF. In
the medium measured by using an enzyme- linked immunosorbent assay, low
concentrations of SCF were found: only the TC32 cellular line produced
significantly higher levels (32 pg) than control. In serum-free culture
the addition of SCF reduced the percentage of apoptotic cells from 25%
to 90% in five out of the six cellular lines. This observation was
confirmed by (1) the functional block of c-kit with MoAb: after
7 days of culture more than 30% of the cells were apoptotic (range
31.5% to 100%) in five out of six cell lines and there was also a
decrease in the percentage of cells in phase S, and (2) c-kit
antisense oligonucleotides: in the cellular lines treated with
oligonucleotides (in relation to the untreated lines) there was a
notable reduction (P < .001) both in the absolute number of
cells and the 3H-thymidine uptake. These results indicate
that ES and PNET express c-kit and its ligand SCF and that SCF
is capable of protecting the tumor cells against apoptosis.
Furthermore, the reverse transcriptase-polymerase chain reaction
performed on the biopsies revealed the presence of mRNA both of SCF and
c-kit in practically all of the samples studied. Our in vitro
data lead us to assume that SCF may also inhibit tumor cell apoptosis
in vivo.
Blood, Vol. 91 No. 7 (April 1), 1998:
pp. 2397-2405
© 1998 by The American Society of Hematology.
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