Growth stimulation of colorectal carcinoma cells via the c-kit receptor is inhibited by TGF-beta 1.
Activation of the receptor tyrosine kinase c-kit by the kit-ligand, also known as stem cell factor (SCF), is essential to melanocyte and germ cell development and during the early stages of hematopoiesis. Deregulated expression of c-kit has been reported in malignancies affecting these lineages, i.e., myeloid leukemias, melanomas, and germ cell tumors. In addition, c-kit and SCF are coexpressed in some breast and colorectal cancer (CRC) cells, raising the question of whether c-kit serves an autocrine role in normal or malignant epithelial tissues. In this study, we demonstrate that human colorectal carcinomas, but not normal colorectal mucosa cells, coexpress SCF and c-kit in situ. Expression of c-kit was also observed in mucosa adjacent to colorectal tumor tissue. Consistent with a growth-regulatory role of SCF in CRC cells, exogenous SCF stimulated anchorage-dependent and anchorage-independent growth in four out of five CRC cell lines. Exogenous transforming growth factor (TGF)-beta 1 added at nanomolar concentrations to HT-29 CRC cells, which express the type I, II, and III TGF-beta receptors, downregulated c-kit expression to background levels and inhibited c-kit-dependent proliferation. Similarly, TGF-beta 1 inhibited SCF-dependent proliferation of three first-passage CRC cell lines. In summary, expression of the potential autocrine SCF/ c-kit axis is a tumor-associated phenomenon in colorectal cancer that can be suppressed by TGF-beta 1 in TGF-beta-responsive CRC cells.
Bellone
G
G
Department of Clinical Physiopathology, University of Torino, Italy. robini@mbox.vol.it
Silvestri
S
S
Artusio
E
E
Tibaudi
D
D
Turletti
A
A
Geuna
M
M
Giachino
C
C
Valente
G
G
Emanuelli
G
G
Rodeck
U
U
D000328:Adult; D000368:Aged; D002277:Carcinoma / Q000473:pathology*; D002448:Cell Adhesion; D002455:Cell Division; D015179:Colorectal Neoplasms / Q000473:pathology*; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D019089:Stem Cell Factor / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D012333:RNA, Messenger; D012334:RNA, Neoplasm; D019089:Stem Cell Factor; D016212:Transforming Growth Factor beta; D019009:Proto-Oncogene Proteins c-kit