Kitlow stem cells cause resistance to Kit/platelet-derived growth factor alpha inhibitors in murine gastrointestinal stromal tumors.

Publication Type:

Journal Article

Source:

Gastroenterology, Volume 139, Issue 3, p.942-52 (2010)

Keywords:

Animalsdigestive disease, digestive deseases Antigens, CD34digestive disease, digestive deseases Antigens, CD44digestive disease, digestive deseases Antineoplastic Agentsdigestive disease, digestive deseases Cell Differentiationdigestive disease, digestive deseases Cell Proliferationdigestive disease, digestive deseases Cell Survivaldigestive disease, digestive deseases Cells, Cultureddigestive disease, digestive deseases Clone Cellsdigestive disease, digestive deseases Dose-Response Relationship, Drugdigestive disease, digestive deseases Down-Regulationdigestive disease, digestive deseases Drug Resistance, Neoplasmdigestive disease, digestive deseases Gastrointestinal Stromal Tumorsdigestive disease, digestive deseases Hyperplasiadigestive disease, digestive deseases Interstitial Cells of Cajaldigestive disease, digestive deseases Micedigestive disease, digestive deseases Mice, Inbred BALB Cdigestive disease, digestive deseases Mice, Inbred C57BLdigestive disease, digestive deseases Mice, Inbred NODdigestive disease, digestive deseases Mice, Nudedigestive disease, digestive deseases Mutationdigestive disease, digestive deseases Neoplastic Stem Cellsdigestive disease, digestive deseases Piperazinesdigestive disease, digestive deseases Proto-Oncogene Proteins c-kitdigestive disease, digestive deseases Pyransdigestive disease, digestive deseases Pyrimidinesdigestive disease, digestive deseases Receptor, Platelet-Derived Growth Factor alphadigestive disease, digestive deseases Time Factorsdigestive disease, digestive deseases Tumor Burdendigestive disease, digestive deseases Tumor Markers, Biological

Abstract:

BACKGROUND & AIMS: Gastrointestinal stromal tumors (GIST) are related to interstitial cells of Cajal (ICC) and often contain activating stem cell factor receptor (Kit) or platelet-derived growth factor receptor alpha (Pdgfra) mutations. Kit/Pdgfra inhibitors such as imatinib mesylate have increased progression-free survival in metastatic GIST but are not curative. In mouse models we investigated whether Kit(low) ICC progenitors could represent an inherently Kit/Pdgfra inhibitor-resistant reservoir for GIST.

METHODS: Isolated Kit(low)Cd44(+)Cd34(+) cells were characterized after serial cloning. The tumorigenic potential of spontaneously transformed cells was investigated in nude mice. The Kit(low)Cd44(+)Cd34(+) cells' responsiveness to Kit activation and blockade was studied by enumerating them in Kit(K641E) mice (a GIST model), in mice with defective Kit signaling, and pharmacologically.

RESULTS: Single isolated Kit(low)Cd44(+)Cd34(+) cells were clonogenic and capable of self-renewal and differentiation into ICC. In nude mice, spontaneously transformed cells formed malignant tumors expressing GIST markers. The Kit(low)Cd44(+)Cd34(+) cells were resistant to in vitro Kit blockade, including by imatinib, and occurred in normal numbers in mice with reduced Kit signaling. In Kit(K641E) mice, the mutant ICC stem cells were grossly hyperplastic but remained imatinib-resistant. In contrast, the cancer stem, cell-targeting drug salinomycin blocked the proliferation of Kit(low)Cd44(+)Cd34(+) cells and increased their sensitivity to imatinib.

CONCLUSIONS: Kit(low)Cd44(+)Cd34(+) progenitors are true stem cells for normal and hyperplastic ICC and give rise to GIST. Resistance to Kit/Pdgfra inhibitors is inherent in GIST and is caused by the native ICC stem cells' lack of dependence on Kit for survival, which is maintained after the acquisition of oncogenic Kit mutation. Cancer stem cell drugs may target these cells.