CD117/c-kit in Cancer Stem Cell-Mediated Progression and Therapeutic Resistance

Abstract

Metastasis is the primary cause of cancer patient morbidity and mortality, but due to persisting gaps in our knowledge, it remains untreatable. Metastases often occur as patient tumors progress or recur after initial therapy. Tumor recurrence at the primary site may be driven by a cancer stem-like cell or tumor progenitor cell, while recurrence at a secondary site is driven by metastatic cancer stem cells or metastasis-initiating cells. Ongoing efforts are aimed at identifying and characterizing these stem-like cells driving recurrence and metastasis. One potential marker for the cancer stem-like cell subpopulation is CD117/c-kit, a tyrosine kinase receptor associated with cancer progression and normal stem cell maintenance. Further, activation of CD117 by its ligand stem cell factor (SCF; kit ligand) in the progenitor cell niche stimulates several signaling pathways driving proliferation, survival, and migration. This review examines evidence that the SCF/CD117 signaling axis may contribute to the control of cancer progression through the regulation of stemness and resistance to tyrosine kinase inhibitors.

Keywords: CD117/c-kit; cancer progression; cancer stem cell; metastasis; stem cell factor; tumor-initiating cell; tyrosine kinase inhibitor.

Figure 1

CD117 is expressed in normal tissues. CD117 expression in (a) normal tissues and (b) bone marrow progenitor cells using data mined from the EMBL—European Bioinformatics Institute Gene Expression Atlas [53] and the NIH GenBank [33,34,54].

Figure 2

CD117 activation stimulates multiple signaling pathways. Stem cell factor (SCF) ligand binding to the CD117 receptor induces dimerization and downstream signaling, resulting in proliferation, differentiation, survival, adhesion, motility, and angiogenesis.

Figure 3

CD117 is amplified or mutated in a variety of cancers. Genomic datasets in cBioPortal [96,97] were examined for amplifications (a) or mutations (b) of CD117 (KIT gene). The mean percentage of patients with each cancer type with amplifications or mutations ± SEM are shown.