Aberrant activation of c-kit protects colon carcinoma cells against apoptosis and enhances their invasive potential.
Multiple genetic aberrations contribute to the development of biologically aggressive, clinically malignant colorectal carcinomas (CRCs). Some of these have been linked to inappropriate signaling through the tyrosine kinase moieties of growth factor receptors. We have described previously (G. Bellone et al., J. Cell. Physiol., 172: 1-11, 1997) that human CRCs overexpress both the receptor tyrosine kinase c-kit and its ligand, stem cell factor (SCF), relative to normal mucosa cells, thus establishing an autocrine c-kit-mediated loop. In addition, we noted that exogenous SCF contributes to anchorage-independent growth of HT-29 colon carcinoma cells in semisolid medium. Here, we investigated possible roles of the c-kit/SCF autocrine/paracrine system in survival and invasive capacity of DLD-1 colon carcinoma cells. We report that SCF was required for migration and invasion of DLD-1 cells through reconstituted basement membranes (Matrigel) and up-regulated gelatinase (matrix metalloproteinase-9) activity in DLD-1 cells. Furthermore, we describe that SCF supported survival of DLD-1 cells in growth factor-deprived conditions. These results suggest multiple roles of c-kit activation in support of the malignant phenotype of DLD-1 cells related to growth, survival, migration, and invasive potential.
Department of Clinical Physiopathology University of Torino, Italy. graziella.bellone@unito.it
G
G
Bellone
A
A
Carbone
N
N
Sibona
O
O
Bosco
D
D
Tibaudi
C
C
Smirne
T
T
Martone
C
C
Gramigni
M
M
Camandona
G
G
Emanuelli
U
U
Rodeck
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000378:metabolism; D009361:Neoplasm Invasiveness; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010641:Phenotype; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism / Q000502:physiology*; D019089:Stem Cell Factor / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D016376:Oligonucleotides, Antisense; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9